microRNA-26a与肿瘤

microRNA( miRNA)是一类长度为18 ～ 25个核苷酸(nt)的非编码小RNA,通过与靶mRNA的互补配对在转录后水平调控基因表达,导致mRNA的降解或翻译抑制,控制哺乳类动物约30％的蛋白质编码基因活性[1-2].miRNA与其靶mRNA分子组成了一个复杂的调控网络,参与包括细胞增殖、分化、凋亡、发育等多种生物学过程.     

microRNA与心血管疾病

microRNA(miRNA)是一类广泛存在于真核生物长度为21～25nt的非蛋白质编码单链RNA,通过与靶基因mRNA分子的3’端非编码区域(3’UTR)互补配对后降低mRNA分子稳定性和翻译抑制两种方式参与靶基因表达调控,在发育、凋亡、代谢以及人类疾病方面都起着不容忽视的作用。新近研究表明,miRNA在心血管疾病中发挥重要的作用,而维持和恢复心脏等靶器官中相应miRNA的稳定表达可能成为心血管等疾病治疗的一个新靶点。深入研究microRNA可能为心血管疾病的诊断和治疗带来全新的方法。     

miRNA与心房颤动关系的最新进展

微小核糖核酸(miRNA)是一类内生的长度为19～24个核苷酸的单链非编码RNA。它通过调节靶目标信使核糖核酸(mRNA)的降解和翻译，指导RNA诱导沉默复合体调节靶基因表达，在细胞生理过程中发挥重要作用，是转录后水平调控基因表达的重要分子。目前miRNA与心血管疾病之间的关系在国内外也成为研究的热点，现选取相关miRNA与心血管疾病中心房颤动的电重构与结构重构之间的关系做一综述。     

微小核糖核酸在胃癌中的研究进展

微小核糖核酸(miRNA)是一类保守、短序列、非编码的单链RNA.miRNA在转录后水平负调控mRNA表达,通过调节多种信号分子调控多种生物学过程,例如应激、凋亡,增殖、代谢,个体发育和细胞分化等.近年来提出了原癌miRNA组学这一概念~([1]),成为了关注热点.     

microRNA 222在心血管疾病中的研究进展

microRNA(miRNA)是一类内源性、非编码小RNA分子,可通过特异性作用降解mRNA或在转录后水平通过抑制翻译、诱导降解等方式负性调节相应靶基因表达,在物质代谢、细胞生长、发育等过程中均具有重要调控作用。microRNA 222(miR-222)作为microRNAs家族中重要一员,在细胞增殖、分化、凋亡及多种生物组织的发育调节过程中发挥重要作用。近期研究发现miR-222能介导多种生理病理过程,显著影响心血管疾病的发生发展,在炎症反应、细胞凋亡等过程中发挥重要作用。本文就miR-222与心血管疾病的关系进行综述。     

microRNA在肝纤维化进程中的作用

微小RNA（microRNA,miRNA）是一类长约21～22nt的内源性非编码调控RNA,可作用于靶mRNA导致其降解或抑制其翻译,对基因表达起重要的负性调控作用,参与体内如发育、细胞分化、细胞增殖、细胞死亡等众多重要的生物学进程。近年研究发现,miRNA这一转录后水平调控分子在肝纤维化发生发展中起着重要的作用。已发现若干miRNA可调控参与肝纤维化形成的细胞因子或通过调控肝星状细胞（HSC）的活化增殖、凋亡等,促进或减缓纤维化进程,本文对miRNA在HSC及肝纤维化进程中的研究进展作一综述。     

miRNA与急性心肌梗死

心肌梗死(MI)是心血管疾病导致死亡的最主要原因之一。miRNA是一类非编码小分子RNA。研究证实,MI后miRNA表达异常,通过转录后水平参与MI及其并发症的病理生理过程,有望成为急性心肌梗死(AMI)新的生化标志物和治疗靶点。     

强心合剂对慢性心力衰竭大鼠心肌细胞凋亡的影响

目的：阐述强心合剂治疗充血性心力衰竭大鼠可能的作用机制。方法：建立腹主动脉缩窄所致后负荷过重的模型。实验疗程结束后，分别用TUNEL法检测心肌细胞凋亡指数。RT—PCR法检测心肌细胞凋亡基因Bcl-2和Bax mRNA的表达，同时测量CHF大鼠左室重量指数(LVMI)，并分别以地高辛、卡托普利作为对照组进行比较。结果：强心合剂可降低左室重量指数(LVMI)。能调控心肌细胞凋亡基因Bcl-2和Bax mRNA表达，即促进Bcl-2mRNA表达，抑制Bax mRNA表达，明显抑制心肌细胞凋亡(心肌细胞凋亡指数显著下降)。其疗效与卡托普利组相当，且与地高辛对照组比较无统计学意义。结论：强心合剂可能通过调控凋亡基因而抑制心肌细胞凋亡，从而延缓或部分逆转心脏重构的发生、发展。     

MicroRNA在心血管系统发育和疾病中作用的研究进展

微小RNA(miRNA)是一类非编码RNA家族成员,常通过负向调节转录后影响基因表达,调节多重信号通路和细胞发育过程。在心血管系统中,miRNA通过调控心肌细胞、内皮细胞、平滑肌细胞和成纤维细胞等参与心血管发育过程,同样miRNA在高血压、心肌梗死、心肌肥厚、心力衰竭、心律失常、动脉粥样硬化等多种心血管疾病中亦发挥关键作用。现综述miRNA在心脏发育和心血管疾病病理生理学中的功能及作用机制。     

microRNAs在心肌梗死中的研究进展

microRNAs(miRNAs)是一种非编码小分子RNA,通过降解mRNA或阻碍其翻译调控基因的表达。心肌梗死是一种常见的心血管疾病,导致心脏重构,最终发展为心力衰竭。miRNAs在心肌梗死的病理生理发展过程中起着重要作用,其可以促进或抑制心肌细胞凋亡,调控心肌细胞增,调节血管再生,此外还能调控心脏成纤维细胞重编程为心肌细胞。本文将综述miRNAs在心肌梗死中的最新进展和治疗前景。     

Non-cardiomyocyte microRNAs in heart failure

Multiple structural changes are known to occur in a failing heart. Myocyte hypertrophy, cardiomyocyte apoptosis, interstitial fibrosis, reduced capillary density, and activation of the immune system are all involved in the pathogenesis and progression of heart failure (HF). The molecular mechanisms underlying these changes of the myocardium have been extensively studied, and many pathways involved in these processes have been uncovered. Recently, it has become evident that a novel class of small non-coding RNAs, called miRNAs, also plays a key role in these structural changes of the heart. This review summarizes the current insights on the role of miRNAs outside myocytes in the heart. Specifically, we will discuss miRNA function in fibroblasts, endothelial cells and immune cells in response to myocardial stress as occurs after myocardial infarction and in the pathogenesis of HF.     

miRNome in myocardial infarction: Future directions and perspective

MicroRNAs(miRNAs), which are small and non-coding RNAs, are genome encoded from viruses to humans. They contribute to various developmental, physiological and pathological processes in living organisms. A huge amount of research results revealed that miRNAs regulate these processes also in the heart. miRNAs may have cell-type-specific or tissue-specific expression patterns or may be expressed ubiquitously. Primary studies of miRNA involvement in hypertrophy, heart failure and myocardial infarction analyzed miRNAs that are enriched in or specific for cardiomyocytes; however, growing evidence suggest that other miRNAs, not cardiac or muscle-specific, play a significant role in cardiovascular disease. Abnormal miRNA regulation has been shown to be involved in cardiac diseases, suggesting that miRNAs might affect cardiac structure and function. In this review, we focus on miRNAs that have been found to contribute to the pathogenesis of myocardial infarction(MI) and the response post-MI and characterized as diagnostic, prognostic and therapeutic targets. The majority of these studies were performed using mouse and rat models of MI, with a focus on the identification of basic cellular and molecular pathways involved in MI and in the response post-MI. Much research has also been performed on human and animal plasma samples from MI patients to identify miRNAs that are possible prognostic and/or diagnostic targets of MI and other MI-related diseases. A large proportion of research is focused on miRNAs as promising therapeutic targets and biomarkers of drug responses and/or stem cell treatment approaches. However, only a few studies have described miRNA expression in human heart tissue following MI.     

Oxidative stress and cardiac repair/remodeling following infarction

Extensive cardiac remodeling after myocardial infarction (MI) contributes significantly to ventricular dysfunction. Factors regulating left ventricular remodeling at different stages after MI are under investigation. There is growing recognition and experimental evidence that oxidative stress mediated by reactive oxygen species plays a role in the pathogeneses of myocardial repair/remodeling in various cardiac diseases. After acute MI, oxidative stress is developed in both infarcted and noninfarcted myocardium. Accumulating evidence has demonstrated that oxidative stress participates in several aspects of cardiac repair/remodeling after infarction that include cardiomyocyte apoptosis, inflammatory/fibrogenic responses, and hypertrophy. The exact pathways on reactive oxygen species-mediated myocardial remodeling are under investigation. The therapeutic potential of oxidative stress-directed drugs in myocardial remodeling after infarction has not been fully realized.     

Role of p38alpha MAPK in cardiac apoptosis and remodeling after myocardial infarction

Acute coronary occlusion results in ischemia-mediated death of cardiomyocytes. In the days and weeks following myocardial infarction (MI), left ventricular remodeling occurs that is characterized by persistent cardiomyocyte apoptosis, thinning and fibrosis at the site of infarction, ventricular chamber dilatation, and growth of remaining viable cardiomyocytes. The p38 mitogen-activated protein kinase (MAPK) signaling cascade has been implicated in the remodeling process. In this work, mice with cardiac-specific expression of a dominant negative mutant form of p38 MAPK (DN-p38alpha) were subjected to MI by occlusion of the left coronary artery. Acute ischemia area was determined by transthoracic echocardiography 2 h after MI surgery, and was found to be nearly identical in DN-p38 mice and their wild-type littermates. Seven days after MI, mice were subjected to repeat echocardiography and histological examination of infarct size. DN-p38 mice had markedly reduced infarct size and increased ventricular systolic function 7 days after MI when compared to wild-type littermates. In addition, DN-p38 mice had less cardiomyocyte apoptosis than wild-type mice in the infarct border zone. Recently, it was discovered that Bcl-X(L) deamidation occurs in vivo, and this results in Bcl-X(L) degradation that sensitizes cells to apoptosis by enhancing BAX activity. Bcl-X(L) deamidation was found to occur in the cardiac tissue of wild-type mice after MI, but was reduced in DN-p38 mice. These results establish that p38 MAPK activity is required for pathological remodeling after MI and suggest that p38 MAPK may promote cardiomyocyte apoptosis through Bcl-X(L) deamidation.     

Sustained cardiomyocyte apoptosis and left ventricular remodelling after myocardial infarction in experimental diabetes

Aims/hypothesis Diabetes is known to reduce survival after myocardial infarction. Our aim was to examine whether diabetes is associated with enhanced cardiomyocyte apoptosis and thus interferes with the post-infarction remodelling process in myocardium in rat.Methods Four weeks after intravenous streptozotocin (diabetic groups) or citrate buffer (controls) injection, myocardial infarction was produced by ligation of left descending coronary artery. Level of cardiomyocyte apoptosis was quantified by TUNEL and caspase-3 methods. Collagen volume fraction and connective tissue growth factor were determined under microscope. Left ventricular dimensions were evaluated by echocardiography and planimetry.Results The number of apoptotic cardiomyocytes was equally high in diabetic and non-diabetic rats after 1 week from infarction. At 12 weeks after infarction the number of apoptotic cells was higher in the diabetic as compared to non-diabetic rats both in the border zone of infarction and in non-infarcted area. Correspondingly, left ventricular end diastolic diameter, relative cardiac weight, connective tissue growth factor-expression and fibrosis were increased in diabetic compared with non-diabetic rats with myocardial infarction.Conclusion/interpretation Sustained cardiomyocyte apoptosis, left ventricular enlargement, increased cardiac fibrosis and enhanced profibrogenic connective tissue growth factor expression were detected after myocardial infarction in experimental diabetes. Apoptotic myocyte loss could be an important mechanism contributing to progressive dilatation of the heart and poor prognosis after myocardial infarction in diabetes.Abbreviations STZ streptozotozin - MI myocardial infarction - CTGF connective tissue growth factor - LV left ventricular - LVEDD LV end-diastolic diameter - BNP B-type natriuretic peptide     

17beta-estradiol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of phospho-inositide-3 kinase/Akt signaling

Female gender and estrogen-replacement therapy in postmenopausal women are associated with improved heart failure survival, and physiological replacement of 17beta-estradiol (E2) reduces infarct size and cardiomyocyte apoptosis in animal models of myocardial infarction (MI). Here, we characterize the molecular mechanisms of E2 effects on cardiomyocyte survival in vivo and in vitro. Ovariectomized female mice were treated with placebo or physiological E2 replacement, followed by coronary artery ligation (placebo-MI or E2-MI) or sham operation (sham) and hearts were harvested 6, 24, and 72 hours later. After MI, E2 replacement significantly increased activation of the prosurvival kinase, Akt, and decreased cardiomyocyte apoptosis assessed by terminal deoxynucleotidyltransferase dUTP nick-end labeling (TUNEL) staining and caspase 3 activation. In vitro, E2 at 1 or 10 nmol/L caused a rapid 2.7-fold increase in Akt phosphorylation and a decrease in apoptosis as measured by TUNEL staining, caspase 3 activation, and DNA laddering in cultured neonatal rat cardiomyocytes. The E2-mediated reduction in apoptosis was reversed by an estrogen receptor (ER) antagonist, ICI 182,780, and by phospho-inositide-3 kinase inhibitors, LY294002 and Wortmannin. Overexpression of a dominant negative-Akt construct also blocked E2-mediated reduction in cardiomyocyte apoptosis. These data show that E2 reduces cardiomyocyte apoptosis in vivo and in vitro by ER- and phospho-inositide-3 kinase-Akt-dependent pathways and support the relevance of these pathways in the observed estrogen-mediated reduction in myocardial injury.     

Apoptosis after reperfused myocardial infarction: Role of angiotensin II

Angiotensin II (Ang II) plays a significant role in apoptosis after myocardial infarction (MI) and reperfused MI. Cumulative evidence suggests that Ang II is a major contributor to cardiomyocyte (CM) apoptosis and left ventricular (LV) dysfunction after acute reperfused MI and that apoptosis mediates a major portion of early LV dysfunction. Importantly, blockade of the Ang II type 1 receptor (AT₁R) limits CM apoptosis and LV dysfunction after acute reperfused MI. Ang II type 2 receptor activation during AT₁R blockade contributes to these beneficial effects. The role of Ang II and apoptosis in chronic LV remodelling, healing and post-MI heart failure is more complex and involves effects on the CMs, fibroblasts and vascular cells. The long-term effects of agents targeting apoptosis after reperfused MI, including AT₁R blockade, on apoptosis in different cell types, windows of enhanced apoptosis and the appropriate timing of therapy need to be considered.     

Effect of vasopeptidase inhibitor omapatrilat on cardiomyocyte apoptosis and ventricular remodeling in rat myocardial infarction

We have shown earlier that cardiomyocyte apoptosis continues at a high level late after myocardial infarction and contributes to adverse cardiac remodeling. Here we studied whether this process can be inhibited by the vasopeptidase inhibitor omapatrilat, a drug which causes simultaneous inhibition of both angiotensin converting enzyme and neutral endopeptidase. Our hypothesis was that omapatrilat-treated rats would have less cardiomyocyte apoptosis, and less adverse cardiac remodeling compared to rats treated with selective inhibitors of angiotensin converting enzyme, neutral endopeptidase or placebo. Myocardial infarction was produced by ligation of the left anterior descending coronary artery. Rats were randomized to receive omapatrilat, captopril, neutral endopeptidase inhibitor SQ-28603 or vehicle. Rats treated with omapatrilat and captopril had reduced cardiac BNP mRNA levels and less myocardial fibrosis by comparison with the vehicle-treated rats. However, omapatrilat was more effective than captopril in attenuating hypertrophy as measured by relative cardiac weight (3.0+/-0.2 vs. 3.8+/-0.2 mg/g, P<0.01) or by echocardiographically determined left ventricular mass (0.61+/-0.05 vs. 0.83+/-0.06 g, P<0.01). Myocardial apoptosis was elevated both in the infarction border zone (0.129+/-0.017%) and in the remote area (0.035+/-0.005%) still 4 weeks after myocardial infarction. Angiotensin converting enzyme inhibition proved to be important in the prevention of apoptosis since both omapatrilat and captopril reduced the number of apoptotic myocytes whereas selective neutral endopeptidase inhibitor SQ-28603 had no effect. In conclusion, myocardial apoptosis, remaining increased 4 weeks after myocardial infarction, was reduced by angiotensin converting enzyme inhibition. Vasopeptidase inhibition was more effective than selective angiotensin converting enzyme inhibition in preventing adverse cardiac remodeling after myocardial infarction.     

Melatonin alleviates postinfarction cardiac remodeling and dysfunction by inhibiting Mst1

Melatonin reportedly protects against several cardiovascular diseases including ischemia/reperfusion (I/R), atherosclerosis, and hypertension. The present study investigated the effects and mechanisms of melatonin on cardiomyocyte autophagy, apoptosis, and mitochondrial injury in the context of myocardial infarction (MI). We demonstrated that melatonin significantly alleviated cardiac dysfunction after MI. Four weeks after MI, echocardiography and Masson staining indicated that melatonin notably mitigated adverse left ventricle remodeling. The mechanism may be associated with increased autophagy, reduced apoptosis, and alleviated mitochondrial dysfunction. Furthermore, melatonin significantly inhibited Mst1 phosphorylation while promoting Sirt1 expression after MI, which indicates that Mst1/Sirt1 signaling may serve as the downstream target of melatonin. We thus constructed a MI model using Mst1 transgenic (Mst1 Tg) and Mst1 knockout (Mst1^−/−) mice. The absence of Mst1 abolished the favorable effects of melatonin on cardiac injury after MI. Consistently, melatonin administration did not further increase autophagy, decrease apoptosis, or alleviate mitochondrial integrity and biogenesis in Mst1 knockout mice subjected to MI injury. These results suggest that melatonin alleviates postinfarction cardiac remodeling and dysfunction by upregulating autophagy, decreasing apoptosis, and modulating mitochondrial integrity and biogenesis. The attributed mechanism involved, at least in part, Mst1/Sirt1 signaling.