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

Adenylyl cyclase (AC) is an effector molecule in β-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 ACVI, a dominant AC isoform in mammalian cardiac myocytes, increases survival and abrogates myocardial hypertrophy in transgenic (TG) mice with Gαq-associated cardiomyopathy. Indeed, it has been proposed that increasing the cardiac content of ACVI 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 Gαq mice have been characterized. Similar to other models of cardiac hypertrophy and failure, cardiac myocytes isolated from Gαq mice show prolonged action potential with reduced transient outward K+ current (Ito) and inward rectifier K+ current (IK1) density compare to wild-type (WT) animals. We directly examined the electrical remodeling of cardiac-directed ACVI over-expression in Gαq mice using ECG recordings and whole-cell patch-clamp recordings. Four groups of animals were used: WT (double negative), ACVI, Gαq and double positive TG mice (Gαq/ACVI). Cardiac-directed expression of ACVI results in the reversal of adverse electrical remodeling in the Gαq mice and is associated with significant improvement in the delay of cardiac repolarization and arrhythmias. Specifically, there is a normalization of Ito, IK1 and action potential duration in Gαq/ACVI compared to Gαq mice. In summary, our data provide evidence that increased cardiac ACVI content has a salutary effect in cardiomyopathy and cardiac electrical remodeling.