Copyright © 2006, European Society of Cardiology
Antioxidant actions contribute to the antihypertrophic effects of atrial natriuretic peptide in neonatal rat cardiomyocytes
aWynn Department of Metabolic Cardiology, Baker Heart Research Institute, Melbourne 8008, Australia
bDepartment of Pharmacology, University of Melbourne 3010, Australia
cDepartment of Pharmacology, Monash University, Clayton 3800, Victoria, Australia
* Corresponding author. Wynn Department of Metabolic Cardiology, Baker Heart Research Institute, PO Box 6492, St Kilda Rd Central, Melbourne, VIC, 8008, Australia. Tel.: +61 3 8532 1392; fax: +61 3 8532 1100. Email address: rebecca.ritchie{at}baker.edu.au
Objective: Reactive oxygen species (ROS) such as superoxide have been linked to the hypertrophic response of the heart to stimuli including angiotensin II (AngII), mechanical stretch, and pressure overload. We have previously demonstrated that cGMP and protein kinase G mediate the antihypertrophic actions of the natriuretic peptides in rat cardiomyocytes and isolated whole hearts. The impact of natriuretic peptides on cardiac ROS generation, however, has not been investigated. We tested the hypothesis that reduced superoxide accumulation contributes to the antihypertrophic action of atrial natriuretic peptide (ANP).
Methods: Neonatal rat cardiomyocytes were cultured in serum-free medium with and without AngII (1µmol/L) or endothelin-1 (ET1, 60nmol/L) in the presence and absence of ANP (1µmol/L) or tempol (100µmol/L). Hypertrophic responses, cardiomyocyte superoxide generation, and cardiomyocyte expression of NADPH oxidase were determined.
Results: AngII induced increases in cardiomyocyte size (to 176±9% n=8 p<0.001, at 48h), β-myosin heavy chain expression (to 4.0±1.6-fold n=6 p<0.05, at 48h), c-fos expression (to 1.9±0.5-fold n=7 p<0.01, at 6h), superoxide generation (to 181±21% n=8 p<0.005, at 24h), and expression of the gp91phox subunit of NADPH oxidase (to 2.4±0.5-fold n=7 p<0.05, at 48h). These effects were all significantly inhibited by ANP: cardiomyocyte size, β-myosin heavy chain expression, c-fos expression, superoxide generation and gp91phox expression were reduced to 107±5% (n=5 p<0.05), 1.2±0.2-fold (n=6 p<0.05), 0.9±0.2-fold (n=7 p<0.05), 141±21% (n=8 p<0.05), and to 1.0±0.5-fold (n=7 p<0.05), respectively. These effects were mimicked by tempol. ANP and tempol also significantly inhibited ET1-induced increases in cardiomyocyte size and superoxide generation, but had no effect on markers of hypertrophy when studied alone.
Conclusion: This data indicates that the antihypertrophic actions of ANP are accompanied by reduced levels of superoxide, suggesting an antioxidant action contributes to the antihypertrophic actions of ANP.
KEYWORDS ANP; Antioxidant; Cardiomyocytes; NADPH oxidase; Oxygen radicals; Peptide hormones
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