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Disruption of adenylyl cyclase type V does not rescue the phenotype of cardiac-specific overexpression of Galphaq protein-induced cardiomyopathy.

Adenylyl cyclase (AC) is the principal effector molecule in the β-adrenergic receptor pathway. AC(V) and AC(VI) are the two predominant isoforms in mammalian cardiac myocytes. The disparate roles among AC isoforms in cardiac hypertrophy and progression to heart failure have been under intense investigation. Specifically, the salutary effects resulting from the disruption of AC(V) have been established in multiple models of cardiomyopathy. It has been proposed that a continual activation of AC(V) through elevated levels of protein kinase C could play an integral role in mediating a hypertrophic response leading to progressive heart failure. Elevated protein kinase C is a common finding in heart failure and was demonstrated in murine cardiomyopathy from cardiac-specific overexpression of G(αq) protein. Here we assessed whether the disruption of AC(V) expression can improve cardiac function, limit electrophysiological remodeling, or improve survival in the G(αq) mouse model of heart failure. We directly tested the effects of gene-targeted disruption of AC(V) in transgenic mice with cardiac-specific overexpression of G(αq) protein using multiple techniques to assess the survival, cardiac function, as well as structural and electrical remodeling. Surprisingly, in contrast to other models of cardiomyopathy, AC(V) disruption did not improve survival or cardiac function, limit cardiac chamber dilation, halt hypertrophy, or prevent electrical remodeling in G(αq) transgenic mice. In conclusion, unlike other established models of cardiomyopathy, disrupting AC(V) expression in the G(αq) mouse model is insufficient to overcome several parallel pathophysiological processes leading to progressive heart failure.