Previous study has shown that Kv4.3, a main coding subunit generating cardiac transient-outward K⁺ current (Ito), can inhibit Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) activity. Based on these observations, we speculate that over-expression of Kv4.3 gene could reverse not only Ito reduction but also cardiac remodeling in the rat myocardial infarction (MI) model.

Healthy male Sprague-Dawley (SD) rats were used to establish MI model by ligation of left anterior descending coronary artery, and adenovirus integrated with Kv4.3 gene (AD-Kv4.3) was delivered in infarct border zone by intramyocardial injection. The hearts were harvested for histological analysis (HE or Masson trichrome staining), western blot or patch clamp 4 weeks after MI. Our data showed that the application of AD-Kv4.3 could reduce myocardial infarct size and fibrosis, and its cardioprotective effects were similar with medicine therapy (combination of metoprolol and captopril). Moreover, Kv4.3 over-expression significantly improved MI-induced cardiac dysfunction and enhanced Ito density while decreasing corrected QT (QTc) intervals and cardiac electrophysiological instability. Western blot showed that Kv4.3 transfection reduced CaMKII, PLB-17 and ryanodine receptor2 (RyR2 Ser2814) phosphorylation level, at same time increased SERCA2 expression dramatically.

Over-expression of Kv4.3 can not only attenuate cardiac electrophysiological instability and cardiac performance, but also reduce myocardial infarct area and cardiac fibrosis. Like traditional anti-remodeling therapy-angiotensin converting enzyme inhibitor (ACEI) combined with β-adrenergic receptor blocker, over-expression of Kv4.3 seems to be an effective and safe therapy for both structural and electrical remodeling induced by MI via CaMKII inhibition.