基质金属蛋白酶及其抑制因子与心肌纤维化

细胞外基质是构成心脏间质的主要成份。在各种致病因素作用下，细胞外基质沉积的异常增加导致了心肌纤维化的发生。基质金属蛋白酶及其抑制因子的相互作用在这一过程中起着关键作用。本文就基质金属蛋白酶及其抑制因子在心肌纤维化中的作用进行综述。     

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。     

瞬时受体电位通道在心脏纤维化中作用的研究进展

心脏纤维化参与多种心脏疾病的发生发展,可导致心脏重塑和功能障碍,最终引起心力衰竭甚至死亡。心脏成纤维细胞异常增殖并分化为心脏肌成纤维细胞以及心脏细胞外基质过度沉积等是心脏纤维化的主要病理基础。瞬时受体电位(TRP)通道是一种非选择性的阳离子通道,主要介导Ca2+内流来调节细胞功能。越来越多的研究表明,在心肌中TRP通道除调控多种生理功能外,同时参与心脏纤维化的发生发展。本文主要对心脏纤维化的发生机制及TRP通道作为治疗心脏纤维化的新靶点进行综述。     

瞬时受体电位通道在心肌纤维化中的作用

随着人类生活方式的改变和整体寿命的延长,老年性疾病逐渐成为医疗难题,心肌纤维化作为心脏疾病的终末阶段可严重影响预后.心肌纤维化与心肌成纤维细胞过度增殖和心肌间质内细胞外基质(ECM)蛋白沉积有关[1].研究表明,心房纤维化与心房颤动(房颤)的持续性密切相关[2].近年来,人们逐渐认识到瞬时受体电位(TRP)通道在调节钙...     

肾素-血管紧张素-醛固酮系统与心肌间质纤维化

心肌间质纤维化发生于多种心血管疾病,引起心脏舒张功能减退,导致泵功能衰竭。目前,肾素-血管紧张素一醛固酮系统（RAAS）与心肌纤维化的关系已得到深入研究,本文拟在这方面作简要阐述。1心肌组织的正常结构与心肌间质纤维化心肌组织由细胞和间质构成。心脏中心肌细胞数不足心脏细胞总数的1／3,大多数细胞是间质细胞,主要是成纤维细胞,它能够合成胶原,可以重新进入细胞周期,进行有丝分裂⑴。细胞外间质决定着心脏的结构和功能,其主要的结构蛋白为Ⅰ型和Ⅲ型胶原,由纤维连接素将它们锚定于心肌细胞和成纤维细胞膜上。Ⅰ型胶原构…     

心肌成纤维细胞在血管紧张素II致心脏间质纤维化中的作用

在心脏纤维化过程中 ,心肌成纤维细胞扮演着重要角色。血管紧张素 可增加心肌成纤维细胞合成 ,分泌整合素、骨桥素等粘附分子 ,从而诱导细胞外基质蛋白合成 ,促进间质纤维化     

基质金属蛋白酶与心肌间质重构

在心力衰竭的进展过程中，心室重构起主要作用。心室重构包括心肌实质重构和心肌间质重构，心肌间质重构是指成纤维细胞增生、纤维化以及细胞外基质胶原网的量和组成的变化。基质金属蛋白酶（MMPs）是一种能特异地降解细胞外基质成分的Zn^2 依赖的酶家族，心肌中的MMPs能够降解心脏中所有的基质成分，是心肌间质重构中基质降解的推动力量。MMPs的表达与活性受到肿瘤坏死因子-α、白介素－1β、血管紧张素Ⅱ、内皮素以及金属蛋白酶组织型抑制物等因子的调控。通过直接或间接的方法调节MMPs的活性，可以改变心肌间质重构过程，从而最终改变心力衰竭的进程。     

心肌成纤维细胞在血管紧张素Ⅱ致心脏间质纤维化中的作用

在心脏纤维化过程中，心肌成纤维细胞扮演着重要角色。血管紧张素Ⅱ可增加心肌成纤维细胞合成，分泌整合素、骨桥素等粘附分子，从而诱导细胞外基质蛋白合成，促进间质纤维化。     

心肌成纤维细胞的特性和调节

心肌成纤维细胞在心脏中是数量最大的细胞,它们通过维持细胞外基质平衡在受损或衰竭心脏中纤维化心肌重塑发挥重要作用。它既调节正常的心脏功能,也参与高血压病、心肌梗死和心力衰竭等的不良心肌重塑。综述心肌成纤维细胞的特性,包括起源、机械电特性、细胞外基质代谢中的作用,以及正常和病理状态下心肌成纤维细胞对环境刺激的功能反应和分泌生物活性因子的能力,并总结以心肌成纤维细胞为靶细胞调节心肌纤维化的研究现状。     

心脏肌成纤维细胞活化的力学调控

在心肌修复或纤维化过程中,以成纤维细胞为主的多种前体细胞向心脏肌成纤维细胞(CMFs)活化,合成大量细胞外基质成分,并持续存在于心肌瘢痕中。CMFs活化除了受促纤维化因子的调控外,还受力学因素的影响。ECM刚度增加及循环应变的改变能促进CMFs活化推动心肌纤维化持续进展。通过调控CMFs对机械应力的敏感性来抑制CMFs活化的方法有可能成为心肌纤维化治疗的新选择。     

Crosstalk Between the Renin–Angiotensin System and the Advance Glycation End Product Axis in the Heart: Role of the Cardiac Fibroblast

Cardiac fibroblasts (CFs) are involved in maintaining extracellular matrix (ECM) homeostasis in the heart. CFs mediate responses to hormonal and mechanical stimuli and relay these to other local cell types through release of autocrine and/or paracrine factors. CFs also play important roles in the setting of injury, i.e., myocardial infarction, where ECM production is key to efficient scarring. However, conditions exist in which excess production of ECM by CFs can lead to cardiac fibrosis. Two important pathways known to be involved in development of cardiac fibrosis are renin?Cangiotensin system (RAS) and advanced glycation end products (AGE) receptor (RAGE) signaling cascades. This report summarizes actions of these two pathways on function of CFs. Because cardiac fibrosis is an important component of diabetic cardiomyopathy, we include new data that suggests a possible crosstalk between the RAS and AGE/RAGE pathway in order to activate CFs in diabetes.     

Cardiac extracellular matrix remodeling: Fibrillar collagens and Secreted Protein Acidic and Rich in Cysteine (SPARC)

The cardiac interstitium is a unique and adaptable extracellular matrix (ECM) that provides a milieu in which myocytes, fibroblasts, and endothelial cells communicate and function. The composition of the ECM in the heart includes structural proteins such as fibrillar collagens and matricellular proteins that modulate cell:ECM interaction. Secreted Protein Acidic and Rich in Cysteine (SPARC), a collagen-binding matricellular protein, serves a key role in collagen assembly into the ECM. Recent results demonstrated increased cardiac rupture, dysfunction and mortality in SPARC-null mice in response to myocardial infarction that was associated with a decreased capacity to generate organized, mature collagen fibers. In response to pressure overload induced-hypertrophy, the decrease in insoluble collagen incorporation in the left ventricle of SPARC-null hearts was coincident with diminished ventricular stiffness in comparison to WT mice with pressure overload. This review will focus on the role of SPARC in the regulation of interstitial collagen during cardiac remodeling following myocardial infarction and pressure overload with a discussion of potential cellular mechanisms that control SPARC-dependent collagen assembly in the heart.     

心肌纤维化的调控因素

心肌间质胶原网络在维持心肌正常结构和功能完整性方面起着重要的作用 ,胶原过多蓄积将引起心肌纤维化。心肌胶原代谢受多种因素调控 ,这些因素涉及肾素 血管紧张素 醛固酮系统、内皮素、儿茶酚胺、缓激肽、生长因子、一氧化氮、基质金属蛋白酶 金属蛋白酶组织抑制剂及细胞内钙等。     

The cell biology of the cardiac interstitium

The cardiac interstitium represents a system of diverse extracellular matrix (ECM) components organized into a complex, three-dimensional network that surrounds the cellular components of the heart (Borg and Caulfield 1981, Weber et al. 1994, Comper 1995). The interaction of the cellular components with the interstitium is dynamic and occurs in response to physiological signals during development, normal homeostasis, and disease (Borg and Caulfield 1981, Weber et al. 1994). Both the quantitative and qualitative expression of ECM components play an important role in cardiac function; however, the mechanisms that regulate the expression and function are not well understood. The manner in which the terminally differentiated myocyte perceives its external environment is of critical importance to the function of the heart. These external signals are delivered via the other two major components of the heart: the vascular system and the surrounding interstitium or ECM. Although it is obvious that the vascular system provides the transport of a variety of regulatory components that influence the contractile ability of the myocyte, the role of the interstitium in relation to cardiac function is less understood and is the focus of this review.     

心血管疾病的胶原重塑及其干预研究

心脏的细胞外间质主要由成纤维细胞合成、分泌的胶原蛋白组成。在多种心血管疾病的病理过程中,致病因子刺激成纤维细胞增生、合成和分泌大量胶原纤维,沉积于心肌间质,导致心脏胶原重塑,由此引起心脏结构、功能异常。抑制胶原重塑,可以改善心脏功能。因此,对心脏胶原代谢的干预为防治心血管疾病提供了广阔的前景。     

Why Clinicians Should Care About the Cardiac Interstitium

Interstitial heart disease, whether primarily from myocardial fibrosis or cardiac amyloidosis, indicates excess protein accumulation in the interstitium and constitutes a major source of heart failure with excess cardiac morbidity and mortality. Myocardial fibrosis (defined as excess myocardial collagen concentration that distorts myocardial architecture) is prevalent and causes cardiac symptoms and ultimately adverse cardiac events, such as heart failure, arrhythmia, and death. Conversely, cardiac amyloidosis is far less prevalent than myocardial fibrosis but represents a more extreme form of interstitial heart disease with marked interstitial expansion, profound architectural distortion, and then rapid clinical decline. Myocardial extracellular volume measures fundamentally advance the understanding of myocardium and specifically highlights the role of the interstitium. Rather than conceptualizing myocardium as a homogenous tissue, dichotomizing the myocardium into its interstitial (including the microvasculature) and cardiomyocyte phenotypes promotes additional understanding of heart failure pathophysiology that may spur the development of more effective therapies.     

Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial fibrillation

Cardiac fibroblasts account for about 75% of all cardiac cells, but because of their small size contribute only ～10-15% of total cardiac cell volume. They play a crucial role in cardiac pathophysiology. For a long time, it has been recognized that fibroblasts and related cell types are the principal sources of extracellular matrix (ECM) proteins, which organize cardiac cellular architecture. In disease states, fibroblast production of increased quantities of ECM proteins leads to tissue fibrosis, which can impair both mechanical and electrical function of the heart, contributing to heart failure and arrhythmogenesis. Atrial fibrosis is known to play a particularly important role in atrial fibrillation (AF). This review article focuses on recent advances in understanding the molecular electrophysiology of cardiac fibroblasts. Cardiac fibroblasts express a variety of ion channels, in particular voltage-gated K(+) channels and non-selective cation channels of the transient receptor potential (TRP) family. Both K(+) and TRP channels are important determinants of fibroblast function, with TRP channels acting as Ca(2+)-entry pathways that stimulate fibroblast differentiation into secretory myofibroblast phenotypes producing ECM proteins. Fibroblasts can couple to cardiomyocytes and substantially affect their cellular electrical properties, including conduction, resting potential, repolarization, and excitability. Co-cultured preparations of cardiomyocytes and fibroblasts generate arrhythmias by a variety of mechanisms, including spontaneous impulse formation and rotor-driven reentry. In addition, the excess ECM proteins produced by fibroblasts can interrupt cardiomyocyte-bundle continuity, leading to local conduction disturbances and reentrant arrhythmias. A better understanding of the electrical properties of fibroblasts should lead to an improved comprehension of AF pathophysiology and a variety of novel targets for antiarrhythmic intervention.     

Role of mechanical factors in modulating cardiac fibroblast function and extracellular matrix synthesis

The cardiac fibroblast is the most abundant cell type present in the myocardium and is mainly responsible for the deposition of extracellular matrix (ECM). Important components of cardiac ECM include structural and adhesive proteins such as collagen and fibronectin. Excess deposition of cardiac ECM (fibrosis) has been associated with the pathophysiological mechanical overload of the heart. Therefore, the role of cardiac fibroblasts in "sensing", "integrating" and "responding" to mechanical stimuli is of great interest. The development of in vitro strain apparatuses has allowed scientists to investigate the effects of mechanical stimuli on cardiac fibroblast function. Cardiac fibroblasts express ECM receptors (integrins) which couple mechanical stimuli to functional responses. Mechanical stimulation of cardiac fibroblasts has been shown to result in activation of various signal transduction pathways. The application of defined mechanical stimuli to cultured cardiac fibroblasts has been associated with ECM gene expression, growth factor production, release and/or bioactivity as well as collagenase activity. Ultimately, for fibrosis to develop the overproduction of ECM must overcome any associated increases in collagenase activity. Mechanically induced upregulation of ECM production may follow direct or indirect pathways through the autocrine or paracrine action of growth factors. Given the complex nature of the interstitial milieu of the working heart, additional research is needed to further our understanding of the roles that mechanical stimuli play in excess deposition of myocardial ECM.     

Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart

When considering the pathological steps in the progression from cardiac overload towards the full clinical syndrome of heart failure, it is becoming increasingly clear that the extracellular matrix (ECM) is an important determinant in this process. Chronic pressure overload induces a number of structural alterations, not only hypertrophy of cardiomyocytes but also an increase in ECM proteins in the interstitium and perivascular regions of the myocardium. When this culminates in excessive fibrosis, myocardial compliance decreases and electrical conduction is affected. Altogether, fibrosis is associated with an increased risk of ventricular dysfunction and arrhythmias. Consequently, anti-fibrotic strategies are increasingly recognized as a promising approach in the prevention and treatment of heart failure. Thus, dissecting the molecular mechanisms underlying the development of cardiac fibrosis is of great scientific and therapeutic interest. In this review, we provide an overview of the available evidence supporting the general idea that fibrosis plays a causal role in deteriorating cardiac function. Next, we will delineate the signalling pathways importantly governed by transforming growth factor β (TGFβ) in the control of cardiac fibrosis. Finally, we will discuss the recent discovery that miRNAs importantly regulate cardiac fibrosis.     

Angiotensin II and TGF-β in the Development of Cardiac Fibrosis, Myocyte Hypertrophy, and Heart Failure

An explanation of the molecular mechanisms that trigger the development of pathological cardiac fibrosis, myocyte hypertrophy, and heart failure associated with common ailments such as chronic postinfarction has been sought at the bench top and clinic for the past 40years, and is a current topic of intensive investigative activity. During the past several years, awareness of the important role of molecular alterations in the cardiac myocyte and interstitium in cardiac physiology has burgeoned among investigators, and this has led to a focus on the role of cardiac fibrosis and myocyte hypertrophy in the development of heart failure. Among the information garnered from these studies is that growth factors including angiotensin II (AII) and transforming growth factorβ1 (TGF-β1 ), in particular, are believed to be involved in modulation of gene products specifically expressed by cardiac fibroblasts and cardiac myocytes in vitro, and their enhanced presence has been associated with myocardial stress and inappropriate cardiac growth and fibrosis in vivo. Although these growth factors certainly may act on the myocardium alone via specific signaling pathways, we will review evidence that the signals modulated by AII and TGF-β may be coordinated among cardiac fibroblasts and myocytes. In this context, cardiac myocyte hypertrophy and alteration of the cardiac interstitium, i.e., cardiac fibrosis, are examined. This revised version was published online in August 2006 with corrections to the Cover Date.