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. Left ventricular hypertrophy (LVH)1 results from the activation of multiple signaling pathways by either mechanical or neurohumoral stimuli (1, 2). A great number of studies have used animal models of transgenesis or gene inactivation to test the possible roles of these pathways in the induction of LVH in vivo. However, the contributions of possible negative regulators of LVH have so far received much less attention. Recently, several lines of evidence have suggested that atrial natriuretic peptide (ANP) and endothelial nitric-oxide synthase may act as such negative regulators, since 1) blood-pressure-independent LVH is present in mice with either general (3) or cardiomyocyte-restricted (4) inactivation of natriuretic peptide receptor A (NPRA); 2) cardiomyocyte-specific expression of NPRA partially rescues the cardiac hypertrophic phenotype seen in NPRA-null mice (5); 3) we have shown that cardiac mass and ventricular expression of ANP were both associated (in an inverse fashion) with a naturally occurring allele of natriuretic peptide precursor A (i.e. the gene that codes for ANP) (6 -8); and 4) overexpression of an endothelial nitric-oxide synthase transgene attenuates isoproterenol-induced LVH (9). The common denominator between ANP and endothelial nitric-oxide synthase is that many (if not most) of their biologic effects are mediated by cGMP (10, 11). Interestingly, it has also been shown that cGMP protects cultured neonatal cardiomyocytes against the effects of hypertrophic agents in vitro (12-14). However, it remains to be proven that cGMP has similar actions in vivo.To add...

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