Atorvastatin Attenuates Myocardial Hypertrophy Induced by Chronic Intermittent Hypoxia In Vitro Partly through miR-31/PKCε Pathway

Atorvastatin is proven to ameliorate cardiac hypertrophy induced by chronic intermittent hypoxia （CIH）. However, little is known about the mechanism by which atorvastatin modulates CIH-induced cardiac hypertrophy, and whether specific hypertrophyrelated microRNAs are involved in the modulation. MiR-31 plays key roles in the development of cardiac hypertrophy induced by ischemia/hypoxia. This study examined whether miR-31 was involved in the protective role of atorvastatin against CIH-induced myocardial hypertrophy. H9c2 cells were subjected to 8-h intermittent hypoxia per day in the presence or absence of atorvastatin for 5 days. The size of cardiomyocytes, and the expression of caspase 3 and miR-31 were determined by Western blotting and RT-PCR, respectively. MiR-31 mimic or Ro 31-8220, a specific inhibitor of protein kinase C epsilon （PKCε）, was used to determine the role of miR-31 in the anti-hypertrophic effect of atorvastatin on cardiomyocytes. PKCε in the cardiomyocytes with miR-31 upregulation or downregulation was detected using RT-PCR and Western blotting. The results showed that CIH induced obvious enlargement of cardiomyocytes, which was paralleled with increased atrial natriuretic peptide （ANP）, brain natriuretic peptide （BNP）, and slow/beta cardiac myosin heavy-chain （MYHT） mRNA levels. All these changes were reversed by the treatment with atorvastatin. Meanwhile, miR-31 was increased by CIH in vitro. Of note, the atorvastatin pretreatment significantly increased the mRNA and protein expression of PKCε and decreased that of miR-31. Moreover, overexpression of miR-31 abolished the anti-hypertrophic effect of atorvastatin on cardiomyocytes. Upregulation and downregulation of miR-31 respectively decreased and increased the mRNA and protein expression of PKCε. These results suggest that atorvastatin provides the cardioprotective effects against CIH probably via up-regulating PKCε and down-regulating miR-31.

The Dynamic Change of TGF-β_1 in the Myocardial Remodeling of Rat after Myocardial Infarction

Summary： To observe the dynamic changes of the TGF-β1 expressed in the infarct and non-infarcted region of rat heart during the ventricular remodeling （day 3, 7, 28, 180）, myocardial infarction rat model was made and relationship between the cytokine and indicator of myocardial remodeling was analyzed. After the detection of hemodynamic parameter was performed by the Powerlab devices, the size of myocardial infarction and the morphology change was detected by TTC and HE, respectively. The relative levels of mRNA of TGF-β 1, collagen type Ⅰ , Ⅲ, and fetal gene beta-MHC were detected by RT-PCR. The distribution of TGF-β1 protein in the myocardium was detected by immunohistochemistry. The results showed that the size of infarction was higher than that of the sham operated groups in the infarcted group （44.5±0.5 vs 0）. The difference in hemodynamic parameters between the infarcted group and sham operated group was significant （P〈0.01）. HE staining showed that inflammatory cells were accumulated in the infarcted region at the beginning of the 3^rd day, which lasted 4 weeks. Then, it decreased gradually. β-MHC in the non-infarcted region rose from the 3^rd day, reaching its peak at the 4^th week, and it decreased gradually. The ratio of the collagen type Ⅰ /Ⅲ showed similar changes as compared with the sham operated groups （P〈0.01）. And the relative mRNA levels in the non-infarcted group were significantly higher than that in the infarcted and sham operated group （P〈0.01） at day 180. Linear regression analysis indicated that the TGF-β1 was positively correlated with the ventricular remodeling. It was concluded that the cytokine TGF-β1 participates in the process of the myocardial remodeling, which could be a strategy in the interference of myocardial remodeling.

Hypoxia training attenuates left ventricular remodeling in rabbit with myocardial infarction

Objective Previous studies showed that hypoxia preconditioning could protect cardiac function against subsequent myo-cardial infarction injury. However, the effect of hypoxia on left ventricular after myocardial infarction is still unclear. This study therefore aims to investigate the effects of hypoxia training on left ventricular remodeling in rabbits post myocardial infarction. Methods Adult male rabbits were randomly divided into three groups： group SO （sham operated）, group MI （myocardial infarc-tion only） and group MI-HT （myocardial infarction plus hypoxia training）. Myocardial infarction was induced by left ventricular branch ligation. Hypoxia training was performed in a hypobaric chamber （having equivalent condition at an altitude of 4000 m, FiO214.9%） for 1 h/day, 5 days/week for four weeks. At the endpoints, vascular endothelial growth factor （VEGF） in the plasma was measured. Infarct size and capillary density were detected by histology. Left ventricular remodeling and function were as-sessed by echocardiography.Results After the 4-week experiment, compared with the group SO, plasma VEGF levels in groups MI （130.27 ± 18.58 pg/mL,P〈 0.01） and MI-HT （181.93 ± 20.29 pg/mL,P〈 0.01） were significantly increased. Infarct size in Group MI-HT （29.67% ± 7.73%） was deceased remarkably, while its capillary density （816.0 ± 122.2/mm2） was significantly increased. For both groups MI and MI-HT, left ventricular end-diastolic and end-systolic dimensions were increased whereas left ventricular ejection fraction was decreased. However, compared with group MI, group MI-HT diminished left ventricular end-diastolic （15.86 ± 1.09 mm,P〈 0.05） and end-systolic dimensions （12.10 ± 1.20 mm,P〈 0.01） significantly and im-proved left ventricular ejection fraction （54.39 ± 12.74 mm,P〈 0.05）.ConclusionHypoxia training may improve left ven-tricular function and reduce remodeling via angiogenesis in rabbits with MI.

Dietary Nε-(carboxymethyl)lysine affects cardiac glucose metabolism and myocardial remodeling in mice

BACKGROUND Myocardial remodeling is a key factor in the progression of cardiovascular disease to the end stage.In addition to myocardial infarction or stress overload,dietary factors have recently been considered associated with myocardial remodeling.Nε-(carboxymethyl)lysine(CML)is a representative foodborne toxic product,which can be ingested via daily diet.Therefore,there is a marked need to explore the effects of dietary CML on the myocardium.AIM To explore the effects of dietary CML(dCML)on the heart.METHODS C57 BL/6 mice were divided into a control group and a dCML group.The control group and the dCML group were respectively fed a normal diet or diet supplemented with CML for 20 wk.Body weight and blood glucose were recorded every 4 wk.^(18)F-fluorodeoxyglucose(FDG)was used to trace the glucose uptake in mouse myocardium,followed by visualizing with micro-positron emission tomography(PET).Myocardial remodeling and glucose metabolism were also detected.In vitro,H9C2 cardiomyocytes were added to exogenous CML and cultured for 24 h.The effects of exogenous CML on glucose metabolism,collagen I expression,hypertrophy,and apoptosis of cardiomyocytes were analyzed.RESULTS Our results suggest that the levels of fasting blood glucose,fasting insulin,and serum CML were significantly increased after 20 wk of dCML.Micro-PET showed that ^(18)F-FDG accumulated more in the myocardium of the dCML group than in the control group.Histological staining revealed that dCML could lead to myocardial fibrosis and hypertrophy.The indexes of myocardial fibrosis,apoptosis,and hypertrophy were also increased in the dCML group,whereas the activities of glucose metabolism-related pathways and citrate synthase(CS)were significantly inhibited.In cardiomyocytes,collagen I expression and cellular size were significantly increased after the addition of exogenous CML.CML significantly promoted cellular hypertrophy and apoptosis,while pathways involved in glucose metabolism and level of Cs mRNA were significantly inhibited.CONCLUSION This study reveals that dCML alters myocardial glucose metabolism and promotes myocardial remodeling.

Progress of ubiquitin-proteasome system in the pathophysiology of heart failure and the intervention of traditional Chinese medicine

Heart failure(HF)represents one of the leading causes of morbidity and mortality in the modern world,which threatened approximately 1%~2%of adults’lives.HF is the end stage of multiple cardiovascular diseases characterized by cardiac hypertrophy and myocardial remodeling,and the pathophysiological processes of which include oxidative stress,endoplasmic reticulum homeostasis,apoptosis,autophagy,energy metabolism disorder,etc.The regulation of protein homeostasis intrinsically interrelates the above pathophysiological processes.Therefore,it is imperative to elucidate the molecular mechanism from the perspective of protein homeostasis to find new therapeutic targets for HF treatment.The dynamic regulation and post-translational modification of protein synthesis and degradation play a vital role in response of living organisms to physiological changes.The ubiquitin-proteasome system(UPS),which degrades 70-90%of endogenous proteins,plays an integral part in the pathophysiological processes of HF.The UPS can regulate oxidative stress,endoplasmic reticulum homeostasis,apoptosis and autophagy of cardiomyocytes(CMs),energy metabolism,targeting degradation signals and structural proteins,thus modulating cardiac hypertrophy,fibrosis and remodeling,finally contributing to the occurrence and progression of HF.Thus,regulating UPS is a promising effective strategy to treat HF.Increasing evidence indicates that traditional Chinese medicine(TCM)targeting the UPS is potential to ameliorate HF.This review will summarize the current knowledge focusing on the underlying mechanism and the important research advances related to UPS in treating HF,and the traditional Chinese medicine targeting UPS.

Effect of Huanglian Jiedu Decoction on cardiac endoplasmic reticulum stress in spontaneously hypertensive rats

Huanglian Jiedu Decoction(HLJDD)is a quintessential prescription renowned for its heat-clearing and detoxifying properties.It is primarily prescribed to counteract the syndrome characterized by the excessive heat of the Sanjiao fire.Notably,the hyperactivity of liver fire is frequently linked with hypertension,where wind fire and wind toxicity emerge as pivotal pathogenic factors.This study aimed to investigate the impact of HLJDD on the endoplasmic reticulum in spontaneously hypertensive rats(SHR),further delving into the interplay between endoplasmic reticulum stress(ERS)and myocardial remodeling and damage.Fifty SHR rats were stratified randomly into five cohorts:model,low-dose HLJDD,medium-dose HLJDD,high-dose HLJDD,and captopril groups.For comparison,a set of Wistar-Kyoto(WKY)rats served as the baseline control group,with each group comprising 10 rats.While the model and control groups received equivalent volumes of normal saline via gavage,the other groups were administered the respective drug dosages through the same route daily for a span of 6 weeks.Upon the experiment’s conclusion,metrics such as the heart mass index(HWI)and left ventricular mass index(LVWI)were assessed.Cardiac tissue anomalies were identified using H&E staining,while ERS-related protein and mRNA expression levels were ascertained via Western blotting analysis and qPCR.Moreover,TUNEL staining was employed to detect cardiomyocyte apoptosis.The findings indicated that increasing HLJDD concentrations corresponded with escalated HWI and LVWI in rat hearts(P<0.05).There was a marked enhancement in myocardial structural integrity,accompanied by a notable reduction in collagen fibers.The mRNA and protein expressions of myocardial inositol-dependent enzyme 1α(IRE1α),X-box binding protein 1(XBP1),glycoregulatory protein 78(GRP78),and CCAAT enhancer binding protein homologous protein(CHOP)in the medium and high-dose groups saw significant declines(P<0.05).These effects mirrored those observed in the captopril group.The study underscored HLJDD’s efficacy in mitigating myocardial tissue damage in SHR.This therapeutic effect was potentially attributed to the downregulation of IRE1α,XBP1,GRP78,and CHOP,curbing excessive ERS,diminishing cardiomyocyte apoptosis,and thereby conferring cardioprotection.

The beta-adrenergic blocker carvedilol restores L-type calcium current in a myocardial infarction model of rabbit

Background Carvedilol, an antagonist of α1- and β-adrenergic receptors, has shown efficacy in reducing all-cause death and arrhythmia death for ischemic heart disease and congestive heart failure in several large-scale trials. It has been found to prevent ventricular remodeling, and recently was reported to reverse down-regulation of Na^+ channel in a chronic heart failure model. This study was conducted to investigate whether carvedilol could reverse the ion remodeling in a myocardial infarction model of rabbit.Methods After the procedure of coronary ligation, animals were randomized to placebo or carvedilol treatment (5 mg/kg). Action potentials, L-type calcium current (I_(ca L)) and the effect of isoproterenol stimulation on I_(ca L) were measured using whole-cell patch method. Evaluation of the expression of calcium channel subunits was carried out by RT-PCR and Western blot. Results The results indicate that mean peak I_(ca L) densities (pA/pF) at +10 mV was reduced in postinfarction myocytes (5.33±0.45, n=25) compared to sham myocytes (6.52±0.21, n=20). Treatment of myocardial infarction rabbits with carvedilol could restore it partially (5.91±0.39, n=20, P<0.05). However, steady-state activation parameters were similar in three groups. With stimulation by isoproterenol (1 μmol/L) I_(ca L) increased in all three groups, but the increase was smaller in postinfarction myocytes. mRNA levels of calcium channel subunit CaA1 gene was decreased but CaB2a, CaB2b and CaB3 mRNA levels did not change after MI. Corresponding change in CaA1 protein was also observed. Conclusions The results demonstrate that carvedilol restores I_(ca L) density and reverse the downregulation of CaA1 postinfarction.

Subcutaneous administration of granulocyte colony stimulating factor and stem cell factor ameliorates the outcome of acute myocardial infarction

Orlic et al treated mice （splenectomized two weeks ago） with granulocyte colony stimulating factor （G-CSF） and stem cell factor （SCF） for five days before acute myocardium infarction （AMI） and three days after AMI. They found that those treatments could repair infarcted hearts, improve heart performance and decrease mortality. However, from the clinical standpoint, the work of Orlic and his co-workers has an obvious limitation.

Serum profiles of circulating granulocyte-macrophage colony-stimulating factor in acute myocardial infarction and relation with post-infarction left ventricular function

Accumulating evidence indicates that inflammation plays an important role in cardiac repairing and remodeling after acute myocardial infarction （AMI）, process of which is mediated by a cytokine reaction cascade. 1 Granulocytemacrophage colony-stimulating factor （GM-CSF） is a cytokine, which belongs to the family of haemopoietic cell colony-stimulating factor and regulates the proliferation and differentiation of myeloid progenitor cells. In addition to its growthpromoting effects, this pro-inflammation cytokine stimulates the function of mature neutrophils, monocytes and eosinophils, including regulation of leukocyte adhesion, augmentation of surface antigen expression, superoxide anion generation, enhancement or induction of other cytokine production.

CHRONIC EFFECTS OF EARLY ANGIOTENSIN-CONVERTING ENZYME INHIBITOR (QUINAPRIL) OR ANGIOTENSIN II RECEPTOR BLOCKADE (LOSARTAN) ON HEMODYNAMICS AND REMODELING IN RATS AFTER EXPERIMENTAL MYOCARDIAL INFARCTION

The long-term effects of an angiotensin-converting enzyme (ACE) inhibitor on hemodynamics and remodeling

Effects of Qili Qiangxin capsule on lung structural remodeling in heart failure rats after myocardial infarction and its mechanism

Objective To observe the effect of Qili Qiangxin Capsule(QQC)in improving lung structural remodeling on heart failure(HF)rats after myocardial infarction(MI)and to study its possible mechanism.Methods The proximal left anterior descending branch of coronary artery was ligated using a terylene suture to establish