Department of Cardiovascular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Antioxid Redox Signal. 2013 Mar 20;18(9):1078-99. doi: 10.1089/ars.2012.4824. Epub 2012 Sep 20.
The regulation of myocardial function by constitutive nitric oxide synthases (NOS) is important for the maintenance of myocardial Ca(2+) homeostasis, relaxation and distensibility, and protection from arrhythmia and abnormal stress stimuli. However, sustained insults such as diabetes, hypertension, hemodynamic overload, and atrial fibrillation lead to dysfunctional NOS activity with superoxide produced instead of NO and worse pathophysiology.
Major strides in understanding the role of normal and abnormal constitutive NOS in the heart have revealed molecular targets by which NO modulates myocyte function and morphology, the role and nature of post-translational modifications of NOS, and factors controlling nitroso-redox balance. Localized and differential signaling from NOS1 (neuronal) versus NOS3 (endothelial) isoforms are being identified, as are methods to restore NOS function in heart disease.
Abnormal NOS signaling plays a key role in many cardiac disorders, while targeted modulation may potentially reverse this pathogenic source of oxidative stress.
Improvements in the clinical translation of potent modulators of NOS function/dysfunction may ultimately provide a powerful new treatment for many hearts diseases that are fueled by nitroso-redox imbalance.
组成型一氧化氮合酶（NOS）对心肌功能的调节对于维持心肌 Ca（2+）稳态、松弛和伸展性、预防心律失常和异常应激刺激非常重要。然而，持续的刺激，如糖尿病、高血压、血流动力学过载和心房颤动，导致NOS 活性异常，产生超氧化物而不是 NO，导致更糟糕的病理生理。
对正常和异常组成型 NOS 在心脏中的作用的深入了解揭示了 NO 调节心肌功能和形态的分子靶点、NOS 的翻译后修饰的作用和性质，以及控制亚硝基-氧化还原平衡的因素。NOS1（神经元）与 NOS3（内皮）同工型的局部和差异信号正在被识别，以及在心脏病中恢复 NOS 功能的方法也正在被识别。
异常的 NOS 信号在许多心脏疾病中起着关键作用，而靶向调节可能潜在地逆转这种氧化应激的致病来源。
改善 NOS 功能/障碍的有效调节剂的临床转化最终可能为许多由亚硝基-氧化还原失衡驱动的心脏病提供一种强大的新治疗方法。
