title: Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load.
abstract: Cardiac pressure load stimulates hypertrophy, often leading to chamber dilation and dysfunction. ROS contribute to this process. Here we show that uncoupling of nitric oxide synthase-3 (NOS3) plays a major role in pressure load-induced myocardial ROS and consequent chamber remodeling/hypertrophy. Chronic transverse aortic constriction (TAC; for 3 and 9 weeks) in control mice induced marked cardiac hypertrophy, dilation, and dysfunction. Mice lacking NOS3 displayed modest and concentric hypertrophy to TAC with preserved function. NOS3(-/-) TAC hearts developed less fibrosis, myocyte hypertrophy, and fetal gene re-expression (B-natriuretic peptide and alpha-skeletal actin). ROS, nitrotyrosine, and gelatinase (MMP-2 and MMP-9) zymogen activity markedly increased in control TAC, but not in NOS3(-/-) TAC, hearts. TAC induced NOS3 uncoupling in the heart, reflected by reduced NOS3 dimer and tetrahydrobiopterin (BH4), increased NOS3-dependent generation of ROS, and lowered Ca(2+)-dependent NOS activity. Cotreatment with BH4 prevented NOS3 uncoupling and inhibited ROS, resulting in concentric nondilated hypertrophy. Mice given the antioxidant tetrahydroneopterin as a control did not display changes in TAC response. Thus, pressure overload triggers NOS3 uncoupling as a prominent source of myocardial ROS that contribute to dilatory remodeling and cardiac dysfunction. Reversal of this process by BH4 suggests a potential treatment to ameliorate the pathophysiology of chronic pressure-induced hypertrophy.
authors.affiliation: Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
authors.forename: Manxiang
authors.initials: M
authors.lastname: Li
authors.forename: Shuxun
authors.initials: S
authors.lastname: Ren
authors.forename: E Rene
authors.initials: ER
authors.lastname: Rodriguez
authors.forename: Barbara
authors.initials: B
authors.lastname: Tavazzi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lazzarino
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Gabrielson
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology*; D005355:Fibrosis; D015151:Immunoblotting; D051379:Mice; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D001708:Biopterins; C023455:tetrahydroneopterin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse