Endogenous NO mediates the stretch dependence of Ca2+

肌肉伸展是心脏性能的主要决定因素。延长肌节（心肌中的基本收缩单位）导致与肌钙蛋白C结合的Ca 2+增强，并响应于从肌浆网（SR）释放Ca 2+而立即增加收缩力。心肌牵张也通过增强兴奋-Ca 2 +-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，肌细胞牵张调节从Ryanodine受体-Ca 2 +-释放通道（RyRC）、Ca 2 +-火花和电刺激Ca 2 +-瞬变的基本Ca 2 +-释放过程。牵张诱导Akt和eNOS的PI 3激酶依赖性磷酸化，NO产生，以及通过抑制NOS和PI 3激酶而消除的Ca 2+火花频率的成比例增加。外源性产生的NO可逆地增加Ca 2 +-火花频率没有细胞拉伸。我们认为，通过激活PI 3激酶-Akt-eNOS轴产生的心肌细胞NO通过增强RyRC活性作为牵张的第二信使，促进心肌收缩激活。这套机制可以作为一个生理传感器的心脏伸展通过产生NO，提供了一个新的联系之间的心肌长度和EC耦合。这种牵张介导的NO通路也可以在适应性心肌负荷依赖性信号传导事件的更大范围内观察，这些事件涉及PI 3 K-Akt轴的自分泌/旁分泌激活，这些激活发散到各种下游效应物。由此产生的eNOS激活可以在短期内调节收缩性，但也可以诱导导致长期肥大的基因，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，在高血压性心脏肥大和心力衰竭中，由于伊卡触发SR释放钙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，eNOS蛋白丰度的降低与LV功能障碍的严重程度成比例。因此，基于这里确定的机制，我们将提出，内源性NO机制的损失可能有助于显着的心肌功能障碍的发展时，其他代偿机制失败。

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.