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...     

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。     

非编码RNA与心脏纤维化的研究进展

心脏的应激状态可激活心脏成纤维细胞,使其产生过多的细胞外基质,形成纤维组织,最终导致心脏结构改变及心脏衰竭。目前心脏纤维化的发生机制还不明确,其过程涉及诸多因素。非编码RNA是一类内源性RNA分子,主要包括微小RNA和长链非编码RNA等,参与细胞的生长、增殖和分化,在心血管疾病的发生发展过程中起着重要的调节作用。该文介绍了非编码RNA在心脏纤维化中的研究进展。     

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。     

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。     

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...     

心脏纤维化中力学信号转导的研究进展

心脏纤维化会引发心脏舒张和收缩障碍,诱发心律失常,增加心血管疾病患者的再入院率和死亡风险。成纤维细胞是维持和促进心脏组织细胞外基质沉积的主要细胞类型,并且对力学微环境改变敏感。最近的研究揭示了力学因素影响成纤维细胞功能的具体力学信号转导通路。文章对此进行了综述,并就体外力学模型和临床研究进展进行了适当讨论。     

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。     

Ⅰ型血管紧张素Ⅱ受体拮抗剂对胰腺星状细胞的影响

目的近年来研究表明,静止状态的胰腺星状细胞(PSC)在多种因子的刺激下可发生表型转化而活化为肌成纤维细胞,后者参与细胞外基质(ECM)的代谢调节而促进胰腺纤维化的发生与发展.     

Sestrin2在不同疾病纤维化过程中的作用研究进展

<正>成纤维细胞的过度增殖和大量细胞外基质的沉积是纤维化的主要病理特征,Sestrin2(Sesn2)是高度保守的应激反应蛋白Sestrin家族的一员,具有抗氧化活性。最近研究发现Sesn2在诸多器官纤维化发生发展过程中起到重要调节作用。本文就Sesn2在肺脏、肝脏、肾脏、心脏等常见器官纤维化中的作用及其可能的分子机制做一综述,以期为抗纤维化治疗提供新的分子靶点。1纤维化概述纤维化是以成纤维细胞过度增殖和大量细胞外基质     

Upregulation of TRPC1 in the development of cardiac hypertrophy

The importance of Ca(2+) entry in the cardiac hypertrophic response is well documented, but the actual Ca(2+) entry channels remain unknown. Transient receptor potential (TRP) proteins are thought to form either homo- or heteromeric Ca(2+) entry channels that are involved in the proliferation and differentiation of various cells. The purpose of this study was to explore the potential involvement of TRP channels in the development of cardiac hypertrophy. The mRNA and protein expression of several TRP channel subunits were evaluated using hearts from abdominal aortic-banded (AAB) rats. Although TRPs C1, C3, C5, and C6 were constitutively expressed, only TRPC1 expression was significantly increased in the hearts of AAB rats compared to sham-operated rats. Using primary cultures of neonatal rat cardiomyocytes, we detected increases in the expression of TRPC1, brain natriuretic peptide (BNP), and atrial natriuretic factor (ANF), as well as increases in store-operated Ca(2+) entry (SOCE) and cell surface area, following endothelin-1 (ET-1) treatment. Silencing of the TRPC1 gene via small interfering RNA (siRNA) attenuated SOCE and prevented ET-1-, angiotensin-II (AT II)-, and phenylephrine (PE)-induced cardiac hypertrophy. In HEK 293T cells, overexpression of TRPC1 augmented SOCE, leading to an increase in nuclear factor of activated T cells (NFAT) promoter activity, while co-transfection with dominant-negative forms of TRPC1 suppressed it. In conclusion, TRPC1 functions in Ca(2+) influx, and its upregulation is involved in the development of cardiac hypertrophy; moreover, it plays an important role in the regulation of the signaling pathways that govern cardiac hypertrophy. These findings establish TRPC1 as a functionally important regulator of cardiac hypertrophy.     

Viewpoints on the Role of Transient Receptor Potential Melastatin Channels in Cardiovascular System and Disease: A Systematic Review

Transient receptor potential (TRP) family play critical roles in cardiovascular system. TRPM family as largest TRP subfamily is non-voltage Ca2+-activated selective channels which has 8 members. This study aimed to discuss the role of TRPM family in cardiovascular system and diseases. Systematic search was performed covering PubMed, ISI Web of Science, and Google Scholar from inception until June 2021 using related keywords and Mesh terms for English studies with human, animal and in-vitro subjects. Finally 10 studies were selected for data extraction. Reviewing the articles showed that TRPM2, TRPM4, TRPM5, TRPM6 and TRPM7 play important roles in cardiovascular system and diseases. TRPM2 could be activated by reactive oxygen species (ROS) and effects on cardiac injury and cardiac fibrosis. TRPM7 and TRPM6 also have been reported to be associated with cardiac fibrosis and atrial fibrosis development respectively. TRPM4 channels contributed to resting membrane potential of cerebral artery smooth muscle cells and atrial contraction. TRPM5 channels are bitter taste sensors and prevent high salt intake and consequently high blood pressure due to the high salt intake. In conclusion based on the proof of the effectiveness of some members of TRPM family in the cardiovascular system, research on other members of this channel group seems to be useful and necessary to find their possible connection to the cardiovascular system.     

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.     

The role of thermosensitive TRP (transient receptor potential) channels in insulin secretion

Insulin secretion from pancreatic β-cells is the only efficient means to decrease blood glucose concentrations. Glucose is the principal stimulator of insulin secretion with the ATP-sensitive K+ channel-voltage-gated Ca2+ channel-mediated pathway being the primary one involved in glucose-stimulated insulin secretion. Recently, several reports demonstrated that some transient receptor potential (TRP) channels are expressed in pancreatic β-cells and contribute to pancreatic β-cell functions. Interestingly, six of them (TRPM2, TRPM4, TRPM5, TRPV1, TRPV2 and TRPV4) are thermosensitive TRP channels. Thermosensitive TRP channels in pancreatic β-cells can function as multimodal receptors and cause Ca2+ influx and membrane depolarization at physiological body temperature. TRPM channels (TRPM2, TRPM4 and TRPM5) control insulin secretion levels by sensing intracellular Ca2+ increase, NAD metabolites, or hormone receptor activation. TRPV2 is involved not only in insulin secretion but also cell proliferation, and is regulated by the autocrine effects of insulin. TRPV1 expressed in sensory neurons is involved in β-cell stress and islet inflammation by controlling neuropeptide release levels. It is thus clear that thermosensitive TRP channels play important roles in pancreatic β-cell functions, and future analyses of TRP channel function will lead to better understanding of the complicated mechanisms involved in insulin secretion and diabetes pathogenesis.     

TRPC channels as effectors of cardiac hypertrophy

Transient receptor potential (TRP) channels of multiple subclasses are expressed in the heart, although their functions are only now beginning to emerge, especially for the TRPC subclass that appears to regulate the cardiac hypertrophic response. Although TRP channels permeate many different cations, they are most often ascribed a specific biological function because of Ca(2+) influx, either for microdomain signaling or to reload internal Ca(2+) stores in the endoplasmic reticulum through a store-operated mechanism. However, adult cardiac myocytes arguably do not require store-operated Ca(2+) entry to regulate sarcoplasmic reticulum Ca(2+) levels and excitation-contraction coupling; hence, TRP channels expressed in the heart most likely coordinate signaling within local domains or through direct interaction with Ca(2+)-dependent regulatory proteins. Here, we review the emerging evidence that TRP channels, especially TRPCs, are critical regulators of microdomain signaling in the heart to control pathological hypertrophy in coordination with signaling through effectors such as calcineurin and NFAT (nuclear factor of activated T cells).     

Remodeling of Cardiac Membranes During the Development of Congestive Heart Failure

Various proteins such as Ca2+channels, Ca2+-pump ATPase, Na+–Ca2+exchanger, and Na+-K+ATPase in the sarcolemmal (SL) membrane are considered to be intimately involved in Ca2+-influx and Ca2+-efflux processes in the cardiomyocyte. On the other hand, Ca2+-pump ATPase, Ca2+-release channels, Ca2+-regulatory protein (phospholamban), and Ca2+-binding protein (calsequestrin) in the sarcoplasmic reticulum (SR) are known to participate in raising and lowering the intracellular concentration of Ca2+for the occurrence of cardiac contraction and relaxation processes. Therefore, a defect in any of the SL and SR proteins can be seen to result in Ca2+-handling abnormalities in cardiomyocytes and subsequently in cardiac dysfunction during the development of heart failure. In this review, evidence is presented to show that changes in the expression of genes specific for cardiac membrane proteins may lead to remodeling of both SR and SL membranes during the development of heart failure. Although a great deal of work on changes in gene expression for the SR membrane proteins has been carried out in the failing heart, relatively little information regarding changes in gene expression for SL proteins has appeared in the literature. Prevention of remodeling of cardiac membranes by modification of changes in the gene expression is suggested to serve as an important target for the treatment of heart failure.     

Recent developments in vascular endothelial cell transient receptor potential channels

Among the 28 identified and unique mammalian TRP (transient receptor potential) channel isoforms, at least 19 are expressed in vascular endothelial cells. These channels appear to participate in a diverse range of vascular functions, including control of vascular tone, regulation of vascular permeability, mechanosensing, secretion, angiogenesis, endothelial cell proliferation, and endothelial cell apoptosis and death. Malfunction of these channels may result in disorders of the human cardiovascular system. All TRP channels, except for TRPM4 and TRPM5, are cation channels that allow Ca2+ influx. However, there is a daunting diversity in the mode of activation and regulation in each case. Specific TRP channels may be activated by different stimuli such as vasoactive agents, oxidative stress, mechanical stimuli, and heat. TRP channels may then transform these stimuli into changes in the cytosolic Ca2+, which are eventually coupled to various vascular responses. Evidence has been provided to suggest the involvement of at least the following TRP channels in vascular function: TRPC1, TRPC4, TRPC6, and TRPV1 in the control of vascular permeability; TRPC4, TRPV1, and TRPV4 in the regulation of vascular tone; TRPC4 in hypoxia-induced vascular remodeling; and TRPC3, TRPC4, and TRPM2 in oxidative stress-induced responses. However, in spite of the large body of data available, the functional role of many endothelial TRP channels is still poorly understood. Elucidating the mechanisms regulating the different endothelial TRP channels, and the associated development of drugs selectively to target the different isoforms, as a means to treat cardiovascular disease should, therefore, be a high priority.     

TRPC 通道蛋白在呼吸系统的研究进展

瞬时感受器电位离子通道蛋白(transient receptor potential ion channel protein,TRP)是发现存在于细胞膜或胞内细胞器膜上的一类非选择性 Ca2+离子通道蛋白。在 TRP 家族中,经典瞬时感受器电位通道(canonical transient receptor potential channel,TRPC)被认为是参与细胞众多生理功能的重要通道蛋白。TRPC 作为主要的 Ca2+内流通道,参与多种生理、病理过程,是目前研究最多、最热点的 TRP 家族成员。本文就 TRPC 在呼吸系统的表达、病理生理机制、调控及临床应用作一综述。     

Cytoskeletal Regulation of TRPC Channels in the Cardiorenal System

Transient receptor potential canonical (TRPC) channels have been implicated in several aspects of cardiorenal physiology including regulation of blood pressure, vasoreactivity, vascular remodeling, and glomerular filtration. Gain and loss of function studies also support the role of TRPC channels in adverse remodeling associated with cardiac hypertrophy and heart failure. This review discusses TRP channels in the cardiovascular and glomerular filtration systems and their role in disease pathogenesis. We describe the regulation of gating of TRPC channels in the cardiorenal system as well as the influence on activation of these channels by the underlying cytoskeleton and scaffolding proteins. We then focus on the role of TRP channels in the pathogenesis of adverse cardiac remodeling and as potential therapeutic targets in the treatment of heart failure.     

The short QT syndrome as a paradigm to understand the role of potassium channels in ventricular fibrillation

The recently discovered hereditary channelopathy, the Short QT Syndrome (SQTS), is an important advance in clinical and molecular cardiology that has opened new doors for investigating the manner in which alterations in excitability and action potential morphology may facilitate the occurrence of ventricular fibrillation. In this brief review we address the molecular and genetic features of SQTS in which specific mutations in one of three different potassium channels involved in cardiac repolarization substantially increase the risk of life-threatening tachyarrhythmias. We then summarize new knowledge on the mechanism of wavebreak, which is the hallmark of reentry initiation, and on the role of potassium channels in the ionic mechanisms underlying cardiac excitation and its frequency dependence. The article argues for a detailed understanding of the ionic mechanisms that promote wavebreaks and stable rotors as an essential tool for successful anti-arrhythmic therapy in SQTS and other diseases leading to sudden cardiac death.