Endogenous No Mediates The Stretch-dependence Of Ca2+-re

内源性No介导Ca2-re的拉伸依赖性

• 批准号: 6667893
• 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/6667893
• 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.

肌肉伸展是心脏表现的主要决定因素。加长心脏肌肉中的基本收缩单元，肌肉延长了肌钙蛋白C的Ca2+结合，并立即增加了收缩力增加，以响应Ca2+从肌浆网（SR）中释放出来。心肌拉伸还通过增强激发CA2+释放过程来调节收缩，但是这种情况的发生仍然不明显。我们发现，肌细胞拉伸从ryanodine-pector-ca2+-release-channels（RyRC），Ca2+sparks和电刺激的Ca2+transient中调节基本Ca2+释放过程。拉伸诱导Akt和Enos的PI3-激酶依赖性磷酸化，无生产，并且通过抑制NOS和PI3-激酶消除的Ca2+spark频率比例增加。外源性生成的无可逆地增加没有细胞伸展的Ca2+spark频率。我们建议通过激活PI3-激酶-Akt-Enos轴激活而产生的心肌细胞，从而通过增强RYRC活性来充当延伸的第二个使者，从而导致心肌收缩激活。这组机制可以通过产生NO来作为心脏伸展的生理传感器，从而在心肌长度和EC耦合之间提供新的联系。这种拉伸介导的没有途径也可以在较大的自适应心肌载荷依赖性信号传导事件的较大背景下进行观察，这些信号传导事件涉及PI3K-AKT轴的自分泌/旁分泌激活，与各种下游效应子分流。所得的eNOS激活可以在短期内调节收缩力，但从长远来看会导致肥大的基因诱导，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，由于ICA在高血压心脏肥大中触发钙释放的能力降低而导致的EC耦合缺陷可能与eNOS蛋白丰度与LV功能障碍的严重程度成比例的降低相关。因此，基于此处确定的机制，我们将提出内源性的丧失，当其他补偿机制失败时，没有机制可以显着促进心肌功能障碍的发展。