AtbHLH29 of Arabidopsis, encoding a bHLH protein, reveals a high similarity to the tomato FER which is proposed as a transcriptional regulator involved in controlling the iron deficiency responses and the iron uptake ...AtbHLH29 of Arabidopsis, encoding a bHLH protein, reveals a high similarity to the tomato FER which is proposed as a transcriptional regulator involved in controlling the iron deficiency responses and the iron uptake in tomato. For identification of its biological functions, AtbHLH29 was introduced into the genome of the tomato FER mutant T3238fer mediated by Agrobacterium tumefaciencs. Transgenic plants were regenerated and the stable integration of AtbHLH29 into their genomes was confirmed by Southern hybridization. Molecular analysis demonstrated that expression of the exogenous AtbHLH29 of Arabidopsis in roots of the FER mutant T3238fer enabled to complement the defect functions of FER. The transgenic plants regained the ability to activate the whole iron deficiency responses and showed normal growth as the wild type under iron-limiting stress. Our transformation data demonstrate that AtbHLH29 is a functional ortholog of the tomato FER and can completely replace FER in controlling the effective iron acquisition in tomato. Except of iron, FER protein was directly or indirectly involved in manganese homeostasis due to that loss functions of FER in T3238fer resulted in strong reduction of Mn content in leaves and the defect function on Mn accumulation in leaves was complemented by expression of AtbHLH29 in the transgenic plants. Identification of the similar biological functions of FER and AtbHLH29, which isolated from two systematically wide-diverged “strategy I” plants, suggests that FER might be a universal gene presented in all strategy I plants in controlling effective iron acquisition system in roots.展开更多
Arachidonic acid cytochrome P-450 (CYP) hydroxylase 4A isoforms, including 4A1, 4A2, 4A3 and 4A8 in the rat kidney, catalyze arachidonic acid to produce 19/20-Hydroxyeicosatetraenoic acids (20-HETE), a biologically ac...Arachidonic acid cytochrome P-450 (CYP) hydroxylase 4A isoforms, including 4A1, 4A2, 4A3 and 4A8 in the rat kidney, catalyze arachidonic acid to produce 19/20-Hydroxyeicosatetraenoic acids (20-HETE), a biologically active metabolite, which plays an important role in the regulation of blood pressure. However, controversial results have been reported regarding the exact role of 20-HETE on blood pressure. In the present study, we used recombinant adeno- associated viral vector (rAAV) to deliver CYP 4A1 cDNA and antisense 4A1 cDNA into Sprague-Dawley (SD) rats and spontaneously hypertensive rats (SHR), respectively, to investigate the effects of long-term modifications of blood pressure and the potential for gene therapy of hypertension. The mean systolic pressure increased by 14.2±2.5 mm Hg in rAAV·4A1-treated SD rats and decreased by 13.7±2.2 mm Hg in rAAV·anti4A1-treated SHR rats 5 weeks after the injection compared with controls and these changes in blood pressure were maintained until the experiments ended at 24 weeks. In 4A1 treated animals CYP4A was overexpressed in various tissues, but preferentially in the kidney at both mRNA and protein levels. In anti-4A1-treated SHR, CYP4A mRNA in various tissues was probed, especially in kidneys, but 4A1 protein expression was almost completely inhibited. These results suggest that arachidonic acid CYP hydroxy- lases contribute not only to the maintenance of normal blood pressure but also to the development of hypertension. rAAV-mediated anti4A administration strategy has the potential to be used as targeted gene therapy in human hyperten- sion by blocking expression of CYP 4A in kidneys.展开更多
Fulminant myocarditis is an acute diffuse inflammatory disease of myocardium.It is characterized by acute onset,rapid progress and high risk of death.Its pathogenesis involves excessive immune activation of the innate...Fulminant myocarditis is an acute diffuse inflammatory disease of myocardium.It is characterized by acute onset,rapid progress and high risk of death.Its pathogenesis involves excessive immune activation of the innate immune system and formation of inflammatory storm.According to China’s practical experience,the adoption of the“life support-based comprehensive treatment regimen”(with mechanical circulation support and immunomodulation therapy as the core)can significantly improve the survival rate and long-term prognosis.Special emphasis is placed on very early identification,very early diagnosis,very early prediction and very early treatment.展开更多
CFIRL is a long noncoding RNA(lnc RNA),we previously identified as the most significantly upregulated lnc RNA in the failing hearts of patients with dilated cardiomyopathy(DCM).In this study,we determined the function...CFIRL is a long noncoding RNA(lnc RNA),we previously identified as the most significantly upregulated lnc RNA in the failing hearts of patients with dilated cardiomyopathy(DCM).In this study,we determined the function of CFIRL and its role in DCM.Real-time polymerase chain reaction and in situ hybridization assays revealed that CFIRL was primarily localized in the nucleus of cardiac fibroblasts and robustly increased in failing hearts.Global knockdown or fibroblast-specific knockout of CFIRL attenuated transverse aortic constriction(TAC)-induced cardiac dysfunction and fibrosis in vivo.Overexpression of CFIRL in vitro promoted fibroblast proliferation and aggravated angiotensin II-induced differentiation to myofibroblasts.CFIRL knockdown attenuated these effects.Mechanistically,RNA pull-down assay and gene expression profiling revealed that CFIRL recruited ENO1,a newly identified noncanonical transcriptional factor,to activate IL-6transcription.IL-6 exerted a paracrine effect on cardiomyocytes to promote cardiac hypertrophy,which can be prevented by CFIRL knockdown.These findings uncover the critical role of CFIRL,a fibroblast-associated lnc RNA,in heart failure by facilitating crosstalk between fibroblasts and cardiomyocytes.CFIRL knockdown might be a potent strategy to prevent cardiac remodeling in heart failure,particularly in DCM.展开更多
lncRNA ZNF593 antisense(ZNF593-AS)transcripts have been implicated in heart failure through the regulation of myocardial contractility.The decreased transcriptional activity of ZNF593-AS has also been detected in card...lncRNA ZNF593 antisense(ZNF593-AS)transcripts have been implicated in heart failure through the regulation of myocardial contractility.The decreased transcriptional activity of ZNF593-AS has also been detected in cardiac hypertrophy.However,the function of ZNF593-AS in cardiac hypertrophy remains unclear.Herein,we report that the expression of ZNF593-AS reduced in a mouse model of left ventricular hypertrophy and cardiomyocytes in response to treatment with the hypertrophic agonist phenylephrine(PE).In vivo,ZNF593-AS aggravated pressure overload–induced cardiac hypertrophy in knockout mice.By contrast,cardiomyocyte-specific transgenic mice(ZNF593-AS MHC-Tg)exhibited attenuated TAC-induced cardiac hypertrophy.In vitro,vector-based overexpression using murine or human ZNF593-AS alleviated PE-induced myocyte hypertrophy,whereas GapmeR-induced inhibition aggravated hypertrophic phenotypes.By using RNA-seq and gene set enrichment analyses,we identified a link between ZNF593-AS and oxidative phosphorylation and found that mitofusin 2(Mfn2)is a direct target of ZNF593-AS.ZNF593-AS exerts an antihypertrophic effect by upregulating Mfn2 expression and improving mitochondrial function.Therefore,it represents a promising therapeutic target for combating pathological cardiac remodeling.展开更多
Phenylacetylglutamine(PAGln)is an amino acid derivate that comes from the amino acid phenylalanine.There are increasing studies showing that the level of PAGln is associated with the risk of different cardiovascular d...Phenylacetylglutamine(PAGln)is an amino acid derivate that comes from the amino acid phenylalanine.There are increasing studies showing that the level of PAGln is associated with the risk of different cardiovascular diseases.In this review,we discussed the metabolic pathway of PAGln production and the quantitative measurement methods of PAGln.We summarized the epidemiological evidence to show the role of PAGln in diagnostic and prognostic value in several cardiovascular diseases,such as heart failure,coronary heart disease/atherosclerosis,and cardiac arrhythmia.The underlying mechanism of PAGln is now considered to be related to the thrombotic potential of platelets via adrenergic receptors.Besides,other possible mechanisms such as inflammatory response and oxidative stress could also be induced by PAGln.Moreover,since PAGln is produced across different organs including the intestine,liver,and kidney,the cross-talk among multiple organs focused on the function of this uremic toxic metabolite.Finally,the prognostic value of PAGln compared to the classical biomarker was discussed and we also highlighted important gaps in knowledge and areas requiring future investigation of PAGln in cardiovascular diseases.展开更多
Dilated cardiomyopathy(DCM)is the leading cause of heart transplantation.By microRNA(miRNA)array,a Kaposi’s sarcoma-associated herpes virus(KSHV)-encoded miRNA,kshv-miR-K12-1-5p,was detected in patients with DCM.The ...Dilated cardiomyopathy(DCM)is the leading cause of heart transplantation.By microRNA(miRNA)array,a Kaposi’s sarcoma-associated herpes virus(KSHV)-encoded miRNA,kshv-miR-K12-1-5p,was detected in patients with DCM.The KSHV DNA load and kshv-miR-K12-1-5p level in plasma from 696 patients with DCM were measured and these patients were followed-up.展开更多
Myocardial injury is one of the most common comorbidity in SARS-CoV-2 infected patients,and has poor prognosis.However,the incidence of myocardial injury in patients with SARS-CoV-2 infection has not been sufficiently...Myocardial injury is one of the most common comorbidity in SARS-CoV-2 infected patients,and has poor prognosis.However,the incidence of myocardial injury in patients with SARS-CoV-2 infection has not been sufficiently investigated during the Omicron wave.We conducted a retrospective study of 2690 patients with confirmed SARS-CoV-2 Omicron infection from Tongji Hospital.The results indicated that the myocardial injury accounted for 30.8%of the total patients with SARS-CoV-2 infection and was associated with higher in-hospital mortality than those without injury before and after propensity score matching(PSM)[adjusted hazard ratio(HR),10.61;95%confidence interval(CI),7.76–14.51;P<0.001;adjusted HR,2.70;95%CI,1.86–3.93;P<0.001;respectively].Further,the levels of cytokines(IL-1β,IL-6,IL-10,and TNF-α)in patients with myocardial injury were higher than those without injury,and the higher levels of cytokines in the myocardial injury group were associated with increased mortality.Administration of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers(ACEI/ARB)could significantly reduce the mortality in patients with myocardial injury(adjusted HR,0.52;95%CI,0.38–0.71;P<0.001).Additionally,the level of angiotensin II increased in patients with SARS-CoV-2 infection was even higher in myocardial injury group compared to those without injury.Collectively,the study summarized the clinical characteristic and outcome of SARS-CoV-2 infected patients with myocardial injury during the Omicron wave in China,and validated the protective role of ACEI/ARB in improving the survival of those with myocardial injury.展开更多
Previous studies have revealed that patients with hypertrophic cardiomyopathy(HCM)exhibit differences in symptom severity and prognosis,indicating potential HCM subtypes among these patients.Here,793 patients with HCM...Previous studies have revealed that patients with hypertrophic cardiomyopathy(HCM)exhibit differences in symptom severity and prognosis,indicating potential HCM subtypes among these patients.Here,793 patients with HCM were recruited at an average follow-up of 32.78±27.58 months to identify potential HCM subtypes by performing consensus clustering on the basis of their echocardiography features.Furthermore,we proposed a systematic method for illustrating the relationship between the phenotype and genotype of each HCM subtype by using machine learning modeling and interactome network detection techniques based on whole-exome sequencing data.Another independent cohort that consisted of 414 patients with HCM was recruited to replicate the findings.Consequently,two subtypes characterized by different clinical outcomes were identified in HCM.Patients with subtype 2 presented asymmetric septal hypertrophy associated with a stable course,while those with subtype 1 displayed left ventricular systolic dysfunction and aggressive progression.Machine learning modeling based on personal whole-exome data identified 46 genes with mutation burden that could accurately predict subtype propensities.Furthermore,the patients in another cohort predicted as subtype 1 by the 46-gene model presented increased left ventricular end-diastolic diameter and reduced left ventricular ejection fraction.By employing echocardiography and genetic screening for the 46 genes,HCM can be classified into two subtypes with distinct clinical outcomes.展开更多
Epoxyeicosatrienoic acids(EETs)have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase(sEH).Heart failure wit...Epoxyeicosatrienoic acids(EETs)have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase(sEH).Heart failure with preserved ejection fraction(HFpEF)has shown an increased prevalence and worse prognosis over the decades.However,the role of sEH activ-ity in HFpEF remains unclear.We enrolled 500 patients with HFpEF and 500 healthy controls between February 2010 and March 2016.Eight types of sEH-related eicosanoids were measured according to target metabolomics,and their correlation with clinical endpoints was also analyzed.The primary endpoint was cardiac mortality,and the secondary endpoint was a composite of cardiac events,including heart failure(HF)readmission,cardiogenic hospitalization,and all-cause mortal-ity.Furthermore,the effect of sEH inhibitors on cardiac diastolic function in HFpEF was investigated in vivo and in vitro.Patients with HFpEF showed significantly enhanced EET degradation by the sEH enzyme compared with healthy controls.More importantly,sEH activity was positively correlated with cardiac mortality in patients with HFpEF,especially in older patients with arrhythmia.A consistent result was obtained in the multiple adjusted models.Decreased sEH activity by the sEH inhibitor showed a significant effective effect on the improvement of cardiac diastolic function by ameliorating lipid disorders in cardiomyocytes of HFpEF mouse model.This study demonstrated that increased sEH activity was associated with cardiac mortality in patients with HFpEF and suggested that sEH inhibition could be a promising therapeutic strategy to improve diastolic cardiac function.Clinical trial identifier:NCT03461107(https://clini caltr ials.gov).展开更多
In December 2019,an outbreak of novel coronavirus(2019-nCoV)occurred in Wuhan,Hubei Province,China.By February 14,2020,it has led to 66492 confirmed patients in China and high mortality up to^2.96%(1123/37914)in Wuhan...In December 2019,an outbreak of novel coronavirus(2019-nCoV)occurred in Wuhan,Hubei Province,China.By February 14,2020,it has led to 66492 confirmed patients in China and high mortality up to^2.96%(1123/37914)in Wuhan.Here we report the first family case of coronavirus disease 2019(COVID-19)confirmed in Wuhan and treated using the combination of western medicine and Chinese traditional patent medicine Shuanghuanglian oral liquid(SHL).This report describes the identification,diagnosis,clinical course,and management of three cases from a family,suggests the expected therapeutic effects of SHL on COVID-19,and warrants further clinical trials.展开更多
The features of myocardial strains from speckle-tracking echocardiography (STE) have not been well defined in fulminant myocarditis (FM) patients.In this study,changes in the left ventricular ejection fraction (LVEF) ...The features of myocardial strains from speckle-tracking echocardiography (STE) have not been well defined in fulminant myocarditis (FM) patients.In this study,changes in the left ventricular ejection fraction (LVEF) and global and layer-specific myocardial strains over time were monitored.We aimed to determine the echocardiographic patterns of FM and ascertain their significance in FM treatment.Twenty patients who were clinically diagnosed with FM and received mechanical life support were prospectively enrolled.Conventional echocardiographic measurements were obtained,and serial strain echocardiography was performed from admission to hospital discharge until LVEF recovery (> 50%).Global/regional peak systolic longitudinal strains (GLS/RLS) and layer-specific longitudinal strains were quantified,and their changes with time were monitored in 14 FM patients.All patients had severely impaired cardiac function.Steep improvement in LVEF and GLS were observed within 6 days.Layer-specific strain analysis showed that reduction at admission or recovery at discharge in the endocardium and epicardium strains were equal.In conclusion,FM patients who received mechanical circulatory supports exhibited steep improvement in ventricular function within 6 days.The patchy and diffused distribution pattern of reduced RLS and equally and severely impaired strain in the endocardium and epicardium are valuable features in the diagnosis of FM.展开更多
Fulminant myocarditis(FM)is characterized by a rapid progressive decline in cardiac function and a high mortality rate.Since the first report of FM patients in the 1980s,several clinical trials and research studies ha...Fulminant myocarditis(FM)is characterized by a rapid progressive decline in cardiac function and a high mortality rate.Since the first report of FM patients in the 1980s,several clinical trials and research studies have been published increasing our knowledge regarding FM.Currently,the diagnosis of FM depends on various techniques including electrocardiography,echocardiography,endomyocardial biopsy,and cardiac magnetic resonance.The development of mechanical circulation support(MCS)devices and progress in our understanding of the pathophysiological mechanisms underlying FM,treatment regimens have evolved from simple symptomatic treatment to a life support-based comprehensive treatment approach.The core mechanism underlying the development of FM is the occurrence of an inflammatory cytokine storm.This review provides a comprehensive account of the current understanding of FM pathophysiology and knowledge regarding its etiology,pathophysiology,treatments,and outcomes.展开更多
The arachidonic acid(AA)pathway plays a key role in cardiovascular biology,carcinogenesis,and many inflammatory diseases,such as asthma,arthritis,etc.Esterified AA on the inner surface of the cell membrane is hydrolyz...The arachidonic acid(AA)pathway plays a key role in cardiovascular biology,carcinogenesis,and many inflammatory diseases,such as asthma,arthritis,etc.Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2),which is in turn further metabolized by cyclooxygenases(COXs)and lipoxygenases(LOXs)and cytochrome P450(CYP)enzymes to a spectrum of bioactive mediators that includes prostanoids,leukotrienes(LTs),epoxyeicosatrienoic acids(EETs),dihydroxyeicosatetraenoic acid(diHETEs),eicosatetraenoic acids(ETEs),and lipoxins(LXs).Many of the latter mediators are considered to be novel preventive and therapeutic targets for cardiovascular diseases(CVD),cancers,and inflammatory diseases.This review sets out to summarize the physiological and pathophysiological importance of the AA metabolizing pathways and outline the molecular mechanisms underlying the actions of AA related to its three main metabolic pathways in CVD and cancer.progression will provide valuable insight for developing new therapeutic drugs for CVD and anti-cancer agents such as inhibitors of EETs or 2J2.Thus,we herein present a synopsis of AA metabolism in human health,cardiovascular and cancer biology,and the signaling pathways involved in these processes.To explore the role of the AA metabolism and potential therapies,we also introduce the current newly clinical studies targeting AA metabolisms in the different disease conditions.展开更多
Dear Editor,Patients presenting with acute myocarditis and sudden hemodynamic instability (termed fulminant myocarditis [FM]) still have a high mortality and need for heart transplantation, up to 28% at 60 days.1,2,3 ...Dear Editor,Patients presenting with acute myocarditis and sudden hemodynamic instability (termed fulminant myocarditis [FM]) still have a high mortality and need for heart transplantation, up to 28% at 60 days.1,2,3 Recent scientific statements and expert opinion consensus suggests early use of temporary mechanical circulatory supports (t-MCS).3,4 Specifically, Chinese scientific statement proposed an extensive use of t-MCS combined with immunoregulatory therapy (IT),4 although formal trials are lacking. We present a multicenter, retrospective study to compare the outcome of patients who were treated with t-MCS and IT vs. patients who didn’t receive these treatments. We included patients with the diagnosis of FM based on the presence of viral prodromal signs/symptoms followed by acute onset of severe heart failure (HF) without other relevant differential diagnosis or pre-existing cardiac disorders. Patients who received both t-MCS and IT during hospitalization were classified as t-MCS+IT group.展开更多
We conducted a randomized,open-label,parallel-controlled,multicenter trial on the use of Shuanghuanglian(SHL),a traditional Chinese patent medicine,in treating cases of COVID-19.A total of 176 patients received SHL by...We conducted a randomized,open-label,parallel-controlled,multicenter trial on the use of Shuanghuanglian(SHL),a traditional Chinese patent medicine,in treating cases of COVID-19.A total of 176 patients received SHL by three doses(56 in low dose,61 in middle dose,and 59 in high dose)in addition to standard care.The control group was composed of 59 patients who received standard therapy alone.Treatment with SHL was not associated with a difference from standard care in the time to disease recovery.Patients with 14-day SHL treatment had significantly higher rate in negative conversion of SARS-CoV-2 in nucleic acid swab tests than the patients from the control group(93.4%vs.73.9%,P=0.006).Analysis of chest computed tomography images showed that treatment with high-dose SHL significantly promoted absorption of inflammatory focus of pneumonia,which was evaluated by density reduction of inflammatory focus from baseline,at day 7(mean difference(95%CI),−46.39(−86.83 to−5.94)HU;P=0.025)and day 14(mean difference(95%CI),−74.21(−133.35 to−15.08)HU;P=0.014).No serious adverse events occurred in the SHL groups.This study illustrated that SHL in combination with standard care was safe and partially effective for the treatment of COVID-19.展开更多
Cardiovascular diseases account for approximately 80%of deaths among individuals with diabetes mellitus,with diabetic cardiomyopathy as the major diabetic cardiovascular complication.Hyperglycemia is a symptom that ab...Cardiovascular diseases account for approximately 80%of deaths among individuals with diabetes mellitus,with diabetic cardiomyopathy as the major diabetic cardiovascular complication.Hyperglycemia is a symptom that abnormally activates multiple downstream pathways and contributes to cardiac hypertrophy,fibrosis,apoptosis,and other pathophysiological changes.Although glycemic control has long been at the center of diabetes therapy,multicenter randomized clinical studies have revealed that intensive glycemic control fails to reduce heart failure-associated hospitalization and mortality in patients with diabetes.This finding indicates that hyperglycemic stress persists in the cardiovascular system of patients with diabetes even if blood glucose level is tightly controlled to the normal level.This process is now referred to as hyperglycemic memory(HGM)phenomenon.We briefly reviewed herein the current advances that have been achieved in research on the underlying mechanisms of HGM in diabetic cardiomyopathy.展开更多
MicroRNAs(miRNAs)are aberrantly expressed in the pathophysiologic process of heart failure(HF).However,the functions of a certain miRNA in different cardiac cell types during HF are scarcely reported,which might be co...MicroRNAs(miRNAs)are aberrantly expressed in the pathophysiologic process of heart failure(HF).However,the functions of a certain miRNA in different cardiac cell types during HF are scarcely reported,which might be covered by the globe effects of it on the heart.In the current study,Langendorff system was applied to isolate card io myocytes(CMs)and cardiac fibroblasts(CFs)from transverse aortic constriction(TAC)-induced mice.Slight increase of miR-320 expression was observed in the whole heart tissue of TAC mice.Interestingly,miR-320 was significantly elevated in CMs but decreased in CFs from TAC mice at different time points.Then,recombinant adeno-associated virus 9 with cell-type-specific promoters were used to manipulate miR-320 expressions in vivo.Both in vitro and in vivo experiments showed the miR-320 overexpression in CMs exacerbated cardiac dysfunction,whereas overexpression of miR-320 in CFs alleviated cardiac fibrosis and hypertrophy.Mechanically,downstream signaling pathway analyses revealed that miR-320 might induce various effects via targeting PLEKHM3 and IFITM1 in CMs and CFs,respectively.Moreover,miR-320 mediated effects could be abolished by PLEKHM3 re-expression in CMs or IFITM1 re-expression in CFs.Interestingly,miR-320 treated CFs were able to indirectly affect CMs function,but not vice versa.Meanwhile,upstream signaling pathway analyses showed that miR-320 expression and decay rate were rigorously manipulated by Ago2,which was regulated by a cluster of cell-type-specific TFs distinctively expressed in CMs and CFs,respectively.Together,we demonstrated that miR-320 functioned differently in various cell types of the heart during the progression of HF.展开更多
基金supported by grants from the Ministry of Science and Technology of China(Grant No.2004AA222110)the National Natural Science Foundation of China(Grant No.30225029).
文摘AtbHLH29 of Arabidopsis, encoding a bHLH protein, reveals a high similarity to the tomato FER which is proposed as a transcriptional regulator involved in controlling the iron deficiency responses and the iron uptake in tomato. For identification of its biological functions, AtbHLH29 was introduced into the genome of the tomato FER mutant T3238fer mediated by Agrobacterium tumefaciencs. Transgenic plants were regenerated and the stable integration of AtbHLH29 into their genomes was confirmed by Southern hybridization. Molecular analysis demonstrated that expression of the exogenous AtbHLH29 of Arabidopsis in roots of the FER mutant T3238fer enabled to complement the defect functions of FER. The transgenic plants regained the ability to activate the whole iron deficiency responses and showed normal growth as the wild type under iron-limiting stress. Our transformation data demonstrate that AtbHLH29 is a functional ortholog of the tomato FER and can completely replace FER in controlling the effective iron acquisition in tomato. Except of iron, FER protein was directly or indirectly involved in manganese homeostasis due to that loss functions of FER in T3238fer resulted in strong reduction of Mn content in leaves and the defect function on Mn accumulation in leaves was complemented by expression of AtbHLH29 in the transgenic plants. Identification of the similar biological functions of FER and AtbHLH29, which isolated from two systematically wide-diverged “strategy I” plants, suggests that FER might be a universal gene presented in all strategy I plants in controlling effective iron acquisition system in roots.
基金This project Was supported by the National Natural Science Foundation of China(NSFC,No.39870307)National Basic Research Program of China(973 Program,No.G2000056901)KC was the recipient of an Fonds de la recherche en sante du Quebec(FRSQ,Quebec-Canada)-NSFC(China exchange grant).
文摘Arachidonic acid cytochrome P-450 (CYP) hydroxylase 4A isoforms, including 4A1, 4A2, 4A3 and 4A8 in the rat kidney, catalyze arachidonic acid to produce 19/20-Hydroxyeicosatetraenoic acids (20-HETE), a biologically active metabolite, which plays an important role in the regulation of blood pressure. However, controversial results have been reported regarding the exact role of 20-HETE on blood pressure. In the present study, we used recombinant adeno- associated viral vector (rAAV) to deliver CYP 4A1 cDNA and antisense 4A1 cDNA into Sprague-Dawley (SD) rats and spontaneously hypertensive rats (SHR), respectively, to investigate the effects of long-term modifications of blood pressure and the potential for gene therapy of hypertension. The mean systolic pressure increased by 14.2±2.5 mm Hg in rAAV·4A1-treated SD rats and decreased by 13.7±2.2 mm Hg in rAAV·anti4A1-treated SHR rats 5 weeks after the injection compared with controls and these changes in blood pressure were maintained until the experiments ended at 24 weeks. In 4A1 treated animals CYP4A was overexpressed in various tissues, but preferentially in the kidney at both mRNA and protein levels. In anti-4A1-treated SHR, CYP4A mRNA in various tissues was probed, especially in kidneys, but 4A1 protein expression was almost completely inhibited. These results suggest that arachidonic acid CYP hydroxy- lases contribute not only to the maintenance of normal blood pressure but also to the development of hypertension. rAAV-mediated anti4A administration strategy has the potential to be used as targeted gene therapy in human hyperten- sion by blocking expression of CYP 4A in kidneys.
基金supported in part by the National Natural Science Foundation of China(81790624,81630010)Top-Notch Talent Program of Hubei Province and Tongji Hospital(2021YBJRC005)。
文摘Fulminant myocarditis is an acute diffuse inflammatory disease of myocardium.It is characterized by acute onset,rapid progress and high risk of death.Its pathogenesis involves excessive immune activation of the innate immune system and formation of inflammatory storm.According to China’s practical experience,the adoption of the“life support-based comprehensive treatment regimen”(with mechanical circulation support and immunomodulation therapy as the core)can significantly improve the survival rate and long-term prognosis.Special emphasis is placed on very early identification,very early diagnosis,very early prediction and very early treatment.
基金supported by the National Natural Science Foundation of China(U22A20266,82170273,81630010)the Fundamental Research Funds for the Central Universities(2019kfy XMBZ035,2021yjs CXCY090)Fundamental Research Funds of Wuhan Innovation Program(2022020801020451)。
文摘CFIRL is a long noncoding RNA(lnc RNA),we previously identified as the most significantly upregulated lnc RNA in the failing hearts of patients with dilated cardiomyopathy(DCM).In this study,we determined the function of CFIRL and its role in DCM.Real-time polymerase chain reaction and in situ hybridization assays revealed that CFIRL was primarily localized in the nucleus of cardiac fibroblasts and robustly increased in failing hearts.Global knockdown or fibroblast-specific knockout of CFIRL attenuated transverse aortic constriction(TAC)-induced cardiac dysfunction and fibrosis in vivo.Overexpression of CFIRL in vitro promoted fibroblast proliferation and aggravated angiotensin II-induced differentiation to myofibroblasts.CFIRL knockdown attenuated these effects.Mechanistically,RNA pull-down assay and gene expression profiling revealed that CFIRL recruited ENO1,a newly identified noncanonical transcriptional factor,to activate IL-6transcription.IL-6 exerted a paracrine effect on cardiomyocytes to promote cardiac hypertrophy,which can be prevented by CFIRL knockdown.These findings uncover the critical role of CFIRL,a fibroblast-associated lnc RNA,in heart failure by facilitating crosstalk between fibroblasts and cardiomyocytes.CFIRL knockdown might be a potent strategy to prevent cardiac remodeling in heart failure,particularly in DCM.
基金supported by grants from the National Natural Science Foundation of China(Nos.82100399,82100400,and 81790624)the project funded by China Postdoctoral Science Foundation(No.2021M701315).
文摘lncRNA ZNF593 antisense(ZNF593-AS)transcripts have been implicated in heart failure through the regulation of myocardial contractility.The decreased transcriptional activity of ZNF593-AS has also been detected in cardiac hypertrophy.However,the function of ZNF593-AS in cardiac hypertrophy remains unclear.Herein,we report that the expression of ZNF593-AS reduced in a mouse model of left ventricular hypertrophy and cardiomyocytes in response to treatment with the hypertrophic agonist phenylephrine(PE).In vivo,ZNF593-AS aggravated pressure overload–induced cardiac hypertrophy in knockout mice.By contrast,cardiomyocyte-specific transgenic mice(ZNF593-AS MHC-Tg)exhibited attenuated TAC-induced cardiac hypertrophy.In vitro,vector-based overexpression using murine or human ZNF593-AS alleviated PE-induced myocyte hypertrophy,whereas GapmeR-induced inhibition aggravated hypertrophic phenotypes.By using RNA-seq and gene set enrichment analyses,we identified a link between ZNF593-AS and oxidative phosphorylation and found that mitofusin 2(Mfn2)is a direct target of ZNF593-AS.ZNF593-AS exerts an antihypertrophic effect by upregulating Mfn2 expression and improving mitochondrial function.Therefore,it represents a promising therapeutic target for combating pathological cardiac remodeling.
基金supported by the National Key Research and Development Program of China(No.2022YFC3400700)National Natural Science Foundation of China(Nos.31971358,82370397,U22A20266,and 82100402)+1 种基金Hubei Provincial Key Research and Developmental Program(No.2022BCA037)Hubei Provincial Natural Science Foundation of China(Nos.2017CFB536 and 2022CFB201).
文摘Phenylacetylglutamine(PAGln)is an amino acid derivate that comes from the amino acid phenylalanine.There are increasing studies showing that the level of PAGln is associated with the risk of different cardiovascular diseases.In this review,we discussed the metabolic pathway of PAGln production and the quantitative measurement methods of PAGln.We summarized the epidemiological evidence to show the role of PAGln in diagnostic and prognostic value in several cardiovascular diseases,such as heart failure,coronary heart disease/atherosclerosis,and cardiac arrhythmia.The underlying mechanism of PAGln is now considered to be related to the thrombotic potential of platelets via adrenergic receptors.Besides,other possible mechanisms such as inflammatory response and oxidative stress could also be induced by PAGln.Moreover,since PAGln is produced across different organs including the intestine,liver,and kidney,the cross-talk among multiple organs focused on the function of this uremic toxic metabolite.Finally,the prognostic value of PAGln compared to the classical biomarker was discussed and we also highlighted important gaps in knowledge and areas requiring future investigation of PAGln in cardiovascular diseases.
基金This work was supported by grants from the National Natural Science Foundation of China(nos.81822002,82270363,91839302,81630010,81790624,31771264,31800973,and 82000387)National Key R&D Program of China(no.2017YFC0909400)the Natural Science Foundation of Hubei Province(no.2020CFA016).The funders had no role in study design,data collection and analysis,manuscript preparation,or decision to publish.
文摘Dilated cardiomyopathy(DCM)is the leading cause of heart transplantation.By microRNA(miRNA)array,a Kaposi’s sarcoma-associated herpes virus(KSHV)-encoded miRNA,kshv-miR-K12-1-5p,was detected in patients with DCM.The KSHV DNA load and kshv-miR-K12-1-5p level in plasma from 696 patients with DCM were measured and these patients were followed-up.
基金grant of National Key Research and Development Program of China(2022YFC3400700)National Natural Science Foundation of China(Nos.82241034,82370397,31971358,U22A20266 and C-0052)+2 种基金Top-Notch Talent Program of Hubei Province and Tongji Hospital(No.2021YBJRC005)Hubei Provincial Key Research and Developmental Program(2022BCA037)Hubei Provincial Natural Science Foundation of China(2017CFB536).
文摘Myocardial injury is one of the most common comorbidity in SARS-CoV-2 infected patients,and has poor prognosis.However,the incidence of myocardial injury in patients with SARS-CoV-2 infection has not been sufficiently investigated during the Omicron wave.We conducted a retrospective study of 2690 patients with confirmed SARS-CoV-2 Omicron infection from Tongji Hospital.The results indicated that the myocardial injury accounted for 30.8%of the total patients with SARS-CoV-2 infection and was associated with higher in-hospital mortality than those without injury before and after propensity score matching(PSM)[adjusted hazard ratio(HR),10.61;95%confidence interval(CI),7.76–14.51;P<0.001;adjusted HR,2.70;95%CI,1.86–3.93;P<0.001;respectively].Further,the levels of cytokines(IL-1β,IL-6,IL-10,and TNF-α)in patients with myocardial injury were higher than those without injury,and the higher levels of cytokines in the myocardial injury group were associated with increased mortality.Administration of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers(ACEI/ARB)could significantly reduce the mortality in patients with myocardial injury(adjusted HR,0.52;95%CI,0.38–0.71;P<0.001).Additionally,the level of angiotensin II increased in patients with SARS-CoV-2 infection was even higher in myocardial injury group compared to those without injury.Collectively,the study summarized the clinical characteristic and outcome of SARS-CoV-2 infected patients with myocardial injury during the Omicron wave in China,and validated the protective role of ACEI/ARB in improving the survival of those with myocardial injury.
基金the National Key R&D Program of China(No.2017YFC0909400)the National Natural Science Foundation of China(Nos.91439203,91839302,and 81700413)+1 种基金Shanghai Municipal Science and Technology Major Project(No.2017SHZDZX01)the Fundamental Research Funds for the Central Universities,HUST(No.2016JCTD117).
文摘Previous studies have revealed that patients with hypertrophic cardiomyopathy(HCM)exhibit differences in symptom severity and prognosis,indicating potential HCM subtypes among these patients.Here,793 patients with HCM were recruited at an average follow-up of 32.78±27.58 months to identify potential HCM subtypes by performing consensus clustering on the basis of their echocardiography features.Furthermore,we proposed a systematic method for illustrating the relationship between the phenotype and genotype of each HCM subtype by using machine learning modeling and interactome network detection techniques based on whole-exome sequencing data.Another independent cohort that consisted of 414 patients with HCM was recruited to replicate the findings.Consequently,two subtypes characterized by different clinical outcomes were identified in HCM.Patients with subtype 2 presented asymmetric septal hypertrophy associated with a stable course,while those with subtype 1 displayed left ventricular systolic dysfunction and aggressive progression.Machine learning modeling based on personal whole-exome data identified 46 genes with mutation burden that could accurately predict subtype propensities.Furthermore,the patients in another cohort predicted as subtype 1 by the 46-gene model presented increased left ventricular end-diastolic diameter and reduced left ventricular ejection fraction.By employing echocardiography and genetic screening for the 46 genes,HCM can be classified into two subtypes with distinct clinical outcomes.
基金supported by grants from the National Natural Science Foundation of China(81790624[to D.W.W.],81900342[to L.P.]and 81790621[to Y.Z.]).
文摘Epoxyeicosatrienoic acids(EETs)have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase(sEH).Heart failure with preserved ejection fraction(HFpEF)has shown an increased prevalence and worse prognosis over the decades.However,the role of sEH activ-ity in HFpEF remains unclear.We enrolled 500 patients with HFpEF and 500 healthy controls between February 2010 and March 2016.Eight types of sEH-related eicosanoids were measured according to target metabolomics,and their correlation with clinical endpoints was also analyzed.The primary endpoint was cardiac mortality,and the secondary endpoint was a composite of cardiac events,including heart failure(HF)readmission,cardiogenic hospitalization,and all-cause mortal-ity.Furthermore,the effect of sEH inhibitors on cardiac diastolic function in HFpEF was investigated in vivo and in vitro.Patients with HFpEF showed significantly enhanced EET degradation by the sEH enzyme compared with healthy controls.More importantly,sEH activity was positively correlated with cardiac mortality in patients with HFpEF,especially in older patients with arrhythmia.A consistent result was obtained in the multiple adjusted models.Decreased sEH activity by the sEH inhibitor showed a significant effective effect on the improvement of cardiac diastolic function by ameliorating lipid disorders in cardiomyocytes of HFpEF mouse model.This study demonstrated that increased sEH activity was associated with cardiac mortality in patients with HFpEF and suggested that sEH inhibition could be a promising therapeutic strategy to improve diastolic cardiac function.Clinical trial identifier:NCT03461107(https://clini caltr ials.gov).
基金This work was supported by Tongji Hospital Clinical Research Flagship Program(No.2019CR207).
文摘In December 2019,an outbreak of novel coronavirus(2019-nCoV)occurred in Wuhan,Hubei Province,China.By February 14,2020,it has led to 66492 confirmed patients in China and high mortality up to^2.96%(1123/37914)in Wuhan.Here we report the first family case of coronavirus disease 2019(COVID-19)confirmed in Wuhan and treated using the combination of western medicine and Chinese traditional patent medicine Shuanghuanglian oral liquid(SHL).This report describes the identification,diagnosis,clinical course,and management of three cases from a family,suggests the expected therapeutic effects of SHL on COVID-19,and warrants further clinical trials.
基金The project was supported by the grant from the National Natural Science Foundation of China(Nos.81873535 and 81570367)We thank Dr.Jonathan R.Linder who gave us helpful suggestions in writing the manuscript.
文摘The features of myocardial strains from speckle-tracking echocardiography (STE) have not been well defined in fulminant myocarditis (FM) patients.In this study,changes in the left ventricular ejection fraction (LVEF) and global and layer-specific myocardial strains over time were monitored.We aimed to determine the echocardiographic patterns of FM and ascertain their significance in FM treatment.Twenty patients who were clinically diagnosed with FM and received mechanical life support were prospectively enrolled.Conventional echocardiographic measurements were obtained,and serial strain echocardiography was performed from admission to hospital discharge until LVEF recovery (> 50%).Global/regional peak systolic longitudinal strains (GLS/RLS) and layer-specific longitudinal strains were quantified,and their changes with time were monitored in 14 FM patients.All patients had severely impaired cardiac function.Steep improvement in LVEF and GLS were observed within 6 days.Layer-specific strain analysis showed that reduction at admission or recovery at discharge in the endocardium and epicardium strains were equal.In conclusion,FM patients who received mechanical circulatory supports exhibited steep improvement in ventricular function within 6 days.The patchy and diffused distribution pattern of reduced RLS and equally and severely impaired strain in the endocardium and epicardium are valuable features in the diagnosis of FM.
基金supported by grants from the National Natural Science Foundation of China(91839302,81630010,and 81790624)Tongji Hospital Clinical Research Flagship Program(2019CR207)JMS is support by a grant from the Canadian Institutes of Health Sciences(FRN156393).
文摘Fulminant myocarditis(FM)is characterized by a rapid progressive decline in cardiac function and a high mortality rate.Since the first report of FM patients in the 1980s,several clinical trials and research studies have been published increasing our knowledge regarding FM.Currently,the diagnosis of FM depends on various techniques including electrocardiography,echocardiography,endomyocardial biopsy,and cardiac magnetic resonance.The development of mechanical circulation support(MCS)devices and progress in our understanding of the pathophysiological mechanisms underlying FM,treatment regimens have evolved from simple symptomatic treatment to a life support-based comprehensive treatment approach.The core mechanism underlying the development of FM is the occurrence of an inflammatory cytokine storm.This review provides a comprehensive account of the current understanding of FM pathophysiology and knowledge regarding its etiology,pathophysiology,treatments,and outcomes.
基金supported in part by National Nature Science Foundation of China(Nos.81790624,81700333,81900363,and 81900244)the Deutsche Forschungsgemeinschaft:SFB1039/A6(to I.F.).
文摘The arachidonic acid(AA)pathway plays a key role in cardiovascular biology,carcinogenesis,and many inflammatory diseases,such as asthma,arthritis,etc.Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2),which is in turn further metabolized by cyclooxygenases(COXs)and lipoxygenases(LOXs)and cytochrome P450(CYP)enzymes to a spectrum of bioactive mediators that includes prostanoids,leukotrienes(LTs),epoxyeicosatrienoic acids(EETs),dihydroxyeicosatetraenoic acid(diHETEs),eicosatetraenoic acids(ETEs),and lipoxins(LXs).Many of the latter mediators are considered to be novel preventive and therapeutic targets for cardiovascular diseases(CVD),cancers,and inflammatory diseases.This review sets out to summarize the physiological and pathophysiological importance of the AA metabolizing pathways and outline the molecular mechanisms underlying the actions of AA related to its three main metabolic pathways in CVD and cancer.progression will provide valuable insight for developing new therapeutic drugs for CVD and anti-cancer agents such as inhibitors of EETs or 2J2.Thus,we herein present a synopsis of AA metabolism in human health,cardiovascular and cancer biology,and the signaling pathways involved in these processes.To explore the role of the AA metabolism and potential therapies,we also introduce the current newly clinical studies targeting AA metabolisms in the different disease conditions.
基金This work grants from the National Natural Science Foundation of China(No.81790624 and 81630010,82070316)National Key R&D Program of China(NO.2017YFC0909400).
文摘Dear Editor,Patients presenting with acute myocarditis and sudden hemodynamic instability (termed fulminant myocarditis [FM]) still have a high mortality and need for heart transplantation, up to 28% at 60 days.1,2,3 Recent scientific statements and expert opinion consensus suggests early use of temporary mechanical circulatory supports (t-MCS).3,4 Specifically, Chinese scientific statement proposed an extensive use of t-MCS combined with immunoregulatory therapy (IT),4 although formal trials are lacking. We present a multicenter, retrospective study to compare the outcome of patients who were treated with t-MCS and IT vs. patients who didn’t receive these treatments. We included patients with the diagnosis of FM based on the presence of viral prodromal signs/symptoms followed by acute onset of severe heart failure (HF) without other relevant differential diagnosis or pre-existing cardiac disorders. Patients who received both t-MCS and IT during hospitalization were classified as t-MCS+IT group.
基金This work was supported by the National Key R&D Program of China(No.2020YFC0841400)Tongji Hospital Clinical Research Project(Nos.XXGZBDYJ009 and 2019YBKY019).
文摘We conducted a randomized,open-label,parallel-controlled,multicenter trial on the use of Shuanghuanglian(SHL),a traditional Chinese patent medicine,in treating cases of COVID-19.A total of 176 patients received SHL by three doses(56 in low dose,61 in middle dose,and 59 in high dose)in addition to standard care.The control group was composed of 59 patients who received standard therapy alone.Treatment with SHL was not associated with a difference from standard care in the time to disease recovery.Patients with 14-day SHL treatment had significantly higher rate in negative conversion of SARS-CoV-2 in nucleic acid swab tests than the patients from the control group(93.4%vs.73.9%,P=0.006).Analysis of chest computed tomography images showed that treatment with high-dose SHL significantly promoted absorption of inflammatory focus of pneumonia,which was evaluated by density reduction of inflammatory focus from baseline,at day 7(mean difference(95%CI),−46.39(−86.83 to−5.94)HU;P=0.025)and day 14(mean difference(95%CI),−74.21(−133.35 to−15.08)HU;P=0.014).No serious adverse events occurred in the SHL groups.This study illustrated that SHL in combination with standard care was safe and partially effective for the treatment of COVID-19.
基金supported by grants from the National Natural Science Foundation of China(Nos.81822002,31771264,31800973)the Fundamental Research Funds for the Central Universities(No.2019kfyXMBZ035).
文摘Cardiovascular diseases account for approximately 80%of deaths among individuals with diabetes mellitus,with diabetic cardiomyopathy as the major diabetic cardiovascular complication.Hyperglycemia is a symptom that abnormally activates multiple downstream pathways and contributes to cardiac hypertrophy,fibrosis,apoptosis,and other pathophysiological changes.Although glycemic control has long been at the center of diabetes therapy,multicenter randomized clinical studies have revealed that intensive glycemic control fails to reduce heart failure-associated hospitalization and mortality in patients with diabetes.This finding indicates that hyperglycemic stress persists in the cardiovascular system of patients with diabetes even if blood glucose level is tightly controlled to the normal level.This process is now referred to as hyperglycemic memory(HGM)phenomenon.We briefly reviewed herein the current advances that have been achieved in research on the underlying mechanisms of HGM in diabetic cardiomyopathy.
基金supported by grant from the National Natural Science Foundation of China(nos.81822002,31771264,31800973,and 81630010).
文摘MicroRNAs(miRNAs)are aberrantly expressed in the pathophysiologic process of heart failure(HF).However,the functions of a certain miRNA in different cardiac cell types during HF are scarcely reported,which might be covered by the globe effects of it on the heart.In the current study,Langendorff system was applied to isolate card io myocytes(CMs)and cardiac fibroblasts(CFs)from transverse aortic constriction(TAC)-induced mice.Slight increase of miR-320 expression was observed in the whole heart tissue of TAC mice.Interestingly,miR-320 was significantly elevated in CMs but decreased in CFs from TAC mice at different time points.Then,recombinant adeno-associated virus 9 with cell-type-specific promoters were used to manipulate miR-320 expressions in vivo.Both in vitro and in vivo experiments showed the miR-320 overexpression in CMs exacerbated cardiac dysfunction,whereas overexpression of miR-320 in CFs alleviated cardiac fibrosis and hypertrophy.Mechanically,downstream signaling pathway analyses revealed that miR-320 might induce various effects via targeting PLEKHM3 and IFITM1 in CMs and CFs,respectively.Moreover,miR-320 mediated effects could be abolished by PLEKHM3 re-expression in CMs or IFITM1 re-expression in CFs.Interestingly,miR-320 treated CFs were able to indirectly affect CMs function,but not vice versa.Meanwhile,upstream signaling pathway analyses showed that miR-320 expression and decay rate were rigorously manipulated by Ago2,which was regulated by a cluster of cell-type-specific TFs distinctively expressed in CMs and CFs,respectively.Together,we demonstrated that miR-320 functioned differently in various cell types of the heart during the progression of HF.