Abstract
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.
Highlights
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
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
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 with a naturally occurring allele of natriuretic peptide precursor A (6 – 8); and 4) overexpression of an endothelial nitric-oxide synthase transgene attenuates isoproterenol-induced LVH [9]
Summary
DNA Constructs and TG Animals—A portion of the rat cDNA coding for NPRA [15] It has been shown that this fragment codes for a soluble cytoplasmic protein that has constitutive guanylate cyclase activity in transfected COS cells [16, 17] This cDNA fragment was cloned downstream of a 5.8-kb fragment of the ␣-myosin heavy chain gene promoter Adult mouse cardiomyocytes were isolated from the ventricles of 12-week-old mice (either NT or TG) by Langendorff perfusion of sequential solutions containing various concentrations of proteases and/or Ca2ϩ, as described previously [18]. This preparation yielded mostly viable and noncontracting rod-shaped cells along with minor amounts of cellular debris. Statistics—Comparisons between groups were performed by one-way analysis of variance followed by Fisher’s LSD post hoc tests
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