Oxidant stress from nitric oxide synthase–3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load
Eiki Takimoto, … , Yibin Wang, David A. Kass
Eiki Takimoto, … , Yibin Wang, David A. Kass
Published May 2, 2005
Citation Information: J Clin Invest. 2005;115(5):1221-1231. https://doi.org/10.1172/JCI21968.
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Categories: Article Cardiology

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 Ca2+-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

Eiki Takimoto, Hunter C. Champion, Manxiang Li, Shuxun Ren, E. Rene Rodriguez, Barbara Tavazzi, Giuseppe Lazzarino, Nazareno Paolocci, Kathleen L. Gabrielson, Yibin Wang, David A. Kass

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Figure 1

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Lack of NOS3 ameliorates cardiac hypertrophy and dilatory remodeling in ...
Lack of NOS3 ameliorates cardiac hypertrophy and dilatory remodeling in response to TAC-induced pressure overload. (A) Formalin-fixed (10%) hearts showing progressive cardiac hypertrophy with marked dilatory remodeling in WT TAC mice versus more modest and concentric cardiac hypertrophy at 3 weeks, with minimal further progression at 9 weeks, in NOS3–/– TAC mice. Scale bar: 10 mm. (B) Mean data for HW/TL ratio (n = 6 or more per group). (C) Histological analysis of WT and NOS3–/– TAC hearts. PAS methenamine staining reveals increased interstitial fibrosis (dark stain, upper right panel) and myocyte size in WT TAC hearts. NOS3–/– TAC hearts reveal minimal fibrosis and blunted increase in myocyte size. Scale bar: 100 μm. (D) Summary quantification of cardiomyocyte diameter (n = 4–5 per genotype, 6–10 regions per heart, 50–60 cells per heart for size estimates). P values shown indicate the effect of genotype on the TAC-stimulated response (2–way ANOVA).