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J. Biol. Chem., Vol. 278, Issue 48, 47694-47699, November 28, 2003

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Expression of Constitutively Active Guanylate Cyclase in Cardiomyocytes Inhibits the Hypertrophic Effects of Isoproterenol and Aortic Constriction on Mouse Hearts^*

Ahmad Zahabi, Sylvie Picard, Nadia Fortin, Timothy L. Reudelhuber, and Christian F. Deschepper

From the Experimental Cardiovascular Biology and Molecular Biochemistry of Hypertension Research Units, Canadian Institutes for Health Research Multidisciplinary Research Group in Hypertension, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada

Evidence from several rodent models has suggested that a reduction of either atrial natriuretic peptide or its receptor in the heart affects cardiac remodeling by promoting the onset of cardiac hypertrophy. The atrial natriuretic peptide receptor mediates signaling at least in part via the generation of intracellular cyclic GMP. To directly test whether accumulation of intracellular cyclic GMP conveys protection against cardiac hypertrophy, we engineered transgenic mice that overexpress a catalytic fragment of constitutively active guanylate cyclase domain of the atrial natriuretic peptide receptor in a cardiomyocyte-specific manner. Expression of the transgene increased the intracellular concentration of cyclic GMP specifically within cardiomyocytes and had no detectable effect on cardiac performance under basal conditions. However, expression of the transgene attenuated the effects of the pharmacologic hypertrophic agent isoproterenol on cardiac wall thickness and prevented the onset of the fetal gene expression program normally associated with cardiac hypertrophy. Likewise, expression of the transgene inhibited the hypertrophic effects of abdominal aortic constriction, since it abolished its effects on ventricular wall thickness and greatly attenuated its effects on cardiomyocyte size. Altogether, our results suggest that cyclic GMP is a cardioprotective agent against hypertrophy that acts via a direct local effect on cardiomyocytes.

Received for publication, September 2, 2003 , and in revised form, September 16, 2003.

^* This work was supported by NHLBI, National Institutes of Health, Grant HL69122, by Canadian Institutes for Health Research (CIHR) Grants MOP-14086 and MOP-36449, by a CIHR group grant to the Multidisciplinary Research Group in Hypertension, and by a grant from the Fondation des Maladies du Coeur du Québec (to C. F. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: IRCM, 110 Pine Ave. W., Montréal, Québec H2W 1R7, Canada. Tel.: 514-987-5759; Fax: 514-987-5585; E-mail: deschec{at}ircm.qc.ca.

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