Simvastatin Modulates Remodeling Of Kv4.3Expression In Rat Hypertrophied Cardiomyocytes

Background and Objectives:：Sudden cardiac death is commonly caused byventricular tachyarrhythmias. Studies have indicated several alterations in cellularelectrophysiology in hypertrophied myocardium, including prolongation of theaction potential duration, which may lead to ventricular arrhythmias. Previousinvestigations have highlighted the importance of potassium channel remodelingin the prolongation of action potential durations in models of hypertrophy.Furthermore, it is believed that suppression of repolarizing potassium currentsleading to action potential prolongation provides an explanation for QTprolongation/dispersion, thereby accounting for a major mechanism of arrhythm-ogenesis. Potassium channels include diverse classes of ion channels in the heart.The transient outward potassium currents (I_to), which can be classified asvoltage-gated currents, contribute to cardiac action potential duration, Ca2+handling, contractility and hypertrophy. Cardiac disease is invariably associatedwith I_toand changes in I_tohave been linked to a long QT-interval and Brugadasyndrome arrhythmias. Kv4.3, which is the pore-forming subunit of I_to, isuniformly expressed in the ventricle. Expression of the Kv4.3gene is decreased by cardiac hypertrophy induced by congestive heart failure in humans.Simvastatin, one of the hydroxymethylglutaryl coenzyme A reductase inhibitors（statins）, has been shown to reduce cardiovascular-related morbidity andmortality in clinical trials independent of its cholesterol-lowering function andhas been demonstrated to impact cardiac remodeling, including hypertrophy.Interestingly, recent studies have also shown that simvastatin decreasesarrhythmogenesis and the potential link between Kv4.3and simvastatin issuggested by these studies of hypertrophy. However, little is known about theeffect of simvastatin on cardiac Kv4.3expression. It is hypothesized thatremodeling of Kv4.3occurs in rat hypertrophied cardiomyocytes and is regulatedby simvastatin. Modulation of Kv4.3expression by simvastatin was investigatedin this study using the abdominal aortic banding （AAB） rat model of cardiachypertrophy. Specifically, the effects of simvastatin on Kv4.3expression wereinvestigated in the subepicardial and subendocardial myocardium of AAB rats.Furthermore, the effects of simvastatin on Kv4.3expression and I_toin neonatal ratventricular myocytes （NRVMs） were investigated. Methods: MaleSprague-Dawley rats and neonatal rat ventricular myocytes （NRVMs） underwentabdominal aortic banding （AAB） for7weeks and angiotensin II （AngII）treatment, respectively, to induce cardiac hypertrophy. Kv4.3expression byNRVMs and myocardium （subepicardial and subendocardial） in the left ventriclewas measured. The transient outward potassium current (I_to) of NRVMs wasrecorded using a whole-cell patch-clamp method. Results: Expression of theKv4.3transcript and protein was significantly reduced in myocardium（subepicardial and subendocardial） in the left ventricle and in NRVMs.Simvastatin partially prevented the reduction of Kv4.3expression in NRVMs andsubepicardial myocardium but not in the subendocardial myocardium. Hypertro- phied NRVMs exhibited a significant reduction in the I_tocurrent and this effectwas partially reversed by simvastatin. Conclusions: Simvastatin alleviated thereduction of Kv4.3expression, I_tocurrents in hypertrophied NRVMs andalleviated the reduced Kv4.3expression in subepicardial myocardium from thehypertrophied left ventricle. It can be speculated that among the pleiotropiceffects of simvastatin, the anti-arrhythmia effect is partly mediated by its effecton Kv4.3.