Exogenous NADPH exerts a positive inotropic effect and enhances energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure.
Exogenous NADPH exerts a positive inotropic effect and enhances energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure.
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DOI：
10.1016/j.ebiom.2023.104863
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发表时间：
2023-12
期刊：
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
迫切需要治疗来改善心力衰竭时的病理性心脏肥大并增强心脏功能。我们的初步实验表明，外源性NADPH对离体心脏具有正性肌力作用。本研究旨在探讨 NADPH 在病理性心脏肥大和心力衰竭中的正性肌力作用及其潜在机制。测定慢性心力衰竭患者和对照成人的内源性血浆 NADPH 含量。在离体蟾蜍心脏或大鼠心脏中研究了 NADPH 的正性肌力作用。研究了 NADPH 对异丙肾上腺素 (ISO) 引起的心脏肥大或主动脉横缩 (TAC) 引起的心力衰竭的影响。使用 SIRT3 敲除小鼠、超声心动图、蛋白质印迹、透射电子显微镜和免疫沉淀研究了 NADPH 的潜在机制。与年龄性别匹配的对照受试者相比，患有病理性心脏肥大或心力衰竭的患者和动物血液中的内源性NADPH含量显着降低。外源性NADPH对离体正常心脏和衰竭心脏均表现出正性肌力作用，而ATP受体的拮抗作用则部分消除了NADPH的正性肌力作用。外源性 NADPH 给药显着降低了病理性心脏肥大或心力衰竭小鼠的心脏重量指数，并改善了心脏功能。 NADPH 增加 SIRT3 的表达和活性，使靶蛋白脱乙酰化，改善线粒体功能并促进肥厚心肌中 ATP 的产生。重要的是，抑制SIRT3会消除NADPH的正性肌力作用，并且NADPH的抗心力衰竭作用在SIRT3敲除小鼠中显着降低。外源性 NADPH 在病理性心脏肥大和心力衰竭中表现出正性肌力作用，并通过 SIRT3 改善能量代谢。因此，NADPH 可能是治疗病理性心脏肥大或心力衰竭的潜在候选者之一。这项工作得到了（编号81973315、82173811、81730092）、（20KJA310008）、（BM2013003）和（PAPD）的资助。
Therapies are urgently required to ameliorate pathological cardiac hypertrophy and enhance cardiac function in heart failure. Our preliminary experiments have demonstrated that exogenous NADPH exhibits a positive inotropic effect on isolated heart. This study aims to investigate the positive inotropic effects of NADPH in pathological cardiac hypertrophy and heart failure, as well as the underlying mechanisms involved. Endogenous plasma NADPH contents were determined in patients with chronic heart failure and control adults. The positive inotropic effects of NADPH were investigated in isolated toad heart or rat heart. The effects of NADPH were investigated in isoproterenol (ISO)–induced cardiac hypertrophy or transverse aortic constriction (TAC)–induced heart failure. The underlying mechanisms of NADPH were studied using SIRT3 knockout mice, echocardiography, Western blotting, transmission electron microscopy, and immunoprecipitation. The endogenous NADPH content in the blood of patients and animals with pathological cardiac hypertrophy or heart failure was significantly reduced compared with age-sex matched control subjects. Exogenous NADPH showed positive inotropic effects on the isolated normal and failing hearts, while antagonism of ATP receptor partially abolished the positive inotropic effect of NADPH. Exogenous NADPH administration significantly reduced heart weight indices, and improved cardiac function in the mice with pathological cardiac hypertrophy or heart failure. NADPH increased SIRT3 expression and activity, deacetylated target proteins, improved mitochondrial function and facilitated ATP production in the hypertrophic myocardium. Importantly, inhibition of SIRT3 abolished the positive inotropic effect of NADPH, and the anti-heart failure effect of NADPH was significantly reduced in the SIRT3 Knockout mice. Exogenous NADPH shows positive inotropic effect and improves energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure. NADPH thus may be one of the potential candidates for the treatment of pathological cardiac hypertrophy or heart failure. This work was supported by grants from the (No. 81973315, 82173811, 81730092), (20KJA310008), (BM2013003) and the (PAPD).
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影响因子：
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