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Endogenous NO Mediates the Stretch-dependence of Ca2+

内源性 NO 介导 Ca2 的拉伸依赖性

基本信息

批准号：
7131102
负责人：
Steven J Sollott
金额：
--
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7131102
关键词：
autocrine calcium channel calcium flux cardiac myocytes enzyme activity muscle contraction myocardium nitric oxide nitric oxide synthase paracrine phosphatidylinositol 3 kinase second messengers stretch reflex

项目摘要

Muscle stretch is a principal determinant of cardiac performance. Lengthening the sarcomere, the basic contractile unit in cardiac muscle, results in enhanced Ca2+-binding to Troponin C and an immediate increase in contractile force in response to the release of Ca2+ from the sarcoplasmic reticulum (SR). Cardiac muscle stretch also modulates contraction via enhancement of excitation-Ca2+-release process, but how this occurs remains obscure. We found that myocyte stretch modulates the elementary Ca2+-release process from ryanodine-receptor-Ca2+-release-channels (RyRC), Ca2+-sparks, and the electrically-stimulated Ca2+-transient. Stretch induces PI3-kinase-dependent phosphorylation of both Akt and eNOS, NO production, and a proportionate increase in Ca2+-spark frequency that is abolished by inhibiting NOS and PI3-kinase. Exogenously-generated NO reversibly increases Ca2+-spark frequency without cell stretch. We propose that myocyte NO produced by activation of the PI3-kinase-Akt-eNOS axis acts as a second messenger of stretch by enhancing RyRC activity, contributing to myocardial contractile activation. This set of mechanisms could serve as a physiologic sensor of cardiac stretch by generating NO, providing a novel link between cardiac muscle length and EC coupling. This stretch-mediated NO pathway could also be viewed in the larger context of a spectrum of adaptive myocardial load-dependent signalling events involving autocrine/paracrine activation of the PI3K-Akt axis diverging to various downstream effectors. The resultant eNOS activation could modulate contractility in the near term but also the induction of genes leading to hypertrophy in the longer term, and promote cell survival. Accordingly, alterations in these mechanisms could contribute to pathological changes in cardiac performance and/or structure. For instance, defects in EC coupling due to a reduced ability of ICa to trigger calcium release from the SR in hypertensive cardiac hypertrophy and heart failure could be correlated with decreases in eNOS protein abundance proportional to the severity of LV dysfunction. Thus, based on the mechanisms identified here, we would propose that the loss of the endogenous NO mechanisms could contribute significantly to the development of functional impairments of cardiac muscle when other compensatory mechanisms fail.

肌肉伸展是心脏功能的主要决定因素。延长肌小节（心肌的基本收缩单位）可增强 Ca2+ 与肌钙蛋白 C 的结合，并响应肌浆网 (SR) 释放 Ca2+ 而立即增加收缩力。心肌拉伸还通过增强兴奋 Ca2+ 释放过程来调节收缩，但这种情况是如何发生的仍不清楚。我们发现肌细胞拉伸调节兰尼碱受体 Ca2+ 释放通道 (RyRC)、Ca2+ 火花和电刺激 Ca2+ 瞬态的基本 Ca2+ 释放过程。拉伸诱导 Akt 和 eNOS 的 PI3 激酶依赖性磷酸化、NO 产生以及 Ca2+ 火花频率的成比例增加，而 Ca2+ 火花频率可通过抑制 NOS 和 PI3 激酶而消除。外源产生的 NO 可逆地增加 Ca2+ 火花频率，而无需细胞拉伸。我们认为，PI3-激酶-Akt-eNOS 轴激活产生的肌细胞 NO 通过增强 RyRC 活性充当拉伸的第二信使，有助于心肌收缩激活。这组机制可以通过产生 NO 作为心脏牵张的生理传感器，在心肌长度和 EC 耦合之间提供新的联系。这种牵张介导的 NO 途径也可以在一系列适应性心肌负荷依赖性信号事件的更大背景下观察，涉及 PI3K-Akt 轴的自分泌/旁分泌激活，分叉到各种下游效应器。由此产生的 eNOS 激活不仅可以在短期内调节收缩性，而且还可以在长期内诱导导致肥大的基因，并促进细胞存活。因此，这些机制的改变可能导致心脏性能和/或结构的病理变化。例如，在高血压心脏肥大和心力衰竭中，由于ICa触发SR中钙释放的能力降低而导致EC偶联缺陷，这可能与eNOS蛋白丰度的降低相关，而eNOS蛋白丰度的降低与左心室功能障碍的严重程度成正比。因此，根据此处确定的机制，我们提出，当其他代偿机制失效时，内源性 NO 机制的丧失可能会显着导致心肌功能损伤的发生。