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（由适用提供）：室性心律失常的突然心脏死亡（SCD）是成人死亡的主要原因，仅在美国，每年在美国每年的寿命超过30万，而心肌缺血是最常见的原因。在这里，我们提供的数据强烈支持了新的假设，该假设使肌膜对CA（心肌细胞）敏感会损害局部冠状动脉灌注（脉管系统），从而产生心律不齐的可观心脏。肌丝Ca敏感性发生在缺血性（ICM）和肥厚性心肌病（HCM）中。我们发现，由于心律不齐突变（TNT-I79N）或对CA敏感性EMD57033的治疗，CA敏感性增加了压力期间对心室心动过速的敏感性。心律不齐是心律不齐的区域间隙连接耦合和传导速度与局灶能量剥夺相关的速度的结果。更具体地说，CA灵敏的心脏显示P0连接蛋白43磷酸异型成型（CX43-P0）和磷酸化AMP激酶的局灶性积累，这都是细胞能量剥夺的标记。未知的是，肌丝Ca敏感性如何导致心肌剥夺，以及为什么在某些地区而不是其他地区发生这种情况。我们的初步数据表明，缺血至少部分负责局灶性剥夺。在压力期间，CX43-P0增加的区域变得低氧，与非催眠区相比，这与冠状动脉灌注大幅降低有关。我们的初步数据还表明，Pannexin（PX）通道在肌丝CA敏感性和局灶性剥夺之间提供了关键的联系。 PX1通道形成大孔，释放ATP等旁分泌信号分子，并在不同细胞类型之间的远距离信号中实现。 TNT-I79N通气中PX1的表达增加了缺血后，异质增加。令人惊讶的是，全局PX1消融抑制了TNT-I79N小鼠的局灶性能量剥夺和心律不齐。我们的总体假设是肌丝Ca敏感性会损害局部冠状动脉灌注，并导致压力期间局部缺血，部分由PX1介导。我们将通过直接量化能源缺陷来检验这一假设，b确定结构特性是否使某些区域偏爱能量剥夺（AIM 1）以及肌膜Ca敏感性如何损害冠状动脉灌注（AIM 2）。我们将通过PX1测试旁分泌信号传导对局灶性缺血的产生（AIM 3）。这些实验将描述一种新型的机械途径，将心肌细胞特性与改变局部血流以产生心律失常 - 易感心脏。结果将促进理解SCD机制的长期目标，定义防止它的策略并确定新颖的治疗靶标。