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MECHANICAL LOAD EFFECT ON CARDIAC EXCITATION-CONTRACTION COUPLING

机械负荷对心脏兴奋-收缩耦合的影响

基本信息

批准号：
10063898
负责人：
Ye Chen-Izu
金额：
$ 63.31万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063898
关键词：
Action Potentials Adrenergic Agents Affect Arrhythmia Blood Pressure Cardiac Cardiac Myocytes Cardiac Output Cells Chronic Contracts Coupling Data Dilated Cardiomyopathy Electrophysiology (science)Emotional Stress Functional disorder Gel Heart Heart Diseases Heart failure Hydrogels Hypertension Ice Impairment Investigation Ion Channel Knowledge Link Measures Mechanical Stress Mediating Membrane Methods Modeling Molecular Muscle Muscle Cells Myocardial dysfunction Myocardium Nitric Oxide Oryctolagus cuniculus Outcome Pathologic Patients Physical activity Physiological Property Reactive Oxygen Species Regulation Research Role Sarcolemma Sarcoplasmic Reticulum Signal Transduction Stress Techniques Technology Testing Thinness Transgenic Mice Ventricular Work base blood pump body position density experimental study innovation mechanical load mechanotransduction mouse model patch clamp response tool uptake viscoelasticity voltage

项目摘要

ABSTRACT The heart must adjust its contractile force to counteract the blood pressure changes (due to physical activity, body position, emotional stress, etc.) to maintain cardiac output. Cardiac muscle cells possess the intrinsic ability to sense mechanical load and fine-tune contractile force accordingly. Previous work by us and others found that increasing mechanical loading on muscle strips or single myocytes results in an increase of the cytosolic Ca2+ transient (CaT) that increases the contractile force to partially compensate for the added mechanical load. A sustained increase in CaT requires augmenting the Ca2+ content of the sarcoplasmic reticulum (SR), which must come from a net increase of Ca2+ across the sarcolemma. However, the mechanism that links mechanical loading to the control of Ca2+ entry remains unknown. Plausible mechanisms for this net increase include a mechanical load-induced increase of Ca2+ influx through L-type Ca2+ channels (ICaL) or a decreased efflux from Na+-Ca2+ exchanger (INCX). However, studying how mechanical loading affects ICaL or INCX has been hampered by the technical difficulty of subjecting myocytes to mechanical loads while simultaneously doing patch-clamp experiments. Now we have overcome this obstacle. Innovation: Recently we invented the Patch-Clamp-in-Gel technique that enables us to simultaneously measure membrane voltage or current, SR or cytosolic Ca2+, and contraction in single myocytes embedded in a viscoelastic hydrogel that controls mechanical load on the cell. Preliminary data reveal that mechanical load increases ICaL, prolongs the action potential (AP), and increases SR Ca2+ content in rabbit ventricular myocytes. Therefore we hypothesize that mechanical load increases Ca2+ entry during AP to elevate the SR Ca2+ content and Ca2+ release that increases CaT, which can partially compensate for increased mechanical load. While a compensatory increase in CaT might be beneficial to offset moderate increases in mechanical loading, we further posit that excessive loading causes SR Ca2+ overload by excessive ICaL increase or INCX decrease, leading to arrhythmogenic spontaneous Ca2+ release. Failing hearts cannot generate enough force to maintain adequate cardiac output. We hypothesize that the compensatory increase of CaT with increased load is blunted in HF. Our interdisciplinary team will develop the new Patch-Clamp-in-Gel technique and test the hypotheses using ventricular myocytes from healthy and HF rabbit, and transgenic mouse to achieving three specific aims. (1) Systematically investigate how mechanical load regulates myocyte E-C- coupling during cardiac cycle. (2) Decipher mechano-electro-transduction effects on ICaL and INCX and Ca2+ entry during AP. (3) Understand how pathological high load may cause Ca2+ dysregulation and arrhythmogenic activities in HF. The outcome of this project will elucidate how mechanical load affects cardiac excitation-contraction coupling in compensatory response to physiological loading, and how mechanotransduction is impaired in heart failure patients to cause arrhythmias and contractile dysfunction.

摘要