Endogenous NO mediates the stretch dependence of Ca2+

内源性 NO 介导 Ca2 的拉伸依赖性

• 批准号: 6530301
• 负责人: Steven J Sollott
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 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/6530301
• 关键词: aging; calcium channel; calcium flux; cardiac myocytes; heart contraction; laboratory rat; muscle contraction; myocardium; nitric oxide; stretch reflex

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.

肌肉拉伸是心脏机能的主要决定因素。延长肌节，心肌的基本收缩单位，导致Ca2+与肌钙蛋白C的结合增强，并立即增加收缩力，以响应肌浆网（SR）释放Ca2+。心肌拉伸也通过增强兴奋- ca2 +释放过程来调节收缩，但这是如何发生的仍然不清楚。我们发现肌细胞拉伸调节基本的Ca2+释放过程，从ryanodine-receptor-Ca2+释放通道（RyRC）， Ca2+火花，和电刺激的Ca2+瞬态。拉伸诱导Akt和eNOS的pi3激酶依赖性磷酸化，NO的产生，以及Ca2+火花频率的比例增加，这通过抑制NOS和pi3激酶来消除。外源产生的NO可逆地增加Ca2+火花频率而不拉伸细胞。我们认为，pi3激酶- akt - enos轴激活产生的肌细胞NO通过增强RyRC活性作为拉伸的第二信使，促进心肌收缩激活。这组机制可以通过产生NO作为心脏拉伸的生理传感器，在心肌长度和EC耦合之间提供了一种新的联系。这种拉伸介导的NO通路也可以在更大的范围内被视为适应性心肌负荷依赖的信号事件，包括自分泌/旁分泌激活PI3K-Akt轴，并向各种下游效应器分化。由此产生的eNOS激活可以在短期内调节收缩性，但也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功能和/或结构的病理改变。例如，在高血压性心脏肥厚和心力衰竭中，由于ICa触发SR钙释放的能力降低而导致的EC偶联缺陷可能与eNOS蛋白丰度的降低相关，而eNOS蛋白丰度与左室功能障碍的严重程度成正比。因此，基于本文确定的机制，我们认为当其他代偿机制失效时，内源性NO机制的缺失可能会显著促进心肌功能损伤的发展。