Reduction of Ito causes hypertrophy in neonatal rat ventricular myocytes

Prolonged action potential duration (APD) and decreased transient outward K+ current (I,,) as a result of decreased expression of K-v4.2 and K-v4.3 genes are commonly observed in heart disease. We found that treatment of cultured neonatal rat ventricular myocytes with Heteropoda Toxin(3), a blocker of cardiac I-to induced hypertrophy as measured using cell membrane capacitance and 3 H-leucine uptake. To dissect the role of specific I-to-encoding genes in hypertrophy, I-to was selectively reduced by overexpressing mutant dominant-negative (DN) trariggenes. I-to amplitude was reduced equally (by about 50%) by overexpression of DN K-v1.4 (Kv1.4N) or DN K-v1.2 (either Kv4.2N or K(v4.2)W362F), but only DN K,4 2 prolonged APD duration (at 1 Hz) and induced myocyte hypertrophy. This hypertrophy was prevented by coexpressing wild-type K-v4.2 channels (Kv4.2F) with the DN K-v4.2 genes, suggesting the hypertrophy is due to I-to reduction and not nonspecific effects of transgene overexpression. The hypertrophy caused by reductions of K-v4.x-based I-to was associated with increased activity of the calcium-dependent phosphatase, calcinceurin, and could be prevented by coinfection with Ad-CAIN, a specific calcineurin inhibitor. The hypertrophy and calcineurin activation induced by Kv4.2N infection were prevented by blocking Ca2+ entry and excitability with verapamil or high [K-=](0). Our studies suggest that reductions of K-v4.2/3-based I-to play a role in hypertrophy signaling by activation of calcincurin.