TRANSMURAL REGULATION Na/K PUMP ACTIVITY IN HEART

跨壁调节 心脏中的 Na/K 泵活动

• 批准号: 7229522
• 负责人: Richard T Mathias
• 金额: $ 37.63万
• 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/7229522
• 关键词: Action Potentials; Affect; Angiotensin II; Biochemical; Biotinylation; Canis familiaris; Cells; Condition; Contracts; Data; Endocardium; Enzymes; Epicardium; Excision; Feedback; Figs - dietary; Heart; Histocytochemistry; Image; Incubated; Ion Channel; Lead; Measurement; Measures; Mechanics; Mediating; Modeling; Morphology; Muscle Cells; Ouabain; Phosphorylation; Physiological; Precipitation; Proteins; Pump; Purpose; Rate; Receptor, Angiotensin, Type 1; Regulation; Renin-Angiotensin System; Reporting; Role; SBFI-AM; Shapes; Signal Pathway; Signal Transduction Pathway; Source; System; Testing; Time; Transcriptional Activation; Up-Regulation; Ventricular; Video Microscopy; autocrine; base; digital; driving force; electrical property; inhibitor/antagonist; novel; patch clamp; pressure; sensor; titin kinase; trafficking; uptake

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。 （2005年）发现，Na/k泵的最大翻转速率（VMAX）在犬心室壁上受到空间调节，其中vmax在心脏心脏（EPI）中最大，中间位于中膜中的中间体（中），内心（endo）中最小。此外，这项研究报道了VMAX中的透射梯度在[Na+] J中产生了一个梯度，该梯度在Endo中最高，中间位于EPI中和最低。我们的初步数据表明，[Na+] J中的梯度改变了Na/Ca交换（NCX），以在[Ca2+]（和收缩。的初步数据）中生成透射梯度。还表明，通过血管紧张素II（A2）产生了这种透射梯度（A2），这似乎是通过机械反馈来调节的，该量子可能会受到机械反馈的调节，该模型依赖于Titin Kinase（titik Kinase），titik Kinase a是一定的。 Na/k泵电流（IP），LNCX，[CA2*] J和收缩。 2）这是一个反馈控制系统，其中传感器是TIK。 TIK的压力依赖性激活会导致对自分泌肾素血管紧张素系统（RAS）的调节，该系统将梯度设置为最大IP，从而[Ca2+] J和收缩力抵消了负载中的传播梯度。该提议的目的是检验这两个假设。我们将结合电生理，NA和CA-IMIMANG，收缩和生化测量来实现这些目标。