Reduction of I(to) causes hypertrophy in neonatal rat ventricular myocytes

Circulation Research
Z KassiriP H Backx

Abstract

Prolonged action potential duration (APD) and decreased transient outward K+ current (I(to)) 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 Toxin3, 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) transgenes. I(to) amplitude was reduced equally (by about 50%) by overexpression of DN K(v1.4) (K(v1.4)N) or DN K(v4.2) (either K(v4.2)N or K(v4.2)W362F), but only DN K(v4.2) prolonged APD duration (at 1 Hz) and induced myocyte hypertrophy. This hypertrophy was prevented by coexpressing wild-type K(v4.2) channels (K(v4.2)F) 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, calcineurin, and could be prevented by coinfection with Ad-CAIN, a specific calcineurin inh...Continue Reading

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