In this study, we have demonstrated for the first time that targeting mitochondrial ROS using mitochondria-targeted SOD mimetic, mitoTEMPO, and the natural red wine constituent, resveratrol blunts and partially attenuates pathogenesis of nicotine-induced cardiac remodeling, dysfunction, and associated aggravation of the myocardial ischemia–reperfusion injury. The gene discussed is SOD1; the disease is myocardial ischemia.