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.