Cardiomyocyte-mediated mechanisms of ischemia

心肌细胞介导的缺血机制

• 批准号: 9247073
• 负责人: Sabine Huke
• 金额: $ 36.99万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247073
• 关键词: Ablation; Acute; Adult; Arrhythmia; Blood Vessels; Blood capillaries; Blood flow; Cardiac Myocytes; Cause of Death; Cell Size; Connexin 43; Coronary; Data; Familial Hypertrophic Cardiomyopathy; Fibrosis; Gap Junctions; Generations; Goals; Heart; Heart Diseases; Histologic; Hypertrophic Cardiomyopathy; Hypoxia; Image; Impairment; Ischemia; Link; Location; Mediating; Microfilaments; Microspheres; Mus; Muscle Cells; Mutation; Myocardial; Myocardial Ischemia; Oxidation-Reduction; Paracrine Communication; Pathway interactions; Perfusion; Pharmacology; Predisposition; Property; Protein Isoforms; Risk; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle; Stress; Tachyarrhythmias; Testing; Tissues; Ventricular; Ventricular Tachycardia; adenylate kinase; capillary; cell type; coronary perfusion; cost; density; deprivation; experimental study; microCT; new therapeutic target; novel; prevent; public health relevance; reconstruction; sudden cardiac death; tool

 DESCRIPTION (provided by applicant): Sudden cardiac death (SCD) from ventricular tachyarrhythmia's is a leading cause of death in adults and costs more than 300,000 lives annually in the US alone, with myocardial ischemia being the most common cause. Here we present data that strongly support the novel hypothesis that sensitizing the myofilaments to Ca (cardiomyocyte) impairs local coronary perfusion (vasculature) to generate an arrhythmia-susceptible heart. Myofilament Ca sensitization occurs in ischemic (ICM) and familial hypertrophic cardiomyopathy (HCM). We found that Ca sensitization, due to a HCM-linked mutation (TnT-I79N) or treatment with the Ca sensitizer EMD57033, increases the susceptibility to ventricular tachycardia during stress. The arrhythmias are the result of arrhythmogenic regional gap junctional uncoupling and conduction velocity slowing linked to focal energy deprivation. More specifically, Ca sensitized hearts showed focal accumulation of the P0 connexin 43 phospho-isoform (Cx43-P0) and phosphorylated AMP-kinase, both markers for cellular energy deprivation. Unknown is though how myofilament Ca sensitization causes myocardial energy deprivation and why this occurs in some regions and not others. Our preliminary data indicate that ischemia is at least in part responsible for the focal energy deprivation. Regions with increased Cx43-P0 become hypoxic during stress and this is associated with drastically reduced coronary perfusion compared to non-hypoxic regions. Our preliminary data also suggest that pannexin (Px) channels provide a critical link between myofilament Ca sensitization and focal energy deprivation. Px1 channels form large pores, release paracrine signaling molecules like ATP and are implicated in long-range signaling between different cell types. Expression of Px1 increases post-ischemia and is heterogeneously increased in TnT-I79N ventricle. Strikingly, global Px1 ablation suppressed focal energy deprivation and arrhythmias in TnT-I79N mice. Our overarching hypothesis is that myofilament Ca sensitization impairs local coronary perfusion and leads to focal ischemia during stress, mediated in part by Px1. We will test this hypothesis by quantifying the energy deficit directly, b determining if structural properties predispose certain regions to energy deprivation (Aim 1) and how myofilament Ca sensitization impairs coronary perfusion (Aim 2). We will test the contribution of paracrine signaling via Px1 for the generation of focal ischemia (Aim 3). These experiments will delineate a novel mechanistic pathway linking myocyte properties to altered local blood flow to generate an arrhythmia- prone heart. The results will advance the long-term goals of understanding mechanisms of SCD, defining strategies to prevent it and identifying novel therapeutic targets.

 描述（由申请人提供）：室性快速性心律失常引起的心源性猝死（SCD）是成人死亡的主要原因，仅在美国每年就有超过30万人死亡，心肌缺血是最常见的原因。在这里，我们提出的数据，强烈支持新的假设，敏感的肌丝钙（心肌细胞）损害局部冠状动脉灌注（脉管系统），以产生一个心肌炎敏感的心脏。肌丝钙敏感化发生在缺血性（ICM）和家族性肥厚型心肌病（HCM）。我们发现，由于HCM连锁突变（TnT-I79 N）或用钙致敏剂EMD 57033治疗，钙致敏增加了应激期间室性心动过速的易感性。心律失常是与局灶性能量剥夺相关的致心律失常性区域间隙连接解偶联和传导速度减慢的结果。更具体地说，钙致敏的心脏表现出局灶性积聚的P0连接蛋白43磷酸化亚型（Cx43-P0）和磷酸化AMP-激酶，这两个标志物的细胞能量剥夺。肌丝Ca敏化如何引起心肌能量剥夺以及为什么这发生在某些区域而不是其他区域尚不清楚。我们的初步数据表明，缺血是至少部分负责局灶性能量剥夺。具有增加的Cx43-P0的区域在应激期间变得缺氧，并且与非缺氧区域相比，这与急剧减少的冠状动脉灌注相关。我们的初步数据还表明，泛连接蛋白（Px）通道提供了肌丝钙敏化和局灶性能量剥夺之间的关键环节。Px 1通道形成大孔，释放旁分泌信号分子，如ATP，并参与不同细胞类型之间的长距离信号传导。心肌缺血后Px 1的表达增加，并且在TnT-I79 N心室中不均匀地增加。引人注目的是，整体Px 1消融抑制了TnT-I79 N小鼠的局灶性能量剥夺和心律失常。我们的总体假设是，肌丝钙敏化损害局部冠状动脉灌注，并导致局灶性缺血，在应力，部分介导的Px 1。我们将通过直接量化能量不足来检验这一假设，B确定结构特性是否使某些区域易受能量剥夺（目的1）以及肌丝Ca敏化如何损害冠状动脉灌注（目的2）。我们将测试通过Px 1的旁分泌信号传导对局灶性缺血的产生的贡献（目的3）。这些实验将描绘出一种新的机制途径，将肌细胞特性与改变的局部血流联系起来，以产生心律失常倾向的心脏。研究结果将推进理解SCD机制的长期目标，确定预防SCD的策略并确定新的治疗靶点。