Molecular mechanisms of neuronal nitric oxide synthase in cardiac function and pathophysiology
Molecular mechanisms of neuronal nitric oxide synthase in cardiac function and pathophysiology
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DOI：
10.1113/jphysiol.2013.270306
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发表时间：
2014-08
期刊：
影响因子：
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通讯作者：
Yin Hua Zhang;C. Jin;J. Jang;Y. Wang
中科院分区：
文献类型：
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作者：
Yin Hua Zhang;C. Jin;J. Jang;Y. Wang
神经元型一氧化氮合酶（nNOS或NOS 1）是心肌一氧化氮（NO）的主要内源性来源，其促进心脏舒张并调节收缩。在健康心脏中，它调节细胞内Ca 2+、信号传导途径和氧化稳态，并且在致病性损伤后从早期阶段上调。nNOS在保护心肌免受衰竭心脏中增加的氧化应激、收缩/舒张功能障碍、不良结构重构和心律失常中起关键作用。在这里，我们发现nNOS的下游靶蛋白和潜在的转录后修饰在疾病进展过程中从健康心脏中的Ca 2+处理蛋白[例如PKA依赖性受磷蛋白磷酸化（PLN-Ser 16）]转移到急性血管紧张素II（Ang II）治疗的cGMP/PKG依赖性PLN-Ser 16。在早期高血压中，nNOS衍生的NO参与cGMP/PKG依赖性肌钙蛋白I（TnI-Ser 23/24）和心肌肌球蛋白结合蛋白C（cMBP-C-Ser 273）的增加。然而，nNOS衍生的NO显示出增加衰竭心肌中各种Ca 2+处理蛋白的S-亚硝基化。nNOS的空间区室化及其在病变心脏中的不同结合伴侣或各种nNOS剪接变体的易位以及响应于病理应激的调节可能负责不同的潜在机制和功能。在这篇综述中，我们努力概述最近的进展，在正常和病变的心脏在心肌nNOS介导的功能的分子机制的知识。深入了解nNOS基因调控在各种组织进行了讨论。总体而言，nNOS是患病心脏中重要的心脏保护剂。nNOS的动态定位和多种介导机制保证了其在应激状态下能够有效地调节心脏功能。
Neuronal nitric oxide synthase (nNOS or NOS1) is the major endogenous source of myocardial nitric oxide (NO), which facilitates cardiac relaxation and modulates contraction. In the healthy heart it regulates intracellular Ca2+, signalling pathways and oxidative homeostasis and is upregulated from early phases upon pathogenic insult. nNOS plays pivotal roles in protecting the myocardium from increased oxidative stress, systolic/diastolic dysfunction, adverse structural remodelling and arrhythmias in the failing heart. Here, we show that the downstream target proteins of nNOS and underlying post‐transcriptional modifications are shifted during disease progression from Ca2+‐handling proteins [e.g. PKA‐dependent phospholamban phosphorylation (PLN‐Ser16)] in the healthy heart to cGMP/PKG‐dependent PLN‐Ser16 with acute angiotensin II (Ang II) treatment. In early hypertension, nNOS‐derived NO is involved in increases of cGMP/PKG‐dependent troponin I (TnI‐Ser23/24) and cardiac myosin binding protein C (cMBP‐C‐Ser273). However, nNOS‐derived NO is shown to increase S‐nitrosylation of various Ca2+‐handling proteins in failing myocardium. The spatial compartmentation of nNOS and its translocation for diverse binding partners in the diseased heart or various nNOS splicing variants and regulation in response to pathological stress may be responsible for varied underlying mechanisms and functions. In this review, we endeavour to outline recent advances in knowledge of the molecular mechanisms mediating the functions of nNOS in the myocardium in both normal and diseased hearts. Insights into nNOS gene regulation in various tissues are discussed. Overall, nNOS is an important cardiac protector in the diseased heart. The dynamic localization and various mediating mechanisms of nNOS ensure that it is able to regulate functions effectively in the heart under stress.