Cardiomyocyte TRPV4 and Angiotensin-II induced ventricular arrhythmia with aging

心肌细胞TRPV4和血管紧张素II诱导的室性心律失常随衰老

基本信息

批准号：
10658009
负责人：
Timothy Lee Domeier
金额：
$ 41.04万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-03 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658009
关键词：
Acute Aging Angiotensin II Arrhythmia Autopsy Biological Aging Blood Pressure Blood Volume Calcium Calcium Signaling Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular Pathology Cardiovascular Physiology Cations Cause of Death Chronic Clinical Trials Coupling Data Echocardiography Electrocardiogram Electrophysiology (science)Experimental Designs Family Genetic Goals Heart Heart Hypertrophy Histologic Homeostasis Hormones Incidence Injections Ion Channel Ischemia Knock-out Knowledge Link Mechanics Mediator Microelectrodes Modeling Monitor Mus Muscle Cells Myocardial Contraction Myocardial Infarction Osmosis Perfusion Physiological Predisposition Publishing Receptor Activation Receptor, Angiotensin, Type 1 Regional Perfusion Reperfusion Injury Reperfusion Therapy Research Role Signal Transduction Stimulus Stress Stretching TRP channel Tail Testing Vanilloid Veins Ventricular Ventricular Arrhythmia Ventricular Remodeling age related aged cell type comorbidity coronary fibrosis genetic approach genetic manipulation heart cell heart damage heart function in vivo in vivo monitoring inhibitor member novel osmotic minipump overexpression peptide hormone pharmacologic prevent programs receptor response therapeutic target trafficking

项目摘要

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.

项目概要/摘要瞬时受体电位香草酸，成员 4 (TRPV4) 是心肌细胞中高度表达的阳离子通道随着衰老，TRPV4 后有助于增强心肌细胞钙循环和过度收缩性门控刺激包括渗透压和机械拉伸。 TRPV4 过度激活会导致心脏损害和室性心律失常。血管紧张素 II (AngII) 是一种肽激素，对于由于其对血容量和压力的调节作用，心血管生理学和病理学。在许多细胞类型，AngII 增加 TRPV4 活性，尽管该信号轴对心肌细胞的贡献钙稳态目前尚不清楚。该更新提案测试了 TRPV4 的中心假设有助于 AngII 依赖性心肌细胞钙信号传导和室性心律失常。为了测试这个假设，我们将使用药理学（TRPV4 抑制）和遗传方法（心肌细胞特异性 TRPV4 缺失或过度表达）以检查 TRPV4 在分离的心肌细胞中的功能作用，分离的灌注心脏和小鼠体内。具体目标 1 使用分离的心肌细胞和分离的灌注心脏来测试 AngII 促进 TRPV4 运输、增加 TRPV4 活性并增强兴奋-收缩耦合期间心肌细胞钙瞬变。具体目标 2 检验以下假设：心肌细胞 TRPV4 有助于 AngII 诱导的心脏重塑，并检查 TRPV4 在 AngII 过量（渗透微型泵）和生物衰老过程中的肥厚和纤维化重塑。具体目标 3 检验了 TRPV4 有助于促心律失常心肌细胞钙信号的假设，并且急性和慢性 AngII 过量引起的室性心律失常。该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。