Role of PDE5/cGMP/cGMP-dependent Protein Kinase in Cardiac Hypertrophy and Remodeling

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Cardiac hypertrophy is effectively decreased by natriuretic peptides, particulate guanylyl cyclase A and cyclic guanosine monophosphate (cGMP). The available evidence including inhibition of phosphodiesterase 5 (PDE5) by sildenafil suggests that cGMP signals through cGMP kinase I (cGKI). So far, mice that carry a global or cardiomyocyte-specific deletion of cGKI showed no cardiac hypertrophy. These discrepant results may be explained either by the use of inadequate mouse models caused by a) multiple interfering diseases observed in the conventional cGKI knockouts or b) by deletion of cGKI in the wrong cells or c) a cGKI-independent signaling cascade for cGMP. For example, it is possible that cardiac fibroblast contribute to the antihypertrophic effects of atrial natriuretic peptide (ANP), because in normal animals we can detect PDE5 only in the latter cells. The focus of the proposed research will be the use of new and better mouse models to study the contribution of cGKl and PDE5/cGMP to cardiac hypertrophy.