Cardiomyocyte TRPV4 and Angiotensin-II induced ventricular arrhythmia with aging

项目概要/摘要 瞬时受体电位香草酸成员4（TRPV 4）是心肌细胞中高表达的阳离子通道 随着年龄的增长，并有助于增强心肌细胞钙循环和过度收缩后TRPV 4 门控刺激包括渗透应力和机械拉伸。TRPV 4过度激活导致心脏 损伤和室性心律失常。血管紧张素II（AngII）是一种肽类激素， 由于其对血容量和血压的调节作用，导致心血管生理学和病理学。在许多 在心肌细胞类型中，AngII增加TRPV 4活性，尽管该信号传导轴对心肌细胞的作用 钙稳态目前是未知的。这一更新建议测试了TRPV 4的核心假设， 导致AngII依赖性心肌细胞钙信号传导和室性心律失常。为了验证这一 假设，我们将使用药理学（TRPV 4抑制）和遗传学方法（心肌细胞特异性 TRPV 4缺失或过表达）以检查TRPV 4在分离的心肌细胞中的功能作用， 离体灌注心脏和小鼠体内。特异性目的1使用分离的心肌细胞和分离的灌注的 心脏，以检验AngII促进TRPV 4运输，增加TRPV 4活性，并增强 兴奋-收缩偶联期间心肌细胞钙瞬变。具体目标2检验假设， 心肌细胞TRPV 4参与AngII诱导的心脏重构，并检测TRPV 4在 AngII过量（渗透性微型泵）后和生物老化期间的肥大和纤维化重塑。 具体目标3检验TRPV 4有助于促心肌细胞钙信号的假设， 急性和慢性血管紧张素II过量后的室性心律失常。该项目的总体目标是 将TRPV 4确立为治疗靶点，以预防衰老引起的心律失常。

Project Summary/Abstract Transient receptor potential vanilloid, member 4 (TRPV4) is a cation channel highly expressed in cardiomyocytes with aging, and contributes to enhanced cardiomyocyte calcium cycling and hypercontractility following TRPV4 gating stimuli including osmotic stress and mechanical stretch. Excessive TRPV4 activation leads to cardiac damage and ventricular arrhythmia. Angiotensin II (AngII) is a peptide hormone critically important to cardiovascular physiology and pathology due to its regulatory effects on blood volume and pressure. In many cell types, AngII increases TRPV4 activity although the contribution of this signaling axis to cardiomyocyte calcium homeostasis is currently unknown. This renewal proposal tests the central hypothesis that TRPV4 contributes to AngII-dependent cardiomyocyte calcium signaling and ventricular arrhythmia. To test this hypothesis, we will use both a pharmacologic (TRPV4 inhibition) and genetic approach (cardiomyocyte specific TRPV4 deletion or overexpression) to examine the functional role of TRPV4 in isolated cardiomyocytes, in isolated perfused hearts, and in mice in vivo. Specific Aim 1 uses isolated cardiomyocytes and isolated perfused hearts to test the hypothesis that AngII promotes TRPV4 trafficking, increases TRPV4 activity, and enhances cardiomyocyte calcium transients during excitation-contraction coupling. Specific Aim 2 tests the hypothesis that cardiomyocyte TRPV4 contributes to AngII-induced cardiac remodeling, and examines the role of TRPV4 in hypertrophic and fibrotic remodeling following AngII excess (osmotic mini-pumps) and during biological aging. Specific Aim 3 tests the hypothesis that TRPV4 contributes to pro-arrhythmic cardiomyocyte calcium signals and ventricular arrhythmia following both acute and chronic AngII excess. The overall goal of this project is to establish TRPV4 as a therapeutic target to prevent arrhythmia with aging.