NAD(+) Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy.
NAD(+) Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy.
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DOI：
10.1161/circheartfailure.120.008170
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发表时间：
2021-08
期刊：
影响因子：
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通讯作者：
Lee CF
中科院分区：
文献类型：
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作者：
Chiao YA;Chakraborty AD;Light CM;Tian R;Sadoshima J;Shi X;Gu H;Lee CF
糖尿病是心力衰竭的危险因素，并促进心功能障碍。糖尿病组织与NAD+氧化还原失衡有关;然而，NAD+氧化还原失衡导致糖尿病心肌病（DCM）的假设尚未得到验证。本研究采用NAD+氧化还原平衡改变的小鼠模型来验证这一假设。用链脲佐菌素诱导小鼠糖尿病应激。超声心动图检测心功能。采集心脏和血浆样本进行生化、组织学和分子分析。使用具有改变的NAD+氧化还原状态的两种小鼠模型（Ndufs 4的心脏特异性敲除小鼠，cKO;烟酰胺磷酸核糖基转移酶转基因小鼠，NAMPT）。糖尿病应激导致野生型小鼠心功能不全和NAD+/NADH降低。用慢性糖尿病应激攻击具有降低的心脏NAD+/NADH而没有基线功能障碍的小鼠，cKO小鼠。cKO心脏中的NAD+氧化还原失衡加剧了两种性别的糖尿病小鼠的收缩功能障碍（FS：4周时27.6%vs 36.9%，雄性队列，P<0.05）和舒张功能障碍（E '/A'：0.99 vs 1.20，P<0.05）。糖尿病cKO心脏的胶原蛋白水平和纤维化转录物以及细胞外基质依赖性途径未显示变化，表明心脏功能障碍加重是由于心肌细胞功能障碍。NAD+氧化还原失衡促进糖尿病cKO心脏中超氧化物歧化酶2乙酰化、蛋白质氧化、肌钙蛋白-I S150磷酸化和能量受损。重要的是，NAMPT升高心脏NAD+水平使NAD+氧化还原平衡正常化，减轻了糖尿病小鼠的心功能障碍（FS：cKO：NAMPT vs cKO中40.2% vs 24.8%，P<0.05; E '/A'：1.32 vs 1.04，P<0.05）并逆转了致病机制。我们的研究结果表明，NAD+氧化还原失衡调节乙酰化和磷酸化是DCM进展的关键介质，并表明通过利用NAD+代谢治疗DCM的潜力。
Diabetes is a risk factor of heart failure and promotes cardiac dysfunction. Diabetic tissues are associated with NAD+ redox imbalance; however, the hypothesis that NAD+ redox imbalance causes diabetic cardiomyopathy (DCM) has not been tested. This investigation employed mouse models with altered NAD+ redox balance to test this hypothesis. Diabetic stress was induced in mice by streptozotocin. Cardiac function was measured by echocardiography. Heart and plasma samples were collected for biochemical, histological and molecular analyses. Two mouse models with altered NAD+ redox states (cardiac-specific knockout mice of Ndufs4, cKO; nicotinamide phosphoribosyltransferase transgenic mice, NAMPT) were used. Diabetic stress caused cardiac dysfunction and lowered NAD+/NADH in wild-type mice. Mice with lowered cardiac NAD+/NADH without baseline dysfunction, cKO mice, were challenged with chronic diabetic stress. NAD+ redox imbalance in cKO hearts exacerbated systolic (FS: 27.6% vs 36.9% at 4-week, male cohort, P<0.05) and diastolic dysfunction (E’/A’: 0.99 vs 1.20, P<0.05) of diabetic mice in both sexes. Collagen levels and transcripts of fibrosis and extracellular matrix-dependent pathways did not show changes in diabetic cKO hearts, suggesting that the exacerbated cardiac dysfunction was due to cardiomyocyte dysfunction. NAD+ redox imbalance promoted superoxide dismutase 2 acetylation, protein oxidation, troponin-I S150 phosphorylation and impaired energetics in diabetic cKO hearts. Importantly, elevation of cardiac NAD+ levels by NAMPT normalized NAD+ redox balance, alleviated cardiac dysfunction (FS: 40.2% vs 24.8% in cKO:NAMPT vs cKO, P<0.05; E’/A’: 1.32 vs 1.04, P<0.05) and reversed pathogenic mechanisms in diabetic mice. Our results show that NAD+ redox imbalance to regulate acetylation and phosphorylation is a critical mediator of the progression of DCM, and suggest the therapeutic potential for DCM by harnessing NAD+ metabolism.