TRANSMURAL REGULATION Na/K PUMP ACTIVITY IN HEART

跨壁调节 心脏中的 Na/K 泵活动

• 批准号: 7128820
• 负责人: Richard T Mathias
• 金额: $ 38.75万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7128820
• 关键词: action potentials; angiotensin II; biological signal transduction; calcium flux; dogs; endocardium; heart contraction; heart electrical activity; muscle proteins; pericardium; renin angiotensin system; sodium potassium exchanging ATPase; voltage /patch clamp; voltage gated channel

DESCRIPTION (provided by applicant): Gao et al. (2005) found the max turn over rate (Vmax) of the Na/K pumps is spatially regulated across the canine ventricular wall, with Vmax being largest in the epicardium (Epi), intermediate in the midmyocardium (Mid) and smallest in the endocardium (Endo). Moreover, this study reported the transmural gradient in Vmax creates a gradient in [Na+]j, which is highest in Endo, intermediate in mid and lowest in Epi. Our preliminary data suggest the gradient in [Na+]j alters Na/Ca exchange (NCX) to generate a transmural gradient in [Ca2+]( and contraction. Preliminary data also suggest this transmural gradient is generated through angiotensin II (A2), which appears to be regulated by mechanical feedback, possible by the titin kinase (TiK), which is a mechanical sensor. We have created a quantitative model relating Na/K pump current (IP), lNCx, [Ca2*]j and contraction. The model successfully predicts differences in contraction and Ca-transients recorded in myocytes from Endo and Epi. Based on these data, we hypothesize: 1) The purpose of the transmural gradient in Vmax is to generate maximum contractility and rate responsiveness in Endo, which contracts first and against the greatest pressure load during each action potential (AP). 2) This is a feedback control system in which the sensor is the TiK. Pressure dependent activation of TiK causes up regulation of an autocrine renin angiotensin system (RAS) that sets the gradient in max IP such that [Ca2+]j and hence contractility offsets transmural gradients in load. The aims of this proposal are to test these two hypotheses. We will use a combination of electrophysiological, Na- and Ca-imaging, contraction, and biochemical measurements to accomplish these aims.

描述（由申请人提供）：Gao等人（2005）发现，Na/K泵的最大转换速率（Vmax）在犬心室壁上受到空间调节，Vmax在心外膜（Epi）中最大，在中层心肌（Mid）中居中，在内膜（Endo）中最小。此外，本研究报告了Vmax的跨壁梯度在[Na+]j中产生梯度，其在Endo中最高，在Mid中居中，在Epi中最低。我们的初步数据表明，[Na+]j的梯度改变Na/Ca交换（NCX），以产生[Ca 2 +]和收缩的跨壁梯度。初步数据还表明，这种跨壁梯度是通过血管紧张素II（A2）产生的，血管紧张素II（A2）似乎受到机械反馈的调节，可能是由肌联蛋白激酶（TiK），这是一种机械传感器。建立了Na/K泵电流（IP）、lNCx、[Ca ~（2+）]j与收缩的定量模型。该模型成功地预测了收缩和钙瞬变记录在肌细胞从Endo和Epi的差异。基于这些数据，我们假设：1）Vmax的跨壁梯度的目的是在Endo中产生最大的收缩力和频率反应性，Endo在每个动作电位（AP）期间首先收缩并对抗最大的压力负荷。2)这是一个反馈控制系统，其中传感器是TiK。TiK的压力依赖性激活引起自分泌肾素血管紧张素系统（RAS）的上调，其设定最大IP中的梯度，使得[Ca 2 +]j和因此的收缩性抵消负荷中的跨壁梯度。本提案的目的是检验这两个假设。我们将使用电生理学，钠和钙成像，收缩和生化测量的组合来实现这些目标。