Objective:To explore the therapeutic efficacy of L-carvone from Mentha spicata L.leaf extracts against isoproterenol-induced cardiac hypertrophy in rats.Methods:Isoproterenol(5 mg/kg)was injected intraperitoneally int...Objective:To explore the therapeutic efficacy of L-carvone from Mentha spicata L.leaf extracts against isoproterenol-induced cardiac hypertrophy in rats.Methods:Isoproterenol(5 mg/kg)was injected intraperitoneally into rats for one month to induce cardiac hypertrophy.L-carvone(25 and 100 mg/kg)was administered orally to treat cardiac hypertrophy.The cardioprotective activity of L-carvone was evaluated by electrocardiogram,histopathological analysis as well as determination of biochemical parameters and enzymatic markers.Results:L-carvone from Mentha spicata L.at 25 and 100 mg/kg ameliorated isoproterenol-induced cardiac hypertrophy,as evidenced by reduced QRS interval on electrocardiogram,and decreased heart weight and heart index.In addition,both doses of L-carvone markedly lowered the levels of glucose,total protein,low-density lipoprotein cholesterol,aspartate transaminase,alanine transaminase,lactate dehydrogenase,creatine kinase MB,troponin-Ⅰ,N-terminal pro-B type natriuretic peptide and triglycerides while increasing high-density lipoprotein cholesterol and lipase level(P<0.05).Moreover,L-carvone alleviated contraction band necrosis,and reorganized the myofibrils with normal striations and myocytes as well as normal nuclei in cardiac histoarchitecture of rats with isoproterenol-induced cardiac hypertrophy.Conclusions:L-carvone from Mentha spicata L.leaf extract can restore abnormal cardiac function and may be further explored as a therapeutic agent against the deleterious effects of cardiac hypertrophy after further evaluation.展开更多
Objective:Cardiac hypertrophy is an adaptive reaction of the heart against cardiac overloading,but continuous cardiac hypertrophy can lead to cardiac remodeling and heart failure.Cardiac hypertrophy is mostly consider...Objective:Cardiac hypertrophy is an adaptive reaction of the heart against cardiac overloading,but continuous cardiac hypertrophy can lead to cardiac remodeling and heart failure.Cardiac hypertrophy is mostly considered reversible,and recent studies have indicated that decorin not only prevents cardiac fibrosis associated with hypertension,but also achieves therapeutic effects by blocking fibrosis-related signaling pathways.However,the mechanism of action of decorin remains unknown and unconfirmed.Methods:We determined the degree of myocardial hypertrophy by measuring the ratios of the heart weight/body weight and left ventricular weight/body weight,histological analysis and immunohistochemistry.Western blotting was performed to detect the expression levels of CaMKⅡ,p-CaMKⅡ and MEF-2 in the heart.Results:Our results confirmed that decorin can regulate the CaMKⅡ/MEF-2 signaling pathway,with inhibition thereof being similar to that of decorin in reducing cardiac hypertrophy.Conclusion:Taken together,the results of the present study showed that decorin induced cardiac hypertrophy by regulating the CaMKⅡ/MEF-2 signaling pathway in vivo,revealing a new therapeutic approach for the prevention of cardiac hypertrophy.展开更多
PRKAG2 cardiac syndrome(PS)is a rare inherited disease due to PRKAG2 gene mutation and characterized by Wolff-Parkinson-White syndrome(WPWs),conduction system lesions and myocardial hypertrophy.It can also lead to ser...PRKAG2 cardiac syndrome(PS)is a rare inherited disease due to PRKAG2 gene mutation and characterized by Wolff-Parkinson-White syndrome(WPWs),conduction system lesions and myocardial hypertrophy.It can also lead to serious consequences,such as sudden death.But the genetic and clinical heterogeneity makes the early diagnosis of PS difficult.Here we studied a family with familial hypertrophic cardiomyopathy and other diverse manifestations.Gene analysis identified a missense mutation(Arg302Gln)in the five affected subjects of the family.The electrocardiograph performance of the five was composed of sinus bradycardia(SB),WPWs,right bundle branch block(RBBB),atrioventricular block(AVB),left bundle branch block(LBBB),supraventricular tachycardia(SVT)and atrial premature beat(APB).Among them,the youngest one began to show paroxysmal palpitation at the age of nine and was confirmed to have WPWs at 17 years old;two members progressed over time to serious conduction damage,and the proband received a pacemaker at the age of 27 due to AVB.Besides,according to cardiac magnetic resonance and echocardiography,the youngest one showed symmetric hypertrophy;three older members showed asymmetric myocardial hypertrophy characterized with a diffuse pattern of middle-anterior-lateral-inferior wall hypertrophy and especially interventricular septal hypertrophy;all five affected patients showed atrial enlargement regardless of myocardial hypertrophy at an earlier stage.In conclusion,the conduction system disorder,familial atrial enlargement and symmetric cardiac hypertrophy may occur in the early stage of PRKAG2 R302Q mutation.展开更多
OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model ...OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model group(SHR,receive distilled water)and SF treatment groups(SF 20,40 and 80 mg·kg^-1 per day,respectively).Age-matched male Wistar-Kyoto(WKY)rats gavaged with distilled water served as controls.After 12 weeks of treatment,the effects of SF on cardiac hypertrophy were evaluated using echocardiographic measurement,pathological analysis and the expression of atrial natriuretic peptide(ANP),myosin heavy chainβ(β-MHC)-a gene related to myocardial hypertrophy.In order to explore the mechanism of SF on myocardial hypertrophy,the calcium-sensing receptor(CaSR),calcineurin(CaN),nuclear factor of activated T cell 3(NFAT3),phosphorylation NFAT3(p-NFAT3),zinc finger transcription factor(GATA4),phosphorylation GATA4(p-GATA4),protein kinase Cβ(PKC-β),Raf-1,extracellular regulated protein kinase 1/2(ERK 1/2),phosphorylation ERK1/2(p-ERK 1/2)and mitogen-activated protein kinase phosphatase-1(MKP-1)were detected.RESULTS The myocardial hypertrophy parameters,myocardial cell cross section area,left ventricular wall thickness and expression of ANP and β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 were significantly increased,while the left ventricular cavity was significantly smaller,expression of p-NFAT3 and MKP-1 were significantly decreased,meanwhile,the ultra⁃structure of cardiomyocytes was significantly damaged in 26-week-old SHR rats.Notably,SF significantly ameliorated myocardial hyper⁃trophy in 26-week-old SHR rats;suppressed the overexpression of ANP,β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 and increased the expression of p-NFAT3 and MKP-1.CONCLUSION SF can inhibit cardiac hypertrophy in SHR rats,and the mechanism may be related to the inhibition of CaSR mediated signaling pathway.展开更多
Objective to explore the molecular mechanism of carvedilol effect on fetal energy metabolism during the development of cardiac hypertrophy. Methods Male Wistar rats were divided into the coarctation of abdominal aorta...Objective to explore the molecular mechanism of carvedilol effect on fetal energy metabolism during the development of cardiac hypertrophy. Methods Male Wistar rats were divided into the coarctation of abdominal aorta group (CAA), sham operation group (SH), and carvedilol intervention group (CAR+CAA, carvedilol 30mg·kg -1 ·day -1 orally) and carvedilol control group (CAR+SH). Hemodynamics, ventricular remodeling parameters, free fatty acid in blood serum and cardiac myocyte, RT PCR analysis of the expressions of Muscle Carnitine Palmitoyltransferase I (M CPT I) and Medium Chain Acyl CoA Dehydrogenase (MCAD) mRNA were measured in all rats at 16 week after operation. Results Left ventricular hypertrophy occurrd after operation 16 weeks in group of CAA, accompanying with plasma free fatty acids accumulation, and both the levels of M CPT I and MCADmRNA were decreased significantly ( P <0.05). Carvedilol can reduce the left ventricular hypertrophy induced by pressure overload. The gene expressions of rate limiting enzyme(M CPT I) and key enzyme of fatty acid (MCAD) were upregulated in the CAR+CAA group, comparing with CAA group ( P <0.05). There was no statistically significant difference between SH group and CAR + SH group. Pressure overload in CAA rats downregulates the gene expression of rate limiting enzyme and key enzyme of fatty acid oxidation. Conclusions The intervention with carvedilol may attenuates the reversion of the metabolic gene expression back towards fetal type through up regulating the expression of M CPT I and MCADmRNA. Thus, carvedilol may confer cardioprotective effects in heart failure partly by preserving of the normal metabolic gene regulation.展开更多
To investigate the reversing effects of DDPH on cardiac hypertrophy and increased collagen content in left ventricle tissue of rats, cardiac hypertrophy of rats were induced by partial narrowing of abdominal aorta. 4 ...To investigate the reversing effects of DDPH on cardiac hypertrophy and increased collagen content in left ventricle tissue of rats, cardiac hypertrophy of rats were induced by partial narrowing of abdominal aorta. 4 weeks after operation, the rats were given DDPH for 8 weeks. 12 weeks later, it was found that in model group, LVW/WHW and WHW/BW increased by 39. 0 % and 36. 9 % than those in control group; collagen content increased by 1. 5 times. I/E, LS decreased (P<0. 01), MMW/E. WZ increased (P<0. 01). The above-mentioned changes in two DDPH groups could be partly or completely reversed. It is concluded that DDPH could reverse cardiac hypertrophy of rats induced by partial narrowing of abdominal aorta and reduce collagen content in left ventricle tissue.展开更多
Objective:To investigate the effect of astragaloside IV on cardiac hypertrophy and its regulation on autophagy.Methods:Fifty male Sprague-Dawley rats were randomly divided into sham operation group and abdominal aorti...Objective:To investigate the effect of astragaloside IV on cardiac hypertrophy and its regulation on autophagy.Methods:Fifty male Sprague-Dawley rats were randomly divided into sham operation group and abdominal aortic coarctation group(AAC group).There were 10 rats in sham operation group and 40 rats in the AAC group.One week after the operation,there were 32 rats in AAC group,10 rats in sham group.AAC group was randomly divided into model group,low-dose astragaloside group,high-dose astragaloside group and rapamycin group,8 rats in each group.Rapamycin group was a positive autophagy contrast agent group.They were given the corresponding solvents once a day by gavage for six weeks.At the end of study,three rats were randomly selected from each group,left ventricular mass index(LVW/BW),cardiac mass index(HW/BW)and the content of hydroxyproline were measured.HE staining,masson staining and sirius red staining were used to observe the morphological changes of myocardium.The expression of LC3II,LC3I,Beclin1,AMPK and mTOR were detected by western blot.Results:Compared with the sham operation group,AAC group showed hypertrophy,LVW/BW,HW/BW,HYP and p-mTOR/mTOR were significantly increased(P<0.05),p-AMPK/AMPK,LC3II/LC3I,Beclin1 were significantly decreased(P<0.05).Compared with the model group,the low-dose astragaloside IV group showed the hypertrophy of cardiomyocytes was relatively light,LVW/BW and HW/BW were significantly decreased(P<0.05),there was no significant difference in HYP and p-mTOR/mTOR(P>0.05),LC3II/LC3I,Beclin1 and p-AMPK/AMPK were significantly increased(P<0.05).Compared with the model group,high-dose astragaloside IV group and rapamycin group showed reduced myocardial hypertrophy,LVW/BW,HW/BW,HYP and p-mTOR/mTOR were significantly decreased(P<0.05),LC3II/LC3I,Beclin1 and p-AMPK/AMPK were significantly increased(P<0.05).Compared with the low-dose astragaloside group,the high-dose astragaloside group showed reduced myocardial hypertrophy,there were significant differences in each index(P<0.05).Compared with rapamycin group,there was no obvious difference in morphology and structure of myocardial cells,LVW/BW,HYP and p-mTOR/mTOR were decreased(P<0.05),HW/BW and p-AMPK/AMPK had no significant difference(P>0.05),LC3II/LC3I and Beclin1 were increased in high-dose astragaloside group(P<0.05).Conclusion:As IV has protective effect on cardiac hypertrophy in a dose-dependent manner and its mechanism may be related to regulate autophagy.展开更多
MicroRNAs(miRNAs) are a class of endogenous small noncoding RNAs that regulate gene expression post-transcriptionally. Recent studies have demonstrated that miRNAs are involved in the pathogenesis of hypertrophy.We in...MicroRNAs(miRNAs) are a class of endogenous small noncoding RNAs that regulate gene expression post-transcriptionally. Recent studies have demonstrated that miRNAs are involved in the pathogenesis of hypertrophy.We investigated miR-16 expression and their potential roles in a rat model of hypertrophy induced by abdominal artery constriction (AAC).miR-16 expression was significantly decreased, and CCND1 and CCND2 protein were markedly increased without obvious change of its mRNA level after hypertrophy induction.CCND1 and CCND2 levels were increased without changing their transcript levels in neonatal rat ventricular cardiomyocytes(NRVC) induced by PE,and miR-16 was down-regulated in this process with significantly up-regulatedβ-MHC,ANF and MLC-2 expression.Conversely,introduction of functional miR-16,CCND1 siRNA or CCND2 siRNA into NRVCs could repress cardiomyocyte hypertrophy.These results implicate that miR-16 is involved in contributing to cardiac hypertrophy,one of the mechanisms may be resulted from post-transcriptional regulation of CCND1 and CCND2.展开更多
Cardiac hypertrophy is the heart's response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress. Traditionally, it has been considered a beneficial mechanism; however, sustained...Cardiac hypertrophy is the heart's response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress. Traditionally, it has been considered a beneficial mechanism; however, sustained hypertrophy has been associated with a significant increase in the risk of cardiovascular disease and mortality. Delineating intracellular signaling pathways involved in the different aspects of cardiac hypertrophy will permit future improvements in potential targets for therapeutic intervention. Generally, there are two types of cardiac hypertrophies, adaptive hypertrophy, including eutrophy (normal growth) and physiological hypertrophy (growth induced by conditioning), and maladaptive hypertrophy, physical including pathologic or reactive hypertrophy (growth induced by pathologic stimuli) and hypertrophic growth caused by genetic mutations affecting sarcomeric or cytoskeletal proteins. Accumulating observations from animal models and human patients have identified a number of intracellular signaling pathways that characterized as important transducers of the hypertrophic response, including calcineurin/nuclear factor of activated Tcells, phosphoinositide 3-kinases/Akt (PI3Ks/Akt), G protein-coupled receptors, small G proteins, MAPK, PKCs, Gp130/STAT3, Na+/H+ exchanger, peroxisome proliferator-activated receptors, myocyte enhancer factor 2/histone deacetylases, and many others. Furthermore, recent evidence suggests that adaptive cardiac hypertrophy is regulated in large part by the growth hormone/insulin-like growth factors axis via signaling through the PI3K/Akt pathway. In contrast, pathological or reactive hypertrophy is triggered by autocrine and paracrine neurohormonal factors released during biomechanical stress that signal through the Gq/phosphorlipase C pathway, leading to an increase in cytosolic calcium and activation of PKC.展开更多
Background:Visceral adipose tissue-derived serine protease inhibitor(vaspin),a secretory adipokine,protects against insulin resistance.Recent studies have demonstrated that serum vaspin levels are decreased in patient...Background:Visceral adipose tissue-derived serine protease inhibitor(vaspin),a secretory adipokine,protects against insulin resistance.Recent studies have demonstrated that serum vaspin levels are decreased in patients with coronary artery disease and that vaspin protects against myocardial ischemia-reperfusion injury and atherosclerosis.However,it remains unclear whether vaspin exerts specific effects on pathological cardiac hypertrophy.Methods:An in vivo study was conducted using a cardiac hypertrophy model established by subcutaneous injection of isoproterenol(ISO)in C57BL/6 and vaspin-ko mice.Rapamycin was administered intraperitoneally to mice,for further study.H9c2 cells and neonatal rat ventricular myocytes(NRVMs)were treated with ISO to induce hypertrophy.Human vaspin fusion protein,the proteasome inhibitor MG132,and chloroquine diphosphate were used for further mechanistic studies.Results:Here,we provide the first evidence that vaspin knockdown results in markedly exaggerated cardiac hypertrophy,fibrosis,and cardiomyocyte senescence in mice treated with ISO.Conversely,the administration of exogenous recombinant human vaspin protected NRVMs in vitro against ISO-induced hypertrophy and senescence.Furthermore,vaspin significantly potentiated the ISO-induced decrease in autophagy.Both rapamycin and chloroquine diphosphate regulated autophagy in vivo and in vitro,respectively,and participated in vaspin-mediated cardioprotection.Moreover,the PI3K-AKT-mTOR pathway plays a critical role in vaspin-mediated autophagy in cardiac tissues and NRVMs.Our data showed that vaspin downregulated the p85 and p110 subunits of PI3K by linking p85 and p110 to NEDD4L-mediated ubiquitination degradation.Conclusion:Our results show,for the first time,that vaspin functions as a critical regulator that alleviates pathological cardiac hypertrophy by regulating autophagy-dependent myocardial senescence,providing potential preventive and therapeutic targets for pathological cardiac hypertrophy.展开更多
Objective:Cymbopogon citratus(DC.)Stapf is a medicinal and edible herb that is widely used for the treatment of gastric,nervous and hypertensive disorders.In this study,we investigated the cardioprotective effects and...Objective:Cymbopogon citratus(DC.)Stapf is a medicinal and edible herb that is widely used for the treatment of gastric,nervous and hypertensive disorders.In this study,we investigated the cardioprotective effects and mechanisms of the essential oil,the main active ingredient of Cymbopogon citratus,on isoproterenol(ISO)-induced cardiomyocyte hypertrophy.Methods:The compositions of Cymbopogon citratus essential oil(CCEO)were determined by gas chromatography-mass spectrometry.Cardiomyocytes were pretreated with 16.9µg/L CCEO for 1 h followed by 10µmol/L ISO for 24 h.Cardiac hypertrophy-related indicators and NLRP3 inflammasome expression were evaluated.Subsequently,transcriptome sequencing(RNA-seq)and target verification were used to further explore the underlying mechanism.Results:Our results showed that the CCEO mainly included citronellal(45.66%),geraniol(23.32%),and citronellol(10.37%).CCEO inhibited ISO-induced increases in cell surface area and protein content,as well as the upregulation of fetal gene expression.Moreover,CCEO inhibited ISO-induced NLRP3 inflammasome expression,as evidenced by decreased lactate dehydrogenase content and downregulated mRNA levels of NLRP3,ASC,CASP1,GSDMD,and IL-1β,as well as reduced protein levels of NLRP3,ASC,pro-caspase-1,caspase-1(p20),GSDMD-FL,GSDMD-N,and pro-IL-1β.The RNA-seq results showed that CCEO inhibited the increase in the mRNA levels of 26 oxidative phosphorylation complex subunits in ISO-treated cardiomyocytes.Our further experiments confirmed that CCEO suppressed ISO-induced upregulation of mt-Nd1,Sdhd,mt-Cytb,Uqcrq,and mt-Atp6 but had no obvious effects on mt-Col expression.Conclusion:CCEO inhibits ISO-induced cardiomyocyte hypertrophy through the suppression of NLRP3 inflammasome expression and the regulation of several oxidative phosphorylation complex subunits.展开更多
Background:Shensong Yangxin Capsule (SSYX),traditional Chinese medicine,has been used to treat arrhythmias,angina,cardiac remodeling,cardiac fibrosis,and so on,but its effect on cardiac energy metabolism is still n...Background:Shensong Yangxin Capsule (SSYX),traditional Chinese medicine,has been used to treat arrhythmias,angina,cardiac remodeling,cardiac fibrosis,and so on,but its effect on cardiac energy metabolism is still not clear.The objective of this study was to investigate the effects of SSYX on myocardium energy metabolism in angiotensin (Ang) Ⅱ-induced cardiac hypertrophy.Methods:We used 2 μl (10-6 mol/L) AngⅡ to treat neonatal rat cardiomyocytes (NRCMs) for 48 h.Myocardial α-ac tinin staining showed that the myocardial cell volume increased.Expression of the cardiac hypertrophic marker-brain natriuretic peptide (BNP) messenger RNA (mRNA) also increased by real-time polymerase chain reaction (PCR).Therefore,it can be assumed that the model of hypertrophic cardiomyocytes was successfully constructed.Then,NRCMs were treated with 1 μl of different concentrations of SSYX (0.25,0.5,and 1.0 μg/ml) for another 24 h.To explore the time-depend effect of SSYX on energy metabolism,0.5 μg/ml SSYX was added into cells for 0,6,12,24,and 48 h.Mitochondria was assessed by MitoTracker staining and confocal microscopy.mRNA and protein expression of mitochondrial biogenesis-related genes-Peroxisome proliferator-activated receptor-γ coactivator-1 α (PGC-1 α),energy balance key factor -adenosine monophosphate-activated protein kinase (AMPK),fatty acids oxidation factor-camitine palmitoyltransferase-1 (CPT-1),and glucose oxidation factor-glucose transporter-4 (GLUT-4) were measured by PCR and Western blotting analysis.Results:With the increase in the concentration of SSYX (from 0.25 to 1.0 μg/ml),an increased mitochondrial density in Angll-induced cardiomyocytes was found compared to that of those treated with Angll only (0.25 μg/ml,18.3300 ± 0.8895 vs.24.4900 ± 0.9041,t =10.240,P 〈 0.0001;0.5 μg/ml,18.3300 ± 0.8895 vs.25.9800 ± 0.8187,t =12.710,P 〈 0.0001;and 1.0 μg/ml,18.3300 ± 0.8895 vs.24.2900 ± 1.3120,t =9.902,P 〈 0.0001;n =5 per dosage group).SSYX also increased the mRNA and protein expression ofPGC-1α (0.25 μg/ml,0.8892 ± 0.0848 vs.1.0970 ± 0.0994,t =4.319,P =0.0013;0.5 μg/ml,0.8892 ± 0.0848 vs.1.2330 ± 0.0564,t =7.150,P 〈 0.0001;and 1.0 μg/ml,0.8892 ± 0.0848 vs.1.1640 ± 0.0755,t =5.720,P 〈 0.0001;n =5 per dosage group),AMPK (0.25 μg/ml,0.8872 ± 0.0779 vs.1.1500 ± 0.0507,t =7.239,P 〈 0.0001;0.5 μg/ml,0.8872 ± 0.0779 vs.1.2280 ± 0.0623,t =9.379,P 〈 0.0001;and 1.0 μg/ml,0.8872 ± 0.0779 vs.1.3020 ± 0.0450,t =11.400,P 〈 0.0001;n =5 per dosage group),CPT-1 (1.0 μg/ml,0.7348 ± 0.0594 vs.0.9880 ± 0.0851,t =4.994,P =0.0007,n =5),and GLUT-4 (0.5 μg/ml,1.5640 ± 0.0599 vs.1.7720 ± 0.0660,t =3.783,P =0.0117;1.0 μg/ml,1.5640 ± 0.0599 vs.2.0490 ± 0.1280,t =8.808,P 〈 0.0001;n =5 per dosage group).The effect became more obvious with the increasing concentration of SSYX.When 0.5 μg/ml SSYX was added into cells for 0,6,12,24,and 48 h,the expression of AMPK (6 h,14.6100 ± 0.6205 vs.16.5200 ± 0.7450,t =3.456,P =0.0250;12 h,14.6100 ± 0.6205 vs.18.3200 ± 0.9965,t =6.720,P 〈 0.0001;24 h,14.6100 ± 0.6205 vs.21.8800 ± 0.8208,t =13.160,P 〈 0.0001;and 48 h,14.6100 ± 0.6205 vs.23.7400 ± 1.0970,t =16.530,P 〈 0.0001;n =5 per dosage group),PGC-1α (12 h,11.4700 ± 0.7252 vs.16.9000 ± 1.0150,t =7.910,P 〈 0.0001;24 h,11.4700 ± 0.7252 vs.20.8800 ± 1.2340,t =13.710,P 〈 0.0001;and 48 h,11.4700 ± 0.7252 vs.22.0300 ± 1.4180,t =15.390;n =5 per dosage group),CPT-1 (24 h,15.1600 ± 1.0960 vs.18.5800 ± 0.9049,t =6.048,P 〈 0.0001,n =5),and GL UT-4 (6 h,10.2100 ± 0.9485 vs.12.9700 ± 0.8221,t =4.763,P =0.0012;12 h,10.2100± 0.9485 vs.16.9100± 0.8481,t=1 1.590,P〈 0.0001;24 h,10.2100±0.9485 vs.19.0900± 0.9797,t=15.360,P〈 0.0001;and 48 h,10.2100 ± 0.9485 vs.14.1900 ± 0.9611,t =6.877,P 〈 0.0001;n =5 per dosage group) mRNA and protein increased gradually with the prolongation of drug action time.Conclusions:SSYX could increase myocardial energy metabolism in AngⅡ-induced cardiac hypertrophy.Therefore,SSYX might be considered to be an alternative therapeutic remedy for myocardial hypertrophy.展开更多
The gut microbiota is involved in host responses to high altitude.However,the dynamics of intestinal microecology and their association with altitude-related illness are poorly understood.Here,we used a rat model of h...The gut microbiota is involved in host responses to high altitude.However,the dynamics of intestinal microecology and their association with altitude-related illness are poorly understood.Here,we used a rat model of hypobaric hypoxia challenge to mimic plateau exposure and monitored the gut microbiome,short-chain fatty acids(SCFAs),and bile acids(BAs)over 28 d.We identified weight loss,polycythemia,and pathological cardiac hypertrophy in hypoxic rats,accompanied by a large compositional shift in the gut microbiota,which is mainly driven by the bacterial families of Prevotellaceae,Porphyromonadaceae,and Streptococcaceae.The aberrant gut microbiota was characterized by increased abundance of the Parabacteroides,Alistipes,and Lactococcus genera and a larger Bacteroides to Prevotella ratio.Trans-omics analyses showed that the gut microbiome was significantly correlated with the metabolic abnormalities of SCFAs and BAs in feces,suggesting an interaction network remodeling of the microbiome-metabolome after the hypobaric hypoxia challenge.Interestingly,the transplantation of fecal microbiota significantly increased the diversity of the gut microbiota,partially inhibited the increased abundance of the Bacteroides and Alistipes genera,restored the decrease of plasma propionate,and moderately ameliorated cardiac hypertrophy in hypoxic rats.Our results provide an insight into the longitudinal changes in intestinal microecology during the hypobaric hypoxia challenge.Abnormalities in the gut microbiota and microbial metabolites contribute to the development of high-altitude heart disease in rats.展开更多
Background: MicroRNA-24 (miR-24) plays an important role in heart failure by reducing the efficiency of myocardial excitation-contraction coupling. Prolonged cardiac hypertrophy may lead to heart failure, but littl...Background: MicroRNA-24 (miR-24) plays an important role in heart failure by reducing the efficiency of myocardial excitation-contraction coupling. Prolonged cardiac hypertrophy may lead to heart failure, but little is known about the role of miR-24 in cardiac hypertrophy. This study aimed to preliminarily investigate the function of miR-24 and its mechanisms in cardiac hypertrophy. Methods: Twelve Sprague-Dawley rats with a body weight of 50 ± 5 g were recruited and randonlly divided into two groups: a transverse aortic constriction (TAC) group and a sham surgery group. Hypertrophy index was measured and calculated by echocardiography and hematoxylin and eosin staining. TargetScans algorithm-based prediction was used to search for the targets of miR-24, which was subsequently confirmed by a real-time polymerase chain reaction and luciferase assay, lmmunofluorescence labeling was used to measure the cell surface area, and 3H-leucine incorporation was used to detect the synthesis of total protein in neonatal rat cardiac myocytes (NRCMs) with the overexpression of miR-24. In addition, flow cytometry was performed to observe the alteration in the cell cycle. Statistical analysis was carried out with GraphPad Prism v5.0 and SPSS 19.0. A two-sided P 〈 0.05 was considered as the threshold for significance. Results: The expression of miR-24 was abnormally increased in TAC rat cardiac tissue ( t =-2.938, P 〈 0.05). TargetScans algorithm-based prediction demonstrated that CDKN 1B (p27, Kip 1 ), a cell cycle regulator, was a putative target of miR-24, and was confirmed by luci ferase assay. The expression of p27 was decreased in TAC rat cardiac tissue (t = 2.896, P 〈 0.05). The overexpression of miR-24 in NRCMs led to the decreased expression of p27 (t = 4.400, P 〈 0.01 ), and decreased G0/G 1 arrest in cell cycle and cardiomyocylc hypertrophy. Conclusion: MiR-24 promotes cardiac hypertrophy partly by affecting the cell cycle through down-regulation of p27 expression.展开更多
Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs(miRNAs) play multiple roles in biological processes...Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs(miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34 c-5 p on cardiac hypertrophy and the mechanism involved. The expression of miR-34 c-5 p was proved to be elevated in heart tissues from isoprenaline(ISO)-infused mice. ISO also promoted miR-34 c-5 p level in primary cultures of neonatal rat cardiomyocytes(NRCMs). Transfection with miR-34 c-5 p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor(Anf) and β-myosin heavy chain(β-Mhc) in NRCMs. In contrast, treatment with miR-34 c-5 p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34 c-5 p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34 c-5 p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34 c-5 p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4 B(ATG4 B) was identified as a direct target of miR-34 c-5 p, and miR-34 c-5 p was certified to interact with 3’untranslated region of Atg4 b mRNA by dual-luciferase reporter assay. miR-34 c-5 p reduced the expression of ATG4 B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34 c-5 p abolished the detrimental effects of ISO by restoring ATG4 B and increasing autophagy. In conclusion, our findings illuminate that miR-34 c-5 p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4 B and autophagy. It suggests that regulation of miR-34 c-5 p may offer a new way for handling hypertrophy-related cardiac dysfunction.展开更多
MicroRNAs(miRNAs)are endogenous small non-coding RNA molecules that posttranscriptionally regulate gene expression.MiRNA expression and function in heart disease remain to be determined but modulation of miRNA express...MicroRNAs(miRNAs)are endogenous small non-coding RNA molecules that posttranscriptionally regulate gene expression.MiRNA expression and function in heart disease remain to be determined but modulation of miRNA expression in vivo has revealed that miRNAs play an important role in controlling heart function and structure.In fact,abnormal expression of miRNAs may initiate and contribute to the progress of heart disease.Here,we summarize the literature relating to the involvement of miRNAs in cardiac hypertrophy,myocardial fibrosis and heart failure.展开更多
Pathological cardiac hypertrophy induced by angiotensin Ⅱ (Ang Ⅱ ) can subsequently give rise to heart failure, a leading cause of mortality. Nardosinone is a pharmacologically active compound extracted from the r...Pathological cardiac hypertrophy induced by angiotensin Ⅱ (Ang Ⅱ ) can subsequently give rise to heart failure, a leading cause of mortality. Nardosinone is a pharmacologically active compound extracted from the roots ofNardostachys chinensis, a well-known traditional Chinese medicine. In order to investigate the effects of nardosinone on Ang Ⅱ-induced cardiac cell hypertrophy and the related mechanisms, the myoblast cell line H9c2, derived from embryonic rat heart, was treated with nardosi- none (25, 50, 100, and 200μmol/L) or Ang Ⅱ (1 μmol/L). Then cell surface area and mRNA expression of classical markers of hypertrophy were detected. The related protein levels in PI3K/Akt/mTOR and MEK/ERK signaling pathways were examined by Western blotting. It was found that pretreatment with nardosinone could significantly inhibit the enlargement of cell surface area induced by Ang Ⅱ. The mRNA expression of ANP, BNP and 13-MHC was obviously elevated in Ang Ⅱ-treated H9c2 cells, which could be effectively blocked by nardosinone at the concentration of 100μmol/L. Further study revealed that the protective effects of nardosinone might be mediated by repressing the phosphorylation of related proteins in PI3K/Akt and MEK/ERK signaling pathways. It was suggested that the inhibitory effect of nardosinone on Ang Ⅱ-induced hypertrophy in H9c2 cells might be mediated by targeting PI3K/Akt and MEK/ERK signaling pathways.展开更多
Cardiac hypertrophy is the strongest predictor of the development of heart failure, and anti-hypertrophic treatment holds the key to improving the clinical syndrome and increasing the survival rates for heart failure....Cardiac hypertrophy is the strongest predictor of the development of heart failure, and anti-hypertrophic treatment holds the key to improving the clinical syndrome and increasing the survival rates for heart failure. The paraoxonase(PON) gene cluster(PC) protects against atherosclerosis and coronary artery diseases. However, the role of PC in the heart is largely unknown. To evaluate the roles of PC in cardiac hypertrophy, transgenic mice carrying the intact human PON1, PON2, and PON3 genes and their flanking sequences were studied. We demonstrated that the PC transgene(PC-Tg) protected mice from cardiac hypertrophy induced by Ang II; these mice had reduced heart weight/body weight ratios, decreased left ventricular wall thicknesses and increased fractional shortening compared with wild-type(WT) control. The same protective tendency was also observed with an Apoe^(-/-)background. Mechanically, PC-Tg normalized the disequilibrium of matrix metalloproteinases(MMPs)/tissue inhibitors of MMPs(TIMPs) in hypertrophic hearts, which might contribute to the protective role of PC-Tg in cardiac fibrosis and, thus, protect against cardiac remodeling. Taken together, our results identify a novel anti-hypertrophic role for the PON gene cluster, suggesting a possible strategy for the treatment of cardiac hypertrophy through elevating the levels of the PON gene family.展开更多
Activation of cardiac sympathetic afferent reflex results in the increase of sympathetic activity.Serotonin(5-HT)activates cardiac sympathetic afferent through stimulating 5-HT_(3) receptors,the aim of present study i...Activation of cardiac sympathetic afferent reflex results in the increase of sympathetic activity.Serotonin(5-HT)activates cardiac sympathetic afferent through stimulating 5-HT_(3) receptors,the aim of present study is to test whether 5-HT_(3) receptor antagonists protect against cardiac hypertrophy.Cardiac hypertrophy induced by TAC for 4 weeks in mice was significantly inhibited by administration of 5-HT_(3) receptor antagonists,ondansetron(2.5 mg/kg,ip.)or tropisetron(2.5 mg/kg,ip.).Histological analysis revealed that the increased cardiac fibrosis in hypertrophic heart was relieved by ondansetron or tropisetron treatment.Ondansetron or tropisetron reduced the elevated plasma level of noradrenalin in mice with cardiac hypertrophy.Ondansetron and tropisetron had no effect on cardiomyocte hypertrophy induced by phenylephrine treatment in vitro.Finally,we took tropisetron as the representative drug and examined the effects of tropisetron on the desensitization of cardiac b-adrenergic receptor in rat treated with abdominal aortic banding(AB).Results showed that tropisetron restored the desensitization of cardiac b-adrenergic receptor in AB-treated rats.In conclusion,5-HT_(3) receptor antagonists protected against cardiac hypertrophy and restored the desensitization of cardiac adrenergic responsiveness,the mechanism in which may be through reducing the sympathetic activity.展开更多
The bromodomain and extraterminal(BET)family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy.BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin,facilitating the phosphor...The bromodomain and extraterminal(BET)family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy.BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin,facilitating the phosphorylation of RNA polymerases II(Pol II)and leading to transcription elongation.The present study identified a novel post-translational modification of BRD4:poly(ADPribosyl)ation(PARylation),that was mediated by poly(ADP-ribose)polymerase-1(PARP1)in cardiac hypertrophy.BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol(ISO),whereas overexpression of BRD4 promoted cardiac hypertrophy,confirming the critical role of BRD4 in pathological cardiac hypertrophy.PARP1 was activated in ISOinduced cardiac hypertrophy and facilitated the development of cardiac hypertrophy.BRD4 was involved in the prohypertrophic effect of PARP1,as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses,and that BRD4 overexpression suppressed the antihypertrophic effect of PARP1 inhibitors.Interactions of BRD4 and PARP1 were observed by coimmunoprecipitation and immunofluorescence.PARylation of BRD4 induced by PARP1 was investigated by PARylation assays.In response to hypertrophic stimuli like ISO,PARylation level of BRD4 was elevated,along with enhanced interactions between BRD4 and PARP1.By investigating the PARylation of truncation mutants of BRD4,the C-terminal domain(CTD)was identified as the PARylation modification sites of BRD4.PARylation of BRD4 facilitated its binding to the transcription start sites(TSS)of hypertrophic genes,resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes.The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.展开更多
文摘Objective:To explore the therapeutic efficacy of L-carvone from Mentha spicata L.leaf extracts against isoproterenol-induced cardiac hypertrophy in rats.Methods:Isoproterenol(5 mg/kg)was injected intraperitoneally into rats for one month to induce cardiac hypertrophy.L-carvone(25 and 100 mg/kg)was administered orally to treat cardiac hypertrophy.The cardioprotective activity of L-carvone was evaluated by electrocardiogram,histopathological analysis as well as determination of biochemical parameters and enzymatic markers.Results:L-carvone from Mentha spicata L.at 25 and 100 mg/kg ameliorated isoproterenol-induced cardiac hypertrophy,as evidenced by reduced QRS interval on electrocardiogram,and decreased heart weight and heart index.In addition,both doses of L-carvone markedly lowered the levels of glucose,total protein,low-density lipoprotein cholesterol,aspartate transaminase,alanine transaminase,lactate dehydrogenase,creatine kinase MB,troponin-Ⅰ,N-terminal pro-B type natriuretic peptide and triglycerides while increasing high-density lipoprotein cholesterol and lipase level(P<0.05).Moreover,L-carvone alleviated contraction band necrosis,and reorganized the myofibrils with normal striations and myocytes as well as normal nuclei in cardiac histoarchitecture of rats with isoproterenol-induced cardiac hypertrophy.Conclusions:L-carvone from Mentha spicata L.leaf extract can restore abnormal cardiac function and may be further explored as a therapeutic agent against the deleterious effects of cardiac hypertrophy after further evaluation.
文摘Objective:Cardiac hypertrophy is an adaptive reaction of the heart against cardiac overloading,but continuous cardiac hypertrophy can lead to cardiac remodeling and heart failure.Cardiac hypertrophy is mostly considered reversible,and recent studies have indicated that decorin not only prevents cardiac fibrosis associated with hypertension,but also achieves therapeutic effects by blocking fibrosis-related signaling pathways.However,the mechanism of action of decorin remains unknown and unconfirmed.Methods:We determined the degree of myocardial hypertrophy by measuring the ratios of the heart weight/body weight and left ventricular weight/body weight,histological analysis and immunohistochemistry.Western blotting was performed to detect the expression levels of CaMKⅡ,p-CaMKⅡ and MEF-2 in the heart.Results:Our results confirmed that decorin can regulate the CaMKⅡ/MEF-2 signaling pathway,with inhibition thereof being similar to that of decorin in reducing cardiac hypertrophy.Conclusion:Taken together,the results of the present study showed that decorin induced cardiac hypertrophy by regulating the CaMKⅡ/MEF-2 signaling pathway in vivo,revealing a new therapeutic approach for the prevention of cardiac hypertrophy.
文摘PRKAG2 cardiac syndrome(PS)is a rare inherited disease due to PRKAG2 gene mutation and characterized by Wolff-Parkinson-White syndrome(WPWs),conduction system lesions and myocardial hypertrophy.It can also lead to serious consequences,such as sudden death.But the genetic and clinical heterogeneity makes the early diagnosis of PS difficult.Here we studied a family with familial hypertrophic cardiomyopathy and other diverse manifestations.Gene analysis identified a missense mutation(Arg302Gln)in the five affected subjects of the family.The electrocardiograph performance of the five was composed of sinus bradycardia(SB),WPWs,right bundle branch block(RBBB),atrioventricular block(AVB),left bundle branch block(LBBB),supraventricular tachycardia(SVT)and atrial premature beat(APB).Among them,the youngest one began to show paroxysmal palpitation at the age of nine and was confirmed to have WPWs at 17 years old;two members progressed over time to serious conduction damage,and the proband received a pacemaker at the age of 27 due to AVB.Besides,according to cardiac magnetic resonance and echocardiography,the youngest one showed symmetric hypertrophy;three older members showed asymmetric myocardial hypertrophy characterized with a diffuse pattern of middle-anterior-lateral-inferior wall hypertrophy and especially interventricular septal hypertrophy;all five affected patients showed atrial enlargement regardless of myocardial hypertrophy at an earlier stage.In conclusion,the conduction system disorder,familial atrial enlargement and symmetric cardiac hypertrophy may occur in the early stage of PRKAG2 R302Q mutation.
基金National Natural Science Foundation of China(81860732)Scientific and Technological Projects for Social Development in Guizhou Province of China([2011]3036)the State Key Laboratory of Cardiovascular Disease(2017kf-03)
文摘OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model group(SHR,receive distilled water)and SF treatment groups(SF 20,40 and 80 mg·kg^-1 per day,respectively).Age-matched male Wistar-Kyoto(WKY)rats gavaged with distilled water served as controls.After 12 weeks of treatment,the effects of SF on cardiac hypertrophy were evaluated using echocardiographic measurement,pathological analysis and the expression of atrial natriuretic peptide(ANP),myosin heavy chainβ(β-MHC)-a gene related to myocardial hypertrophy.In order to explore the mechanism of SF on myocardial hypertrophy,the calcium-sensing receptor(CaSR),calcineurin(CaN),nuclear factor of activated T cell 3(NFAT3),phosphorylation NFAT3(p-NFAT3),zinc finger transcription factor(GATA4),phosphorylation GATA4(p-GATA4),protein kinase Cβ(PKC-β),Raf-1,extracellular regulated protein kinase 1/2(ERK 1/2),phosphorylation ERK1/2(p-ERK 1/2)and mitogen-activated protein kinase phosphatase-1(MKP-1)were detected.RESULTS The myocardial hypertrophy parameters,myocardial cell cross section area,left ventricular wall thickness and expression of ANP and β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 were significantly increased,while the left ventricular cavity was significantly smaller,expression of p-NFAT3 and MKP-1 were significantly decreased,meanwhile,the ultra⁃structure of cardiomyocytes was significantly damaged in 26-week-old SHR rats.Notably,SF significantly ameliorated myocardial hyper⁃trophy in 26-week-old SHR rats;suppressed the overexpression of ANP,β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 and increased the expression of p-NFAT3 and MKP-1.CONCLUSION SF can inhibit cardiac hypertrophy in SHR rats,and the mechanism may be related to the inhibition of CaSR mediated signaling pathway.
文摘Objective to explore the molecular mechanism of carvedilol effect on fetal energy metabolism during the development of cardiac hypertrophy. Methods Male Wistar rats were divided into the coarctation of abdominal aorta group (CAA), sham operation group (SH), and carvedilol intervention group (CAR+CAA, carvedilol 30mg·kg -1 ·day -1 orally) and carvedilol control group (CAR+SH). Hemodynamics, ventricular remodeling parameters, free fatty acid in blood serum and cardiac myocyte, RT PCR analysis of the expressions of Muscle Carnitine Palmitoyltransferase I (M CPT I) and Medium Chain Acyl CoA Dehydrogenase (MCAD) mRNA were measured in all rats at 16 week after operation. Results Left ventricular hypertrophy occurrd after operation 16 weeks in group of CAA, accompanying with plasma free fatty acids accumulation, and both the levels of M CPT I and MCADmRNA were decreased significantly ( P <0.05). Carvedilol can reduce the left ventricular hypertrophy induced by pressure overload. The gene expressions of rate limiting enzyme(M CPT I) and key enzyme of fatty acid (MCAD) were upregulated in the CAR+CAA group, comparing with CAA group ( P <0.05). There was no statistically significant difference between SH group and CAR + SH group. Pressure overload in CAA rats downregulates the gene expression of rate limiting enzyme and key enzyme of fatty acid oxidation. Conclusions The intervention with carvedilol may attenuates the reversion of the metabolic gene expression back towards fetal type through up regulating the expression of M CPT I and MCADmRNA. Thus, carvedilol may confer cardioprotective effects in heart failure partly by preserving of the normal metabolic gene regulation.
文摘To investigate the reversing effects of DDPH on cardiac hypertrophy and increased collagen content in left ventricle tissue of rats, cardiac hypertrophy of rats were induced by partial narrowing of abdominal aorta. 4 weeks after operation, the rats were given DDPH for 8 weeks. 12 weeks later, it was found that in model group, LVW/WHW and WHW/BW increased by 39. 0 % and 36. 9 % than those in control group; collagen content increased by 1. 5 times. I/E, LS decreased (P<0. 01), MMW/E. WZ increased (P<0. 01). The above-mentioned changes in two DDPH groups could be partly or completely reversed. It is concluded that DDPH could reverse cardiac hypertrophy of rats induced by partial narrowing of abdominal aorta and reduce collagen content in left ventricle tissue.
基金Scientific Research Project of Sichuan Education Department(No.14ZA0137)。
文摘Objective:To investigate the effect of astragaloside IV on cardiac hypertrophy and its regulation on autophagy.Methods:Fifty male Sprague-Dawley rats were randomly divided into sham operation group and abdominal aortic coarctation group(AAC group).There were 10 rats in sham operation group and 40 rats in the AAC group.One week after the operation,there were 32 rats in AAC group,10 rats in sham group.AAC group was randomly divided into model group,low-dose astragaloside group,high-dose astragaloside group and rapamycin group,8 rats in each group.Rapamycin group was a positive autophagy contrast agent group.They were given the corresponding solvents once a day by gavage for six weeks.At the end of study,three rats were randomly selected from each group,left ventricular mass index(LVW/BW),cardiac mass index(HW/BW)and the content of hydroxyproline were measured.HE staining,masson staining and sirius red staining were used to observe the morphological changes of myocardium.The expression of LC3II,LC3I,Beclin1,AMPK and mTOR were detected by western blot.Results:Compared with the sham operation group,AAC group showed hypertrophy,LVW/BW,HW/BW,HYP and p-mTOR/mTOR were significantly increased(P<0.05),p-AMPK/AMPK,LC3II/LC3I,Beclin1 were significantly decreased(P<0.05).Compared with the model group,the low-dose astragaloside IV group showed the hypertrophy of cardiomyocytes was relatively light,LVW/BW and HW/BW were significantly decreased(P<0.05),there was no significant difference in HYP and p-mTOR/mTOR(P>0.05),LC3II/LC3I,Beclin1 and p-AMPK/AMPK were significantly increased(P<0.05).Compared with the model group,high-dose astragaloside IV group and rapamycin group showed reduced myocardial hypertrophy,LVW/BW,HW/BW,HYP and p-mTOR/mTOR were significantly decreased(P<0.05),LC3II/LC3I,Beclin1 and p-AMPK/AMPK were significantly increased(P<0.05).Compared with the low-dose astragaloside group,the high-dose astragaloside group showed reduced myocardial hypertrophy,there were significant differences in each index(P<0.05).Compared with rapamycin group,there was no obvious difference in morphology and structure of myocardial cells,LVW/BW,HYP and p-mTOR/mTOR were decreased(P<0.05),HW/BW and p-AMPK/AMPK had no significant difference(P>0.05),LC3II/LC3I and Beclin1 were increased in high-dose astragaloside group(P<0.05).Conclusion:As IV has protective effect on cardiac hypertrophy in a dose-dependent manner and its mechanism may be related to regulate autophagy.
文摘MicroRNAs(miRNAs) are a class of endogenous small noncoding RNAs that regulate gene expression post-transcriptionally. Recent studies have demonstrated that miRNAs are involved in the pathogenesis of hypertrophy.We investigated miR-16 expression and their potential roles in a rat model of hypertrophy induced by abdominal artery constriction (AAC).miR-16 expression was significantly decreased, and CCND1 and CCND2 protein were markedly increased without obvious change of its mRNA level after hypertrophy induction.CCND1 and CCND2 levels were increased without changing their transcript levels in neonatal rat ventricular cardiomyocytes(NRVC) induced by PE,and miR-16 was down-regulated in this process with significantly up-regulatedβ-MHC,ANF and MLC-2 expression.Conversely,introduction of functional miR-16,CCND1 siRNA or CCND2 siRNA into NRVCs could repress cardiomyocyte hypertrophy.These results implicate that miR-16 is involved in contributing to cardiac hypertrophy,one of the mechanisms may be resulted from post-transcriptional regulation of CCND1 and CCND2.
文摘Cardiac hypertrophy is the heart's response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress. Traditionally, it has been considered a beneficial mechanism; however, sustained hypertrophy has been associated with a significant increase in the risk of cardiovascular disease and mortality. Delineating intracellular signaling pathways involved in the different aspects of cardiac hypertrophy will permit future improvements in potential targets for therapeutic intervention. Generally, there are two types of cardiac hypertrophies, adaptive hypertrophy, including eutrophy (normal growth) and physiological hypertrophy (growth induced by conditioning), and maladaptive hypertrophy, physical including pathologic or reactive hypertrophy (growth induced by pathologic stimuli) and hypertrophic growth caused by genetic mutations affecting sarcomeric or cytoskeletal proteins. Accumulating observations from animal models and human patients have identified a number of intracellular signaling pathways that characterized as important transducers of the hypertrophic response, including calcineurin/nuclear factor of activated Tcells, phosphoinositide 3-kinases/Akt (PI3Ks/Akt), G protein-coupled receptors, small G proteins, MAPK, PKCs, Gp130/STAT3, Na+/H+ exchanger, peroxisome proliferator-activated receptors, myocyte enhancer factor 2/histone deacetylases, and many others. Furthermore, recent evidence suggests that adaptive cardiac hypertrophy is regulated in large part by the growth hormone/insulin-like growth factors axis via signaling through the PI3K/Akt pathway. In contrast, pathological or reactive hypertrophy is triggered by autocrine and paracrine neurohormonal factors released during biomechanical stress that signal through the Gq/phosphorlipase C pathway, leading to an increase in cytosolic calcium and activation of PKC.
基金the State Key Program of the National Natural Science Foundation of China(82030059)National Natural Science Foundation of China(82172178,82072144,81873950,81873953,81300219,81671951)+6 种基金National Key R&D Program of China(2020YFC1512700,2020YFC1512705,2020YFC1512703)National S&T Fundamental Resources Investigation Project(2018FY100600,2018FY100602)Natural Science Foundation of Shandong Province(ZR2022MH078)Key R&D Program of Shandong Province(2019GSF108131)Taishan Pandeng Scholar Program of Shandong Province(tspd20181220)Taishan Young Scholar Program of Shandong Province(tsqn202103173,tsqn20161065,tsqn201812129)Youth Top-Talent Project of National Ten Thousand Talents Plan,and Qilu Young Scholar Program.
文摘Background:Visceral adipose tissue-derived serine protease inhibitor(vaspin),a secretory adipokine,protects against insulin resistance.Recent studies have demonstrated that serum vaspin levels are decreased in patients with coronary artery disease and that vaspin protects against myocardial ischemia-reperfusion injury and atherosclerosis.However,it remains unclear whether vaspin exerts specific effects on pathological cardiac hypertrophy.Methods:An in vivo study was conducted using a cardiac hypertrophy model established by subcutaneous injection of isoproterenol(ISO)in C57BL/6 and vaspin-ko mice.Rapamycin was administered intraperitoneally to mice,for further study.H9c2 cells and neonatal rat ventricular myocytes(NRVMs)were treated with ISO to induce hypertrophy.Human vaspin fusion protein,the proteasome inhibitor MG132,and chloroquine diphosphate were used for further mechanistic studies.Results:Here,we provide the first evidence that vaspin knockdown results in markedly exaggerated cardiac hypertrophy,fibrosis,and cardiomyocyte senescence in mice treated with ISO.Conversely,the administration of exogenous recombinant human vaspin protected NRVMs in vitro against ISO-induced hypertrophy and senescence.Furthermore,vaspin significantly potentiated the ISO-induced decrease in autophagy.Both rapamycin and chloroquine diphosphate regulated autophagy in vivo and in vitro,respectively,and participated in vaspin-mediated cardioprotection.Moreover,the PI3K-AKT-mTOR pathway plays a critical role in vaspin-mediated autophagy in cardiac tissues and NRVMs.Our data showed that vaspin downregulated the p85 and p110 subunits of PI3K by linking p85 and p110 to NEDD4L-mediated ubiquitination degradation.Conclusion:Our results show,for the first time,that vaspin functions as a critical regulator that alleviates pathological cardiac hypertrophy by regulating autophagy-dependent myocardial senescence,providing potential preventive and therapeutic targets for pathological cardiac hypertrophy.
基金supported by grants from the National Natural Science Foundation of China(Nos.81960732 and 82060733)the Natural Science Foundation of Jiangxi Province(No.20224BAB206111)+2 种基金the Science and Technology Plan of Jiangxi Provincial Health Commission(No.202311141)the Open Project of Jiangxi Provincial Key Laboratory of Drug Design and Evaluation(No.JKLDE-KF-2101)the Open Project of Key Laboratory of Modern Preparation of TCM,Ministry of Education,Jiangxi University of Chinese Medicine(No.TCM-201911).
文摘Objective:Cymbopogon citratus(DC.)Stapf is a medicinal and edible herb that is widely used for the treatment of gastric,nervous and hypertensive disorders.In this study,we investigated the cardioprotective effects and mechanisms of the essential oil,the main active ingredient of Cymbopogon citratus,on isoproterenol(ISO)-induced cardiomyocyte hypertrophy.Methods:The compositions of Cymbopogon citratus essential oil(CCEO)were determined by gas chromatography-mass spectrometry.Cardiomyocytes were pretreated with 16.9µg/L CCEO for 1 h followed by 10µmol/L ISO for 24 h.Cardiac hypertrophy-related indicators and NLRP3 inflammasome expression were evaluated.Subsequently,transcriptome sequencing(RNA-seq)and target verification were used to further explore the underlying mechanism.Results:Our results showed that the CCEO mainly included citronellal(45.66%),geraniol(23.32%),and citronellol(10.37%).CCEO inhibited ISO-induced increases in cell surface area and protein content,as well as the upregulation of fetal gene expression.Moreover,CCEO inhibited ISO-induced NLRP3 inflammasome expression,as evidenced by decreased lactate dehydrogenase content and downregulated mRNA levels of NLRP3,ASC,CASP1,GSDMD,and IL-1β,as well as reduced protein levels of NLRP3,ASC,pro-caspase-1,caspase-1(p20),GSDMD-FL,GSDMD-N,and pro-IL-1β.The RNA-seq results showed that CCEO inhibited the increase in the mRNA levels of 26 oxidative phosphorylation complex subunits in ISO-treated cardiomyocytes.Our further experiments confirmed that CCEO suppressed ISO-induced upregulation of mt-Nd1,Sdhd,mt-Cytb,Uqcrq,and mt-Atp6 but had no obvious effects on mt-Col expression.Conclusion:CCEO inhibits ISO-induced cardiomyocyte hypertrophy through the suppression of NLRP3 inflammasome expression and the regulation of several oxidative phosphorylation complex subunits.
基金This study was supported by a grant from the National Natural Science Foundation of China (No. 81670363).
文摘Background:Shensong Yangxin Capsule (SSYX),traditional Chinese medicine,has been used to treat arrhythmias,angina,cardiac remodeling,cardiac fibrosis,and so on,but its effect on cardiac energy metabolism is still not clear.The objective of this study was to investigate the effects of SSYX on myocardium energy metabolism in angiotensin (Ang) Ⅱ-induced cardiac hypertrophy.Methods:We used 2 μl (10-6 mol/L) AngⅡ to treat neonatal rat cardiomyocytes (NRCMs) for 48 h.Myocardial α-ac tinin staining showed that the myocardial cell volume increased.Expression of the cardiac hypertrophic marker-brain natriuretic peptide (BNP) messenger RNA (mRNA) also increased by real-time polymerase chain reaction (PCR).Therefore,it can be assumed that the model of hypertrophic cardiomyocytes was successfully constructed.Then,NRCMs were treated with 1 μl of different concentrations of SSYX (0.25,0.5,and 1.0 μg/ml) for another 24 h.To explore the time-depend effect of SSYX on energy metabolism,0.5 μg/ml SSYX was added into cells for 0,6,12,24,and 48 h.Mitochondria was assessed by MitoTracker staining and confocal microscopy.mRNA and protein expression of mitochondrial biogenesis-related genes-Peroxisome proliferator-activated receptor-γ coactivator-1 α (PGC-1 α),energy balance key factor -adenosine monophosphate-activated protein kinase (AMPK),fatty acids oxidation factor-camitine palmitoyltransferase-1 (CPT-1),and glucose oxidation factor-glucose transporter-4 (GLUT-4) were measured by PCR and Western blotting analysis.Results:With the increase in the concentration of SSYX (from 0.25 to 1.0 μg/ml),an increased mitochondrial density in Angll-induced cardiomyocytes was found compared to that of those treated with Angll only (0.25 μg/ml,18.3300 ± 0.8895 vs.24.4900 ± 0.9041,t =10.240,P 〈 0.0001;0.5 μg/ml,18.3300 ± 0.8895 vs.25.9800 ± 0.8187,t =12.710,P 〈 0.0001;and 1.0 μg/ml,18.3300 ± 0.8895 vs.24.2900 ± 1.3120,t =9.902,P 〈 0.0001;n =5 per dosage group).SSYX also increased the mRNA and protein expression ofPGC-1α (0.25 μg/ml,0.8892 ± 0.0848 vs.1.0970 ± 0.0994,t =4.319,P =0.0013;0.5 μg/ml,0.8892 ± 0.0848 vs.1.2330 ± 0.0564,t =7.150,P 〈 0.0001;and 1.0 μg/ml,0.8892 ± 0.0848 vs.1.1640 ± 0.0755,t =5.720,P 〈 0.0001;n =5 per dosage group),AMPK (0.25 μg/ml,0.8872 ± 0.0779 vs.1.1500 ± 0.0507,t =7.239,P 〈 0.0001;0.5 μg/ml,0.8872 ± 0.0779 vs.1.2280 ± 0.0623,t =9.379,P 〈 0.0001;and 1.0 μg/ml,0.8872 ± 0.0779 vs.1.3020 ± 0.0450,t =11.400,P 〈 0.0001;n =5 per dosage group),CPT-1 (1.0 μg/ml,0.7348 ± 0.0594 vs.0.9880 ± 0.0851,t =4.994,P =0.0007,n =5),and GLUT-4 (0.5 μg/ml,1.5640 ± 0.0599 vs.1.7720 ± 0.0660,t =3.783,P =0.0117;1.0 μg/ml,1.5640 ± 0.0599 vs.2.0490 ± 0.1280,t =8.808,P 〈 0.0001;n =5 per dosage group).The effect became more obvious with the increasing concentration of SSYX.When 0.5 μg/ml SSYX was added into cells for 0,6,12,24,and 48 h,the expression of AMPK (6 h,14.6100 ± 0.6205 vs.16.5200 ± 0.7450,t =3.456,P =0.0250;12 h,14.6100 ± 0.6205 vs.18.3200 ± 0.9965,t =6.720,P 〈 0.0001;24 h,14.6100 ± 0.6205 vs.21.8800 ± 0.8208,t =13.160,P 〈 0.0001;and 48 h,14.6100 ± 0.6205 vs.23.7400 ± 1.0970,t =16.530,P 〈 0.0001;n =5 per dosage group),PGC-1α (12 h,11.4700 ± 0.7252 vs.16.9000 ± 1.0150,t =7.910,P 〈 0.0001;24 h,11.4700 ± 0.7252 vs.20.8800 ± 1.2340,t =13.710,P 〈 0.0001;and 48 h,11.4700 ± 0.7252 vs.22.0300 ± 1.4180,t =15.390;n =5 per dosage group),CPT-1 (24 h,15.1600 ± 1.0960 vs.18.5800 ± 0.9049,t =6.048,P 〈 0.0001,n =5),and GL UT-4 (6 h,10.2100 ± 0.9485 vs.12.9700 ± 0.8221,t =4.763,P =0.0012;12 h,10.2100± 0.9485 vs.16.9100± 0.8481,t=1 1.590,P〈 0.0001;24 h,10.2100±0.9485 vs.19.0900± 0.9797,t=15.360,P〈 0.0001;and 48 h,10.2100 ± 0.9485 vs.14.1900 ± 0.9611,t =6.877,P 〈 0.0001;n =5 per dosage group) mRNA and protein increased gradually with the prolongation of drug action time.Conclusions:SSYX could increase myocardial energy metabolism in AngⅡ-induced cardiac hypertrophy.Therefore,SSYX might be considered to be an alternative therapeutic remedy for myocardial hypertrophy.
基金supported by the National Natural Science Foundation of China(81790632,31970863,and 31970088)the National Key Technology Research and Development Program of the Ministry of Science and Technology of China(2020YFA0509600)。
文摘The gut microbiota is involved in host responses to high altitude.However,the dynamics of intestinal microecology and their association with altitude-related illness are poorly understood.Here,we used a rat model of hypobaric hypoxia challenge to mimic plateau exposure and monitored the gut microbiome,short-chain fatty acids(SCFAs),and bile acids(BAs)over 28 d.We identified weight loss,polycythemia,and pathological cardiac hypertrophy in hypoxic rats,accompanied by a large compositional shift in the gut microbiota,which is mainly driven by the bacterial families of Prevotellaceae,Porphyromonadaceae,and Streptococcaceae.The aberrant gut microbiota was characterized by increased abundance of the Parabacteroides,Alistipes,and Lactococcus genera and a larger Bacteroides to Prevotella ratio.Trans-omics analyses showed that the gut microbiome was significantly correlated with the metabolic abnormalities of SCFAs and BAs in feces,suggesting an interaction network remodeling of the microbiome-metabolome after the hypobaric hypoxia challenge.Interestingly,the transplantation of fecal microbiota significantly increased the diversity of the gut microbiota,partially inhibited the increased abundance of the Bacteroides and Alistipes genera,restored the decrease of plasma propionate,and moderately ameliorated cardiac hypertrophy in hypoxic rats.Our results provide an insight into the longitudinal changes in intestinal microecology during the hypobaric hypoxia challenge.Abnormalities in the gut microbiota and microbial metabolites contribute to the development of high-altitude heart disease in rats.
基金This work was supported by grant from National Natural Science Foundation of China (No. 91339105, and No. 81625001).
文摘Background: MicroRNA-24 (miR-24) plays an important role in heart failure by reducing the efficiency of myocardial excitation-contraction coupling. Prolonged cardiac hypertrophy may lead to heart failure, but little is known about the role of miR-24 in cardiac hypertrophy. This study aimed to preliminarily investigate the function of miR-24 and its mechanisms in cardiac hypertrophy. Methods: Twelve Sprague-Dawley rats with a body weight of 50 ± 5 g were recruited and randonlly divided into two groups: a transverse aortic constriction (TAC) group and a sham surgery group. Hypertrophy index was measured and calculated by echocardiography and hematoxylin and eosin staining. TargetScans algorithm-based prediction was used to search for the targets of miR-24, which was subsequently confirmed by a real-time polymerase chain reaction and luciferase assay, lmmunofluorescence labeling was used to measure the cell surface area, and 3H-leucine incorporation was used to detect the synthesis of total protein in neonatal rat cardiac myocytes (NRCMs) with the overexpression of miR-24. In addition, flow cytometry was performed to observe the alteration in the cell cycle. Statistical analysis was carried out with GraphPad Prism v5.0 and SPSS 19.0. A two-sided P 〈 0.05 was considered as the threshold for significance. Results: The expression of miR-24 was abnormally increased in TAC rat cardiac tissue ( t =-2.938, P 〈 0.05). TargetScans algorithm-based prediction demonstrated that CDKN 1B (p27, Kip 1 ), a cell cycle regulator, was a putative target of miR-24, and was confirmed by luci ferase assay. The expression of p27 was decreased in TAC rat cardiac tissue (t = 2.896, P 〈 0.05). The overexpression of miR-24 in NRCMs led to the decreased expression of p27 (t = 4.400, P 〈 0.01 ), and decreased G0/G 1 arrest in cell cycle and cardiomyocylc hypertrophy. Conclusion: MiR-24 promotes cardiac hypertrophy partly by affecting the cell cycle through down-regulation of p27 expression.
基金supported by grants from the National Natural Science Foundation of China (81872860,81673433,and82070268)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093,China)+4 种基金National Major Special Projects for the Creation and Manufacture of New Drugs (2019ZX09301104,China)National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province,2017B090903004,China)Special Program for Applied Science and Technology of Guangdong Province (2015B020232009,China)Guangdong Basic and Applied Basic Research Foundation(2020A1515011512,China)Young Teacher Training Program of Sun Yat-sen University (18ykpy26,China)。
文摘Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs(miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34 c-5 p on cardiac hypertrophy and the mechanism involved. The expression of miR-34 c-5 p was proved to be elevated in heart tissues from isoprenaline(ISO)-infused mice. ISO also promoted miR-34 c-5 p level in primary cultures of neonatal rat cardiomyocytes(NRCMs). Transfection with miR-34 c-5 p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor(Anf) and β-myosin heavy chain(β-Mhc) in NRCMs. In contrast, treatment with miR-34 c-5 p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34 c-5 p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34 c-5 p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34 c-5 p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4 B(ATG4 B) was identified as a direct target of miR-34 c-5 p, and miR-34 c-5 p was certified to interact with 3’untranslated region of Atg4 b mRNA by dual-luciferase reporter assay. miR-34 c-5 p reduced the expression of ATG4 B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34 c-5 p abolished the detrimental effects of ISO by restoring ATG4 B and increasing autophagy. In conclusion, our findings illuminate that miR-34 c-5 p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4 B and autophagy. It suggests that regulation of miR-34 c-5 p may offer a new way for handling hypertrophy-related cardiac dysfunction.
基金supported by the China Postdoctoral Special Science Foundation,the Foundation for the Author of a National Excellent Doctoral Dissertation of P.R.China(2007B72)the National Basic Research Program of China(2007CB512006)。
文摘MicroRNAs(miRNAs)are endogenous small non-coding RNA molecules that posttranscriptionally regulate gene expression.MiRNA expression and function in heart disease remain to be determined but modulation of miRNA expression in vivo has revealed that miRNAs play an important role in controlling heart function and structure.In fact,abnormal expression of miRNAs may initiate and contribute to the progress of heart disease.Here,we summarize the literature relating to the involvement of miRNAs in cardiac hypertrophy,myocardial fibrosis and heart failure.
基金supported by the grants from the National Natural Science Foundation of China(No.30971245 and No.81000112)
文摘Pathological cardiac hypertrophy induced by angiotensin Ⅱ (Ang Ⅱ ) can subsequently give rise to heart failure, a leading cause of mortality. Nardosinone is a pharmacologically active compound extracted from the roots ofNardostachys chinensis, a well-known traditional Chinese medicine. In order to investigate the effects of nardosinone on Ang Ⅱ-induced cardiac cell hypertrophy and the related mechanisms, the myoblast cell line H9c2, derived from embryonic rat heart, was treated with nardosi- none (25, 50, 100, and 200μmol/L) or Ang Ⅱ (1 μmol/L). Then cell surface area and mRNA expression of classical markers of hypertrophy were detected. The related protein levels in PI3K/Akt/mTOR and MEK/ERK signaling pathways were examined by Western blotting. It was found that pretreatment with nardosinone could significantly inhibit the enlargement of cell surface area induced by Ang Ⅱ. The mRNA expression of ANP, BNP and 13-MHC was obviously elevated in Ang Ⅱ-treated H9c2 cells, which could be effectively blocked by nardosinone at the concentration of 100μmol/L. Further study revealed that the protective effects of nardosinone might be mediated by repressing the phosphorylation of related proteins in PI3K/Akt and MEK/ERK signaling pathways. It was suggested that the inhibitory effect of nardosinone on Ang Ⅱ-induced hypertrophy in H9c2 cells might be mediated by targeting PI3K/Akt and MEK/ERK signaling pathways.
基金supported by the National Natural Science Foundation of China(81422002,91339201,31271227,31571193)the National Science and Technology Support Project(2013YQ0309230502,2014BAI02B01)the Beijing Nova Program(XX2013064)
文摘Cardiac hypertrophy is the strongest predictor of the development of heart failure, and anti-hypertrophic treatment holds the key to improving the clinical syndrome and increasing the survival rates for heart failure. The paraoxonase(PON) gene cluster(PC) protects against atherosclerosis and coronary artery diseases. However, the role of PC in the heart is largely unknown. To evaluate the roles of PC in cardiac hypertrophy, transgenic mice carrying the intact human PON1, PON2, and PON3 genes and their flanking sequences were studied. We demonstrated that the PC transgene(PC-Tg) protected mice from cardiac hypertrophy induced by Ang II; these mice had reduced heart weight/body weight ratios, decreased left ventricular wall thicknesses and increased fractional shortening compared with wild-type(WT) control. The same protective tendency was also observed with an Apoe^(-/-)background. Mechanically, PC-Tg normalized the disequilibrium of matrix metalloproteinases(MMPs)/tissue inhibitors of MMPs(TIMPs) in hypertrophic hearts, which might contribute to the protective role of PC-Tg in cardiac fibrosis and, thus, protect against cardiac remodeling. Taken together, our results identify a novel anti-hypertrophic role for the PON gene cluster, suggesting a possible strategy for the treatment of cardiac hypertrophy through elevating the levels of the PON gene family.
基金This work was supported by National Natural Science Foundation of China(30873064)Foundation of Key Laboratory of Bio-pharmaceutical-engineering(Harbin Medical University),Ministry of Education(2010-07).
文摘Activation of cardiac sympathetic afferent reflex results in the increase of sympathetic activity.Serotonin(5-HT)activates cardiac sympathetic afferent through stimulating 5-HT_(3) receptors,the aim of present study is to test whether 5-HT_(3) receptor antagonists protect against cardiac hypertrophy.Cardiac hypertrophy induced by TAC for 4 weeks in mice was significantly inhibited by administration of 5-HT_(3) receptor antagonists,ondansetron(2.5 mg/kg,ip.)or tropisetron(2.5 mg/kg,ip.).Histological analysis revealed that the increased cardiac fibrosis in hypertrophic heart was relieved by ondansetron or tropisetron treatment.Ondansetron or tropisetron reduced the elevated plasma level of noradrenalin in mice with cardiac hypertrophy.Ondansetron and tropisetron had no effect on cardiomyocte hypertrophy induced by phenylephrine treatment in vitro.Finally,we took tropisetron as the representative drug and examined the effects of tropisetron on the desensitization of cardiac b-adrenergic receptor in rat treated with abdominal aortic banding(AB).Results showed that tropisetron restored the desensitization of cardiac b-adrenergic receptor in AB-treated rats.In conclusion,5-HT_(3) receptor antagonists protected against cardiac hypertrophy and restored the desensitization of cardiac adrenergic responsiveness,the mechanism in which may be through reducing the sympathetic activity.
基金supported by grants from the National Natural Science Foundation of China(81872860,81673433,and 81973318)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093,China)+6 种基金National Major Special Projects for the Creation and Manufacture of New Drugs(2019ZX09301104,China)Special Program for Applied Science and Technology of Guangdong Province(2015B020232009,China)National Engineering and Technology Research Center for New drug Druggability Evaluation(Seed Program of Guangdong Province,2017B090903004,China)Guangdong Basic and Applied Basic Research Foundation(2019A1515011256,China)Guangzhou Science and Technology Program Project(201604020121 and 201804010227,China)Yang Fan Project of Guangdong Province(Grant No.2014YT02S044,China)Guangdong Provincial Key Laboratory of Construction Foundation(No.2017B030314030,China)。
文摘The bromodomain and extraterminal(BET)family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy.BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin,facilitating the phosphorylation of RNA polymerases II(Pol II)and leading to transcription elongation.The present study identified a novel post-translational modification of BRD4:poly(ADPribosyl)ation(PARylation),that was mediated by poly(ADP-ribose)polymerase-1(PARP1)in cardiac hypertrophy.BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol(ISO),whereas overexpression of BRD4 promoted cardiac hypertrophy,confirming the critical role of BRD4 in pathological cardiac hypertrophy.PARP1 was activated in ISOinduced cardiac hypertrophy and facilitated the development of cardiac hypertrophy.BRD4 was involved in the prohypertrophic effect of PARP1,as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses,and that BRD4 overexpression suppressed the antihypertrophic effect of PARP1 inhibitors.Interactions of BRD4 and PARP1 were observed by coimmunoprecipitation and immunofluorescence.PARylation of BRD4 induced by PARP1 was investigated by PARylation assays.In response to hypertrophic stimuli like ISO,PARylation level of BRD4 was elevated,along with enhanced interactions between BRD4 and PARP1.By investigating the PARylation of truncation mutants of BRD4,the C-terminal domain(CTD)was identified as the PARylation modification sites of BRD4.PARylation of BRD4 facilitated its binding to the transcription start sites(TSS)of hypertrophic genes,resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes.The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.