Cardiac-directed expression of adenylyl cyclase reverses electrical remodeling in cardiomyopathy

Adenylyl cyclase (AC) is an effector molecule in beta-adrenergic receptor signaling, catalyzing conversion of ATP to cAMP. Agents that increase intracellular levels of cAMP have been used previously to treat clinical heart failure. Recently, Roth et al. have shown that long-term cardiac-directed expression of AC(VI), a dominant AC isoform in mammalian cardiac myocytes, increases survival and abrogates myocardial hypertrophy in Ltransgenic (TG) mice with G(alpha q)-associated cardiomyopathy. Indeed, it has been proposed that increasing the cardiac content of AC(VI) is fundamentally different than other strategies used to increase cAMP function. However, one important but unexplored issue is its effects on electrical remodeling. Electrophysiological properties of G(alpha q) mice have been characterized. Similar to other models of cardiac hypertrophy and failure, cardiac myocytes isolated from G(alpha q) mice show prolonged action potential with reduced transient outward K+ current (I-to) and inward rectifier K+ current (I-K1) density compare to wild-type (WT) animals. We directly examined the electrical remodeling of cardiac-directed AC(VI), over-expression in G(alpha q) mice using ECG recordings and whole-cell patch-clamp recordings. Four groups of animals were used: WT (double negative), AC(VI), G(alpha q) and double positive TG mice (G(alpha q)/AC(VI)). Cardiac-directed expression of AC(VI) results in the reversal of adverse electrical remodeling in the G(alpha q) mice and is associated with significant improvement in the delay of cardiac repolarization and arrhythmias. Specifically, there is a normalization of I-to, I-K1 and action potential duration in G(alpha q)/AC(VI) compared to G(alpha q) mice. In summary, our data provide evidence that increased cardiac AC(VI) content has a salutary effect in cardiomyopathy and cardiac electrical remodeling. (c) 2006 Elsevier Inc. All rights reserved.