我们的预实验发现还原性烟酰胺腺嘌呤二核苷酸磷酸（NADPH）对离体心脏具有强而持久的正性肌力作用；NADPH外源给药对抗小鼠心衰模型的病理改变，改善心功能；抑制SIRT3取消NADPH的强心作用。我们据此推测外源性给予NADPH能够经由细胞膜或线粒体膜的特异转运体或受体，直接或间接靶向于线粒体SIRT3，调节线粒体自噬，抑制氧化应激，改善能量代谢，发挥强心作用，逆转心肌肥厚及心衰进程。本课题建立大小鼠、离体心脏和培养心肌细胞心衰模型，研究NADPH强心抗心衰的作用及机制，旨在：①发现NADPH的强心作用，为防治心肌肥厚或心衰提供潜在候选药物。②阐明NADPH靶向线粒体SIRT3改善线粒体功能产生强心抗心衰作用，为研究靶向线粒体SIRT3的新型强心药提供思路。③研究NADPH作用于心肌细胞或线粒体的特异靶点，发现新颖的NADPH转运体或受体，扩展NADPH及多种内源性活性物质的生物功能。

Our preliminary data found that reduced nicotinamide adenine dinucleotide phosphate (NADPH) elicited strong and sustained positive inotropic effects on isolated toad heart. Endogenous NADPH levels were significantly reduced in the serum of mice and human patients with heart failure. Exogenous administration of NADPH alleviated isoproterenol induced heart failure and transverse aortic constriction induced heart failure in mice. Inhibition of SIRT3 canceled the cardiac positive inotropic effect of NADPH. We thus hypothesize that exogenous administration of NADPH can target mitochondrial SIRT3 directly or indirectly via a specific transporter or receptor on cell membrane or mitochondrial membrane. NADPH may then regulate mitophagy, inhibit mitochondrial oxidative stress and improve energy metabolism, to exert positive inotropic action and to reverse the progression of cardiac hypertrophy and heart failure. In this study, we will establish heart failure models in mice and rats, isolated hearts, primary cultured rodent cardiomyocytes and H9c2 cardiomyocytes to characterize the cardioprotective role of NADPH against heart failure and the underlying mechanisms. First, we intend to discover the positive inotropic action of NADPH on heart to provide a candidate drug for the prevention and treatment of cardiac hypertrophy or heart failure. Second, we will test whether NADPH exert positive inotropic action and anti-heart failure effect by targeting mitochondrial SIRT3 to improve mitochondrial function. The study will provide new insights for the development of cardiotonic agents targeting mitochondrial SIRT3. Finally, we want to characterize the specific target of NADPH’s action on mitochondria or cardiomyocytes. We may discover the novel transporter or receptor of NADPH on cell membrane or mitochondria, thus extending our knowledge of the biological functions and molecular mechanisms of NADPH and related endogenous active substances.