糖原合成酶激酶-3β和心肌肥厚的负性调控

心肌肥大和心力衰竭是大多数心血管疾病的严重和终末阶段,研究其信号转导机制具有重要意义。目前,治疗心肌肥厚的药物主要是以促肥厚的信号分子作为靶点,例如血管紧张素转化酶抑制剂、B肾上腺素阻断剂,能够减少肥厚反应,但不能完全逆转肥厚。因此,开发另一类作用机制完全不同但能有效阻断病理性心肌肥厚的药物就显得十分必要。日益增多的证据表明,探索心肌肥大的负性调控机制和研究心肌肥大的致病机制一样重要。     

microRNAs在心力衰竭分子通路中作用研究进展及中医药干预展望

心肌肥厚是心力衰竭的特征之一,具有高发病率、高致残率、高死亡风险。控制心脏生理功能的分子通路的显著变化是心肌肥厚和心衰进展的基础机制。microRNAs（miRs）作为能够调控基因表达的小核苷酸序列,可能在调控上述分子通路变化中发挥重要作用,这源于心肌肥厚心力衰竭时显示出高度特异性的miRs表达谱。并且,在心肌肥厚和心力衰竭动物模型实验研究中,以miRs为靶目标的实验性干预已经显示出了有益的效果。本文以分子通路为主总结miRs在心肌肥厚和心力衰竭中作用机制及并对中医药干预进行展望。     

血管紧张素转换酶抑制剂与心肌肥厚

心脏对不同类型的工作负荷过度增加的反应不同，因而所产生的病理性心肌肥厚的类型也不同，血管紧张素Ⅱ在压力和容量负荷性心肌肥厚的发生发展中起着重要的作用，然而血管紧张素转换酶抑制剂对二种病理性心肌肥厚的影响却不尽相同，ＡＣＥＩ对容量负荷性心肌肥厚的影响尤应引起重视。     

不同交感-儿茶酚胺系统激活模式在心脏重塑中的作用

目的交感神经的过度激活是导致心肌肥厚的重要因素，但它在生理性及病理性心肌重塑中所起的作用是否存在差异及其机制，目前尚不清楚。本研究旨在探讨不同的交感．儿茶酚胺系统激活模式在生理性和病理性心肌重塑中的作用及其可能的机制。方法分别采用大鼠游泳训练与去甲肾上腺素（norepinephrine，NE）微泵灌注模拟两种不同的儿茶酚胺分泌模式（间断型及持续型），制备心肌肥厚动物模型；利用超声心动图检测、免疫组化等手段观察心脏的功能及结构变化；采用Westernblot及生化方法检测能量代谢的关键激酶——腺苷酸．活化蛋白激酶（AMP-activated protein kinase，AMPK）α亚单位的活性。结果与对照组相比，游泳训练与NE灌注均可显著增加大鼠血浆中去甲肾上腺素的水平。但是，NE灌注组大鼠的心肌肥厚和组织纤维化程度均较游泳训练组明显增强，且伴有心功能的进行性下降，出现心力衰竭。NE灌注同时可诱导心肌组织AMPK活性显著增强。结论上述资料提示，不同的交感-儿茶酚胺激活模式可能是影响心肌重塑转归的一个重要因素，而AMPK可能参与调控病理性心脏重塑过程中能量代谢的适应性变化。     

蛋白泛素化修饰在心肌纤维化中的作用研究进展

正近年来,中国心血管病患病率持续上升,心血管疾病病死率居于首位。临床上,心血管疾病在中老年群体中十分常见。多种心血管疾病与心肌纤维化有关,缺血性心脏病和心内膜心肌纤维化是终末期心力衰竭的主要原因[1]。在心肌受损时,心肌再生能力十分有限,主要表现为心肌成纤维细胞转化为肌成纤维细胞表型并导致心脏纤维化。心肌纤维化是病理性细胞外基质重构的过程,其特征是胶原代谢紊乱,间质和血管周围胶原过度弥漫性沉积[2]。最初,细胞外基质沉积是一种适应性、保护性机制,但是过度和持续的细胞外基质沉积,最终会导致不可逆的病理变化,包括心室扩张、心肌细胞肥厚和凋亡,组织顺应性下降,最终加速心力衰竭进展[3]。因此,寻找心肌纤维化的关键靶点并阻止纤维化过程,对减缓心血管疾病的发生发展至关重要。     

雷米普利联合螺内酯对心血管胶原更新影响及机制探讨

减低心肌间质重构是控制高血压心血管并发症进展的关键。神经内分泌激素异常是启动和加剧重构的重要因素，除血管紧张素Ⅱ（AngⅡ）外，醛固酮主要通过促进冠状动脉小血管周膜和心肌间质纤维化，成为病理性心肌肥厚和心肌僵硬度增加的主要原因。本研究旨在了解高血压患平稳有效控制血压前提下抑制AngⅡ和醛固酮对心血管系统胶原更新的影响。     

线粒体功能障碍与心肌肥厚的病理发生机制

【摘要】心肌肥厚是心脏对本身超载做出的适应性反应，适度的肥厚能保持心脏功效，但持久的肥厚终究会致使心力衰竭，探究心肌肥厚的发病机制对防止恶化为心力衰竭有重要意义。线粒体是有氧呼吸的主要场所，不仅提供细胞生存所必需的能量，还介导细胞分化、信息传递和细胞凋亡等，线粒体出现任何改变都会影响细胞的存活。由于心肌细胞线粒体密度高，且心肌收缩完全依赖于线粒体氧化磷酸化产生的ATP，因此心脏组织的病理改变往往与线粒体代谢及功能密切相关。越来越多的研究证明线粒体形态和功能异常是心肌肥厚发生发展的重要机制，本文就线粒体功能障碍作为心肌肥厚的发病机制作一论述。     

microRNAs在心肌肥厚中的作用

生理或病理性刺激会导致心肌肥厚性生长,表现为心肌细胞增大,蛋白合成增加及胎儿基因的再表达。在心脏中有很多信号分子影响着基因表达、细胞凋亡、细胞因子释放等病理生理过程。利用心肌细胞肥厚模型已经发现病理性心肌肥厚可以被抑制或逆转,这些发现为寻找调控心肌肥厚的因子及信号通路提供了基础。该文着重讨论近年来发现的microRNAs(miRNAs)在调节心肌肥厚中的作用。     

Ca2+依赖性信号通路与心肌肥大研究的进展

心肌肥厚是心脏对强体力活动的生理性反应．而在许多心血管疾病．它又是共有的病理生理过程．也是心力衰竭发生的结构基础。因此研究心肌肥厚具有重要的理论和临床意义。目前细胞内信号转导通路是生命科学研究的热点．仅就心肌肥大而言．已知心肌细胞内Ca^2 的变化是触发心肌肥大相关信号转导的始动因素。近年来有关心肌细胞内的Ca^2 依赖性信号通路调控心肌肥大机制的研究有明显进展．现综述如下。     

他汀类药物在心肌肥厚治疗中的作用

心肌肥厚是血压升高和后负荷增加最初的生理适应性反应,也是许多心血管疾病,如高血压、心肌梗死、心脏瓣膜病、心肌病等共同的病理生理过程。尽管通过药物干预可将血压控制于正常范围,但心肌肥厚仍将不可避免地逐渐进展至慢性心力衰竭。事实上心肌肥厚是心血管疾病的一个独立危险因素,成倍地增加心血管疾病的死亡率。对于心肌肥厚的治疗目前仍局限于扩张血管、降低心肌收缩力和降低后负荷等,很少直接针对心肌肥大的形成过程进行干预。羟甲基戊二酸甲酰辅酶A还原酶抑制剂[3 hydroxy 3 methylglutaryl CoA (HMGCoA)reductaseinhibitors],…     

A comparative serial echocardiographic analysis of cardiac structure and function in rats subjected to pressure or volume overload

Heart failure is a leading cause of death that is reaching epidemic proportions. It is a clinical syndrome attributable to a multitude of factors that begins with a compensatory response known as hypertrophy, followed by a decompensatory response that eventually results in failure. Heart failure can be triggered when the heart is subjected to extended periods of pathological pressure overload (PO) or volume overload (VO). To date there have been no comparative serial echocardiographic studies outlining the progression of hypertrophy in PO versus VO rats. We hypothesized that PO or VO would induce differential cardiac remodeling leading to contractile dysfunction with subsequent heart failure. To address this hypothesis we used echocardiography to study the serial progression of heart structure and function in rat models of both PO- and VO-induced hypertrophy. PO or VO were induced by performing abdominal aortic banding or aortocaval shunt procedures, respectively, while cardiac structure and function were assessed in both models by M-mode and Doppler echocardiography at key time intervals. PO rats showed progressive wall thickening consistent with concentric hypertrophy, while VO rats showed marked left ventricular dilatation consistent with eccentric hypertrophy. Systolic dysfunction occurred early in VO compared to PO. Diastolic dysfunction was evident in PO, while VO showed signs of enhanced diastolic function. PO and VO induced differential changes in cardiac structure and function during the progression of compensated hypertrophy to decompensated heart failure.     

Bone morphogenetic protein-4: a novel therapeutic target for pathological cardiac hypertrophy/heart failure

Bone morphogenetic protein-4 (BMP4) is a member of the bone morphogenetic protein family which plays a key role in the bone formation and embryonic development. In addition to these predominate and well-studied effects, the growing evidences highlight BMP4 as an important factor in cardiovascular diseases, such as hypertension, pulmonary hypertension and valve disease. Our recent works demonstrated that BMP4 mediated cardiac hypertrophy, apoptosis, fibrosis and ion channel remodeling in pathological cardiac hypertrophy. In this review, we discussed the role of BMP4 in pathological cardiac hypertrophy, as well as the recent advances about BMP4 in cardiovascular diseases closely related to pathological cardiac hypertrophy/heart failure. We put forward that BMP4 is a novel therapeutic target for pathological cardiac hypertrophy/heart failure.     

Noncoding RNAs in Cardiac Hypertrophy

Cardiac hypertrophy is classified as pathological and physiological hypertrophy. Pathological hypertrophy typically precedes the onset of heart failure, one of the largest contributors to disease burden and deaths worldwide. In contrast, physiological hypertrophy is an adaptive response and protects against adverse cardiac remodeling. Noncoding RNAs (ncRNAs) have drawn significant attention over the last couple of decades, and their dysregulation is increasingly being linked to cardiac hypertrophy and cardiovascular diseases. In this review, we will summarize the profiling, function, and molecular mechanism of microRNAs, long noncoding RNAs, and circular RNAs in pathological cardiac hypertrophy. Additionally, we also review microRNAs responsible for physiological hypertrophy. With better understanding of ncRNAs in cardiac hypertrophy, manipulation of the important ncRNAs will offer exciting avenues for the prevention and therapy of heart failure.     

The C-terminus of the long AKAP13 isoform (AKAP-Lbc) is critical for development of compensatory cardiac hypertrophy

The objective of this study was to determine the role of A-Kinase Anchoring Protein (AKAP)-Lbc in the development of heart failure, by investigating AKAP-Lbc-protein kinase D1 (PKD1) signaling in vivo in cardiac hypertrophy.Using a gene-trap mouse expressing a truncated version of AKAP-Lbc (due to disruption of the endogenous AKAP-Lbc gene), that abolishes PKD1 interaction with AKAP-Lbc (AKAP-Lbc-ΔPKD), we studied two mouse models of pathological hypertrophy: i) angiotensin (AT-II) and phenylephrine (PE) infusion and ii) transverse aortic constriction (TAC)-induced pressure overload.Our results indicate that AKAP-Lbc-ΔPKD mice exhibit an accelerated progression to cardiac dysfunction in response to AT-II/PE treatment and TAC. AKAP-Lbc-ΔPKD mice display attenuated compensatory cardiac hypertrophy, increased collagen deposition and apoptosis, compared to wild-type (WT) control littermates. Mechanistically, reduced levels of PKD1 activation are observed in AKAP-Lbc-ΔPKD mice compared to WT mice, resulting in diminished phosphorylation of histone deacetylase 5 (HDAC5) and decreased hypertrophic gene expression. This is consistent with a reduced compensatory hypertrophy phenotype leading to progression of heart failure in AKAP-Lbc-ΔPKD mice. Overall, our data demonstrates a critical in vivo role for AKAP-Lbc-PKD1 signaling in the development of compensatory hypertrophy to enhance cardiac performance in response to TAC-induced pressure overload and neurohumoral stimulation by AT-II/PE treatment.     

Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy

Physical activity protects against cardiovascular disease, and physiological cardiac hypertrophy associated with regular exercise is usually beneficial, in marked contrast to pathological hypertrophy associated with disease. The p110alpha isoform of phosphoinositide 3-kinase (PI3K) plays a critical role in the induction of exercise-induced hypertrophy. Whether it or other genes activated in the athlete's heart might have an impact on cardiac function and survival in a setting of heart failure is unknown. To examine whether progressive exercise training and PI3K(p110alpha) activity affect survival and/or cardiac function in two models of heart disease, we subjected a transgenic mouse model of dilated cardiomyopathy (DCM) to swim training, genetically crossed cardiac-specific transgenic mice with increased or decreased PI3K(p110alpha) activity to the DCM model, and subjected PI3K(p110alpha) transgenics to acute pressure overload (ascending aortic constriction). Life-span, cardiac function, and molecular markers of pathological hypertrophy were examined. Exercise training and increased cardiac PI3K(p110alpha) activity prolonged survival in the DCM model by 15-20%. In contrast, reduced PI3K(p110alpha) activity drastically shortened lifespan by approximately 50%. Increased PI3K(p110alpha) activity had a favorable effect on cardiac function and fibrosis in the pressure-overload model and attenuated pathological growth. PI3K(p110alpha) signaling negatively regulated G protein-coupled receptor stimulated extracellular responsive kinase and Akt (via PI3K, p110gamma) activation in isolated cardiomyocytes. These findings suggest that exercise and enhanced PI3K(p110alpha) activity delay or prevent progression of heart disease, and that supraphysiologic activity can be beneficial. Identification of genes important for hypertrophy in the athlete's heart could offer new strategies for treating heart failure.     

Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy

An unresolved question in cardiac biology is whether distinct signaling pathways are responsible for the development of pathological and physiological cardiac hypertrophy in the adult. Physiological hypertrophy is characterized by a normal organization of cardiac structure and normal or enhanced cardiac function, whereas pathological hypertrophy is associated with an altered pattern of cardiac gene expression, fibrosis, cardiac dysfunction, and increased morbidity and mortality. The elucidation of signaling cascades that play distinct roles in these two forms of hypertrophy will be critical for the development of more effective strategies to treat heart failure. We examined the role of the p110alpha isoform of phosphoinositide 3-kinase (PI3K) for the induction of pathological hypertrophy (pressure overload-induced) and physiological hypertrophy (exercise-induced) by using transgenic mice expressing a dominant negative (dn) PI3K(p110alpha) mutant specifically in the heart. dnPI3K transgenic mice displayed significant hypertrophy in response to pressure overload but not exercise training. dnPI3K transgenic mice also showed significant dilation and cardiac dysfunction in response to pressure overload. Thus, PI3K(p110alpha) appears to play a critical role for the induction of physiological cardiac growth but not pathological growth. PI3K(p110alpha) also appears essential for maintaining contractile function in response to pathological stimuli.     

MEF2 in cardiac hypertrophy in response to hypertension

Hypertension is a globally prevalent pathological condition and an underlying risk factor for the development of cardiac hypertrophy leading to heart failure. Myocyte enhancer factor 2 (Mef2) has been identified as one of the primary effectors of morphological changes in the hypertensive heart, as part of a complex network of molecular signaling controlling cardiac gene expression. Experimental chronic pressure-overload models that mimic hypertension in the mammalian heart lead to the activation of various pathological mechanisms that result in structural changes leading to debilitating cardiac hypertrophy and ultimately heart failure. The purpose here is to survey the literature implicating Mef2 in hypertension induced cardiac hypertrophy, towards illuminating points of interest for understanding and potentially treating heart failure.     

Derepression of pathological cardiac genes by members of the CaM kinase superfamily

In response to pathologic stresses such as hypertension or myocardial infarction, the heart undergoes a remodeling process that is characterized by myocyte hypertrophy, myocyte death and fibrosis, resulting in impaired cardiac function and heart failure. Cardiac remodeling is associated with derepression of genes that contribute to disease progression. This review focuses on evidence linking members of the Ca(2+)/calmodulin-dependent protein kinase (CaMK) superfamily, specifically CaMKII, protein kinase D (PKD) and microtubule associated kinase (MARK), to stress-induced derepression of pathological cardiac gene expression through their effects on class IIa histone deacetylases (HDACs).     

Small changes can make a big difference - microRNA regulation of cardiac hypertrophy

Cardiac hypertrophy is a thickening of the heart muscle that results in enlargement of the ventricles, which is the primary response of the myocardium to stress or mechanical overload. Cardiac pathological and physiological hemodynamic overload causes enhanced protein synthesis, sarcomeric reorganization and density, and increased cardiomyocyte size, all culminating into structural remodeling of the heart. With clinical evidence demonstrating that sustained hypertrophy is a key risk factor in heart failure development, much effort is centered on the identification of signals and pathways leading to pathological hypertrophy for future rational drug design in heart failure therapy. A wide variety of studies indicate that individual microRNAs exhibit altered expression profiles under experimental and clinical conditions of cardiac hypertrophy and heart failure. Here we review the recent literature, illustrating how single microRNAs regulate cardiac hypertrophy by classifying them by their prohypertrophic or antihypertrophic properties and their specific effects on intracellular signaling cascades, ubiquitination processes, sarcomere composition and by promoting inter-cellular communication.     

Melatonin differentially regulates pathological and physiological cardiac hypertrophy: Crucial role of circadian nuclear receptor RORα signaling

Exercise‐induced physiological hypertrophy provides protection against cardiovascular disease, whereas disease‐induced pathological hypertrophy leads to heart failure. Emerging evidence suggests pleiotropic roles of melatonin in cardiac disease; however, the effects of melatonin on physiological vs pathological cardiac hypertrophy remain unknown. Using swimming‐induced physiological hypertrophy and pressure overload‐induced pathological hypertrophy models, we found that melatonin treatment significantly improved pathological hypertrophic responses accompanied by alleviated oxidative stress in myocardium but did not affect physiological cardiac hypertrophy and oxidative stress levels. As an important mediator of melatonin, the retinoid‐related orphan nuclear receptor‐α (RORα) was significantly decreased in human and murine pathological hypertrophic cardiomyocytes, but not in swimming‐induced physiological hypertrophic murine hearts. In vivo and in vitro loss‐of‐function experiments indicated that RORα deficiency significantly aggravated pathological cardiac hypertrophy, and notably weakened the anti‐hypertrophic effects of melatonin. Mechanistically, RORα mediated the cardioprotection of melatonin in pathological hypertrophy mainly by transactivation of manganese‐dependent superoxide dismutase (MnSOD) via binding to the RORα response element located in the promoter region of the MnSOD gene. Furthermore, MnSOD overexpression reversed the pro‐hypertrophic effects of RORα deficiency, while MnSOD silencing abolished the anti‐hypertrophic effects of RORα overexpression in pathological cardiac hypertrophy. Collectively, our findings provide the first evidence that melatonin exerts an anti‐hypertrophic effect on pathological but not physiological cardiac hypertrophy via alleviating oxidative stress through transactivation of the antioxidant enzyme MnSOD in a RORα‐dependent manner.