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。     

心脏肌成纤维细胞与心肌细胞偶联的致心律失常作用

心肌组织中数量最多的是成纤维细胞,此类细胞可以合成和维持细胞外基质,具有自分泌和旁分泌功能,对维持心脏正常功能起着重要的作用。当发生各种原因的心肌损害时,成纤维细胞增生、转化为肌成纤维细胞,增加细胞外基质沉积,导致心脏纤维化。以往研究认为心肌纤维化致心律失常的成因与增生的胶原纤维束破坏心肌细胞间连接,导致传导减慢或产生不连续性传导有关。但近年研究发现心脏成纤维细胞和肌成纤维细胞与心肌细胞之间可形成缝隙连接和紧密连接。由于心肌细胞和成纤维细胞的静息膜电位水平不同,两类细胞间形成的电偶联可降低心肌细胞除极速率和电活动传导速度。缝隙连接电流还直接参与心肌细胞早期后除极和动作电位时程电交替的发生;而肌成纤维细胞的紧张性收缩活动可通过细胞间的紧密连接,作用于心肌细胞的机械牵张敏感性离子通道,影响心脏的电生理功能。     

肌成纤维细胞在心肌梗死后重构中的作用及机制

成纤维细胞在心肌梗死后心脏修复和重构中起着重要作用,参与其中多个环节,调节细胞外基质的代谢,具有分化为肌成纤维细胞的潜能。肌成纤维细胞比成纤维细胞的表型更丰富,能更有效地对坏死细胞及间质进行修复和重构。然而,持久的肌成纤维细胞激活则会引起病理性纤维化,导致心律失常、心肌僵硬、心力衰竭的发生。     

心脏间质细胞在心肌纤维化中的作用机制及研究进展

心肌纤维化是多种损伤因素引起的心脏间质中细胞外基质过量沉积,可导致心室顺应性下降、心肌舒缩功能障碍及心律失常的发生,与心功能不全的严重程度及不良预后密切相关.心脏间质中的成纤维细胞、内皮细胞、周细胞和免疫细胞等细胞类型因基因组学表达差异可区分为多种亚群,并通过表型转化、精细调控细胞外基质组分及分泌促纤维化或抗纤维化因子...     

T细胞免疫调节机制在心力衰竭心肌纤维化中的作用

心肌重构在心力衰竭(心衰)的发生及发展中起着至关重要的作用,当心脏急性或慢性损伤时,多种细胞机制参与了心肌的重构过程,这其中免疫细胞如T淋巴细胞可以通过细胞信号相关蛋白,激活心肌成纤维细胞,导致前胶原在细胞外基质沉积促使心肌纤维化的形成。了解T细胞亚群与成纤维细胞在免疫炎症机制介导心肌纤维化中的作用,有助于从免疫炎症角度进一步了解心肌重构,为心力衰竭的预后及治疗提供新的思路。     

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。     

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。     

细胞外基质重建规律衍变与梗死后缺血心肌纤维化发生

细胞外基质（extracellular matrix，ECM）是梗死后缺血心肌纤维化发生的主要病理产物，随着病程进展而出现重建规律的衍变:炎症期坏死胶原基质瓦解，临时基质网络形成；增殖期基质细胞蛋白富集，肌成纤维细胞活化；修复期胶原基质瘢痕稳定，基质蛋白时序清除。靶向干预ECM降解、优化调节ECM分泌能够为心脏再生提供骨架支撑、维持心脏结构完整和舒缩韧性的同时，防止异常ECM重建带来的心脏功能衰竭。     

心肌纤维母细胞的自分泌/旁分泌作用

心肌纤维母细胞在调节正常心肌功能和干预异常心肌重塑中都起着极其重要的作用。除了合成和降解细胞外基质,心肌纤维母细胞还产生各种生物活性分子,包括细胞因子,血管活性肽和生长因子。这些生物活性分子经自分泌/旁分泌途径、信号转导途径和基因水平调控等调节机制,维持心脏正常的结构、机械、生物化学及电活动。     

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...     

Origins of cardiac fibroblasts

Cardiac fibroblasts play a critical role in maintenance of normal cardiac function. They are indispensable for damage control and tissue remodeling on myocardial injury and principal mediators of pathological cardiac remodeling and fibrosis. Despite their manyfold functions, cardiac fibroblasts remain poorly characterized in molecular terms. Evidence is evolving that cardiac fibroblasts are a heterogeneous population and likely derive from various distinct tissue niches in health and disease. Here, we review our emerging understanding of where cardiac fibroblasts come from, as well as how we can possibly use this knowledge to develop novel therapies for cardiac fibrosis.     

Implication of cardiac remodeling in heart failure: mechanisms and therapeutic strategies

The concept and clinical implication of left ventricular remodeling have been gradually extended. Cardiac remodeling plays important roles in the progression of cardiovascular diseases including myocardial infarction, valvular heart diseases, myocarditis, and dilated cardiomyopathy. In addition to cardiac myocytes, fibroblasts, extracellular matrix proteins and coronary vasculature are also involved in the remodeling process. Cardiac remodeling is associated with alterations of many mediators such as neurohumoral factors, cytokines, enzymes, ion channels, oxidative stress and mechanical stress. Although remodeling is initially an adaptive response to maintain normal cardiac function, it gradually becomes maladaptive and leads to progressive decompensation. Recent research has attempted to elucidate underlying molecular mechanisms of cardiac remodeling and to develop novel therapeutic strategies for heart failure. The modulation of remodeling process is effective for preventing the progression of heart failure.     

激活蛋白1及基质金属蛋白酶在急性心肌梗死后心脏组织中的表达

目的 观察激活蛋白-1(AP-1)、基质金属蛋白酶类(MMPs)在急性心肌梗死(AMI)患者心脏组织中的表达及意义.方法 采用免疫组化技术分别榆测AP-1亚单位c-Jun、MMP-2及MMP-9在人正常及AMI心脏组织中的表达.结果 (1)正常心脏组织可少量表达c-Jun、MMP-2及MMP-9;在AMI心脏组织中c-Jun、MMP-2及MMP-9表达较正常心脏组织明显增加(P值均<0.05).(2)在AMI心脏组织中,MMP-9表达水平与c-Jun表达水平明显呈正相关(r=0.773,P<0.01).结论 在AMI心脏组织中AP-1及MMPs表达均明显升高,提示AP-1转录激活及MMPs表达增加可能在AMI后心室重构中发挥重要的作用.     

Non-fibrillar collagens: Key mediators of post-infarction cardiac remodeling?

Cardiac remodeling is accelerated during pathological conditions and several anabolic and catabolic regulators work in concert to repair the myocardium and maintain its functionality. The fibroblasts play a major role in this process via collagen deposition as well as supplying the degradative matrix metalloproteinases. During the more acute responses to a myocardial infarction (MI) the heart relies on a more aggressive wound healing sequence that includes the myofibroblasts, specialized secretory cells necessary for infarct scar formation and thus, rescue of the myocardium. The activated fibroblasts and myofibroblasts deposit large amounts of fibrillar collagen during the post-MI wound healing phase, type I and III collagen are the most abundant collagens in the heart and they maintain the structural integrity under normal and disease states. While collagen I and III have been the traditional focus of the myocardial matrix, recent studies have suggested that the non-fibrillar collagens (types IV and VI) are also deposited during pathological wound healing and may play key roles in myofibroblast differentiation and organization of the fibrillar collagen network. This review highlights the potential roles of the non-fibrillar collagens and how they work in concert with the fibrillar collagens in mediating myocardial remodeling.     

Remodeling and reparation of the cardiovascular system.

Growth or altered metabolism of nonmyocyte cells (cardiac fibroblasts, vascular smooth muscle and endothelial cells) alters myocardial and vascular structure (remodeling) and function. However, the precise roles of circulating and locally generated factors such as angiotensin II, aldosterone and endothelin that regulate growth and metabolism of nonmyocyte cells have yet to be fully elucidated. Trials of pharmacologic therapy aimed at preventing structural remodeling and repairing altered myocardial structure to or toward normal in the setting of hypertension, heart failure and diabetes are reviewed. It is proposed that these are therapeutic goals that may reduce cardiovascular morbidity and mortality. Although this hypothesis remains unproved the primary goal of therapy should be to preserve or restore tissue structure and function.     

微小RNA在心肌重构中的作用

微小RNAs（miRNAs）是生物体中内源性的调控因子,它通过抑制相应mRNAs的翻译或降解特异mRNAs来调节特异基因的表达。新近研究发现miRNAs能调控心血管疾病的发生发展,如心肌肥厚、心脏纤维化、心律失常、心力衰竭等,参与了心肌的机械重构和电重构过程。随着对它的深入研究,发现人和动物心脏受损时血浆中某些miRNAs特异升高。以上发现使miRNAs有可能成为诊断心肌重构的生物标志物和治疗靶点。本文重点阐述miRNAs在心肌机械重构和电重构中的调控作用及其临床意义。     

Origin of Developmental Precursors Dictates the Pathophysiologic Role of Cardiac Fibroblasts

Fibroblasts in the heart play a critical function in the secretion and modulation of extracellular matrix critical for optimal cellular architecture and mechanical stability required for its mechanical function. Fibroblasts are also intimately involved in both adaptive and nonadaptive responses to cardiac injury. Fibroblasts provide the elaboration of extracellular matrix and, as myofibroblasts, are responsible for cross-linking this matrix to form a mechanically stable scar after myocardial infarction. By contrast, during heart failure, fibroblasts secrete extracellular matrix, which manifests itself as excessive interstitial fibrosis that may mechanically limit cardiac function and distort cardiac architecture (adverse remodeling). This review examines the hypothesis that fibroblasts mediating scar formation and fibroblasts mediating interstitial fibrosis arise from different cellular precursors and in response to different autocoidal signaling cascades. We demonstrate that fibroblasts which generate scars arise from endogenous mesenchymal stem cells, whereas those mediating adverse remodeling are of myeloid origin and represent immunoinflammatory dysregulation.     

Heart failure in pressure overload hypertrophy. The relative roles of ventricular remodeling and myocardial dysfunction

OBJECTIVES: We sought to explore the relative contributions of ventricular remodeling and myocardial dysfunction to heart failure in pressure overload hypertrophy (POH). BACKGROUND: The mechanism that underlies heart failure in POH is adverse left ventricular (LV) chamber remodeling or decreased myocardial function, or a combination of these. METHODS: Twenty weeks after suprarenal aortic banding in rats, animals with POH were classified as those with heart failure (POH-HF) or those with no heart failure (POH-NHF). The LV chamber and myocardial systolic and diastolic functions were determined from in vivo and ex vivo experiments. RESULTS: The LV mass was similar in both POH groups. Chamber remodeling in the POH-HF group was characterized by marked LV enlargement with a normal relative wall thickness (eccentric remodeling), whereas remodeling in the POH-NHF group was characterized by a normal chamber size and increased relative wall thickness (concentric remodeling). The LV systolic function, as determined in vivo from the end-systolic pressure-diameter relationship and ex vivo from the pressure-volume relationship, was lower in the POH-HF group than in the POH-NHF and sham-operated control groups. In contrast, myocardial function was similar in both POH groups, as determined in vivo from the stress-midwall fractional shortening relationship and myocardial systolic stiffness, and ex vivo from the slope of the LV systolic stress-strain relationship. The diastolic chamber stiffness constant was lower in the POH-HF group than in the POH-NHF group, but the myocardial stiffness constant was similar in the two POH groups. CONCLUSIONS: The two POH groups differed primarily in their remodeling process, which led to a chronically compensated state in one group and to heart failure in the other. Hence, heart failure in POH is more closely related to deleterious LV remodeling than to depressed myocardial function.     

心肌梗死后心脏修复与心肌细胞再生的研究进展

心肌梗死后组织缺血缺氧,坏死,导致一个多相的修复过程,受损的组织由成纤维细胞和肌成纤维细胞产生纤维瘢痕所取代。非梗死的心室壁反应性重塑,包括间质和血管周围纤维化,导致心室壁几何、生物力学、生化等发生改变。虽然最初的修复性纤维化对防止心室壁破裂至关重要,但是过度的纤维化反应导致心功能进行性损害,最终导致心功能衰竭。近年来研究表明,心脏具有可塑性,恢复受损心脏功能,促进梗死心肌修复是心血管疾病治疗的重要目标。为此,人们不断探索新的治疗手段,再生治疗给心肌梗死治疗带来了新的希望,本文对目前心肌梗死的修复性及反应心肌纤维化的机制进行总结,探讨诱导成纤维细胞和肌成纤维细胞转化为心肌细胞,以及心肌细胞再生的潜力,对目前现有和未来抑制心肌纤维化治疗策略进行综述。