title: Molecular mechanisms of neuronal nitric oxide synthase in cardiac function and pathophysiology.
abstract: 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 Ca(2+), 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 Ca(2+)-handling proteins [e.g. PKA-dependent phospholamban phosphorylation (PLN-Ser(16))] in the healthy heart to cGMP/PKG-dependent PLN-Ser(16) with acute angiotensin II (Ang II) treatment. In early hypertension, nNOS-derived NO is involved in increases of cGMP/PKG-dependent troponin I (TnI-Ser(23/24)) and cardiac myosin binding protein C (cMBP-C-Ser(273)). However, nNOS-derived NO is shown to increase S-nitrosylation of various Ca(2+)-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.
authors.affiliation: Department of Physiology, College of Medicine, Seoul National University, Seoul, South Korea Ischaemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, South Korea Clinical Research Center, Yanbian University Hospital, Yanji, Jilin Province, China yinzhang87@gmail.com.
authors.forename: Yin Hua
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Clinical Research Center, Yanbian University Hospital, Yanji, Jilin Province, China.
authors.forename: Chun Zi
authors.initials: CZ
authors.lastname: Jin
authors.affiliation: Department of Physiology, College of Medicine, Seoul National University, Seoul, South Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Department of Physiology, College of Medicine, Seoul National University, Seoul, South Korea.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000201:enzymology / Q000378:metabolism*; D001341:Autonomic Nervous System / Q000378:metabolism; D020013:Calcium Signaling; D006801:Humans; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D052248:Nitric Oxide Synthase Type I
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