Cardiomyocyte TRPV4 and Angiotensin-II induced ventricular arrhythmia with aging

项目摘要/摘要 瞬时受体电位香草素成员4(TRPV4)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TRPV4后心肌细胞的钙循环和超收缩能力 门控刺激包括渗透应激和机械拉伸。TRPV4过度激活导致心脏 损害和室性心律失常。血管紧张素II(AngII)是一种多肽激素，对 心血管生理学和病理学由于其对血容量和血压的调节作用。在许多 细胞类型，Angii增加TRPV4的活性，尽管这个信号轴对心肌细胞的贡献 钙稳态目前尚不清楚。这项续签提案检验了TRPV4的核心假设 有助于血管紧张素Ⅱ依赖的心肌细胞钙信号转导和室性心律失常。为了测试这一点 假设，我们将同时使用药理学方法(TRPV4抑制)和遗传学方法(心肌细胞特异性 TRPV4缺失或过表达)来检测TRPV4在分离的心肌细胞中的功能作用，在 分离灌流的心脏，并在小鼠体内。特定目的1使用分离的心肌细胞和隔离的灌流 心脏测试假设，血管紧张素转换酶促进TRPV4的贩运，增加TRPV4的活性，并增强 心肌细胞在兴奋-收缩偶联过程中的钙瞬变。《特定目标2》验证了这一假设 心肌细胞TRPV4参与血管紧张素转换酶诱导的心脏重构，并检测TRPV4在 血管紧张素转换过多(渗透压迷你泵)和生物老化后的肥大和纤维化重塑。 特定目标3验证了TRPV4有助于促心律失常的心肌细胞钙信号和 急性和慢性血管紧张素Ⅱ过量后的室性心律失常。这个项目的总体目标是 建立TRPV4作为预防衰老引起的心律失常的治疗靶点。

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.