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 α-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.

Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent

“…When BH 4 availability is limiting, electron transport within the active site becomes "uncoupled" from L-arginine oxidation, causing a reduction of oxygen to superoxide (34). Depletion in BH 4 and eNOS uncoupling has been correlated with cardiac dysfunction in murine models of hypertension and transverse aortic constriction (35,36). Compared with WT mice, CSE KO mice had significantly lower cardiac BH 4 levels, and a trend toward higher dihydrobiopterin (BH 2 ) levels.…”

Direct monitoring pressure overload predicts cardiac hypertrophy in mice

“…Cardiac hypertrophy, fibrosis and gene expression changes are all consequences of POL, a commonly used animal model for cardiovascular research (Rockman et al 1991, De Windt et al 2001, Asakawa et al 2002, McMullen et al 2003, Liao et al 2004, De Acetis et al 2005, Takimoto et al 2005. However, their correlations with direct measurements of hemodynamic parameters in POL have not been determined in conscious ambulatory mice.…”

“…This model, including both transverse aortic constriction and abdominal aortic constriction, was adapted to mice and has been widely used in cardiovascular research (Rockman et al 1991, De Windt et al 2001, Asakawa et al 2002, McMullen et al 2003, Liao et al 2004, De Acetis et al 2005, Takimoto et al 2005. To produce the POL the aorta is commonly constricted by tying a suture against a needle to standardize the degree of restriction.…”

Effects of Tetrahydrobiopterin Oral Treatment in Hypoxia‐Induced Pulmonary Hypertension in Rat

“…7,8 This imbalance in NO/superoxide production results in oxidative stress, a major contributing factor in a variety of vascular diseases, 7,9,10 which also leads to detrimental effects on cardiac function. 11 Previous studies in our group and others have shown that BH 4 plays a pivotal role in regulating NO/superoxide balance in the pulmonary vasculature. [12][13][14] It has been shown that hph-1 mice, deficient in GTP-cyclohydrolase 1 (GTPCH-1), the rate limiting enzyme for BH 4 production, show pulmonary vascular remodeling and right ventricular hypertrophy under normoxic conditions, accompanied by significantly increased superoxide production in the lung.…”