Abstract
Myocardial oxidative stress and inflammation are key mechanisms in cardiovascular remodeling. C-type natriuretic peptide (CNP) is an endothelium-derived cardioprotective factor, although its effect on cardiac superoxide generation has not been investigated in vivo. This study tested the hypothesis that suppression of superoxide production contributes to the cardioprotective action of CNP. Angiotensin II (Ang II) or saline was continuously infused subcutaneously into mice using an osmotic minipump. Simultaneously with the initiation of Ang II treatment, mice were infused with CNP (0.05 μg/kg/min) or vehicle for 2 weeks. The heart weight to tibial length ratio was significantly increased by Ang II in vehicle-treated mice. Treatment with CNP decreased Ang II-induced cardiac hypertrophy without affecting systolic blood pressure. Echocardiography showed that CNP attenuated Ang II-induced increase in wall thickness, left ventricular dilatation, and decrease in fractional shortening. CNP reduced Ang II-induced increases in cardiomyocyte size and interstitial fibrosis and suppressed hypertrophic- and fibrosis-related gene expression. Finally, CNP decreased Ang II-induced cardiac superoxide production. These changes were accompanied by suppression of NOX4 gene expression. Our data indicate that treatment with CNP attenuated Ang II-induced cardiac hypertrophy, fibrosis, and contractile dysfunction which were accompanied by reduced cardiac superoxide production.
Highlights
C-type natriuretic peptide (CNP) belongs to the natriuretic peptides (NPs) family, which was originally isolated from porcine brain tissues and later established as a positive regulator of endochondral ossification [1]
heart rate (HR) was unaffected by Angiotensin II (Ang II) infusion in both CNP- and vehicle-treated mice compared to saline-infused mice
This study provides the first in vivo evidence that continuous infusion of exogenous CNP attenuated Ang IIinduced myocardial superoxide production and cardiac dysfunction
Summary
C-type natriuretic peptide (CNP) belongs to the natriuretic peptides (NPs) family, which was originally isolated from porcine brain tissues and later established as a positive regulator of endochondral ossification [1]. CNP is secreted from endothelial cells and cardiac fibroblasts, and acts as an autocrine/paracrine regulator [2, 3]. ANP and BNP bind to natriuretic peptide receptor (NPR)-A, inducing natriuresis and diuresis, whereas CNP preferentially binds to its specific receptor, NPR-B. Because of the relative abundance of NPR-B over NPR-A in cardiac fibroblasts and in cardiomyocytes, CNP reportedly has more potent antihypertrophic and antifibrotic properties, despite less hypotensive and less natriuretic effects compared with ANP and BNP [6, 7]. It is of interest to elucidate the precise role of CNP in cardiovascular pathophysiology from both a basic and clinical medicine perspective
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