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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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Article Cardiology

Oxidant stress from nitric oxide synthase–3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load

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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).
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