GATA-4 Transcription Factor Regulates Cardiac COX-2 Expression Induced by Nicorandil in Left Ventricle of Rats

Abstract

Background and Aims: Cardioprotective effects induced by delayed ischemic preconditioning and by nicorandil are mediated via expression of cardioprotective factors such as COX-2. The present study was undertaken to evaluate whether nicorandil could induce COX-2 in rats and to elucidate its mode of induction pharmacologically. Methods and Results: Three hours after administration of nicorandil (10 mg/kg, p.o.), COX-2 mRNA and protein were significantly increased in the left ventricle, although other cardioprotective factors (Bcl-2, eNOS, hexokinase, HSP, and iNOS) were not increased. This COX-2 induction in the left ventricle was preceded by induction of GATA-4, which was significant from 1 h after administration. Ventricular levels of 6-keto-prostaglandin F_1α were increased 6 h after administration. Although pinacidil or isosorbide dinitrate alone did not increase COX-2 mRNA, their combined application significantly increased COX-2 mRNA. Moreover, although glibenclamide or ODQ each partly inhibited the induction of COX-2 mRNA by nicorandil, their combined application significantly inhibited it. These results suggest that nicorandil induces COX-2 protein through both the activation of K_ATP channels and guanylate cyclase. Conclusion: The present study demonstrated that nicorandil induces COX-2 via GATA-4 induction in the heart through both K_ATP channel activation and its nitrate-like properties.