Effects of pravastatin on ventricular remodeling by activation of myocardial K^ATP channels in infarcted rats: Role of70-kDa S6 kinase

Reactive cardiomyocyte hypertrophy after myocardial infarction is an important risk factor for arrhythmias. Myocardial ATP-sensitive potassium (K_ATP) channels have been implicated in attenuating cardiac hypertrophyby inhibition of 70-kDa S6 kinase. We investigated the effect of pravastatin on ventricular hypertrophy during remodeling after myocardial infarction and whether the attenuated hypertrophic effect was via activation of myocardial K_ATP channels. Twenty-four hours after ligation of the anterior descending artery, male Wistar rats were randomized to either vehicle, nicorandil (an agonist of K_ATP channels), pravastatin, glibenclamide (an antagonist of K_ATP channels), or a combination of nicorandil and glibenclamide orpravastatin and glibenclamide for 4 weeks. Infarct size and mortality weresimilar among the infarcted groups. Cardiomyocyte sizes isolated by enzymatic dissociation after infarction significantly increased at the border zonein vehicle-treated infarcted rats compared with sham-operated rats. Rats inthe nicorandil- and pravastatin-treated groups significantly attenuated cardiomyocyte hypertrophy, as compared with the vehicle-treated group. Arrhythmicscores during programmed stimulation mirrored those of cardiomyocyte hypertrophy. Increased 70-kDa S6 kinase mRNA expression in cardiac remodeling was confirmed by reverse transcription-polymerase chain reaction, consistent with the results of immunohistochemistry and Western blot for the phosphorylation of 70-kDa S6 kinase. Nicorandil-induced effects were abolished by administering glibenclamide. Similarly, the beneficial effects of pravastatin were abolished by administering glibenclamide, implicating K_ATP channels as the relevant target. Activation of K_ATPchannels by pravastatin administration can attenuate ventricular remodeling through a S6 kinase-dependent pathway after infarction.