Background:Diabetes is a risk factor for heart failure and promotes cardiac dysfunction. Diabetic tissues are associated with nicotinamide adenine dinucleotide (NAD⁺) redox imbalance; however, the hypothesis that NAD⁺ redox imbalance causes diabetic cardiomyopathy has not been tested. This investigation used mouse models with altered NAD⁺ redox balance to test this hypothesis.Methods: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 (1, Ndufs4 [NADH:ubiquinone oxidoreductase subunit S4] knockout, cKO, and 2, NAMPT [nicotinamide phosphoribosyltranferase] transgenic mice, NMAPT) were used.Results:Diabetic stress caused cardiac dysfunction and lowered NAD⁺/NADH ratio (oxidized/reduced ratio of nicotinamide adenine dinucleotide) in wild-type mice. Mice with lowered cardiac NAD⁺/NADH ratio without baseline dysfunction, cKO mice, were challenged with chronic diabetic stress. NAD⁺ redox imbalance in cKO hearts exacerbated systolic (fractional shortening: 27.6% versus 36.9% at 4 weeks, male cohort P<0.05), and diastolic dysfunction (early-to-late ratio of peak diastolic velocity: 0.99 versus 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 (fractional shortening: 40.2% versus 24.8% in cKO:NAMPT versus cKO, P<0.05; early-to-late ratio of peak diastolic velocity: 1.32 versus 1.04, P<0.05), and reversed pathogenic mechanisms in diabetic mice.Conclusions:Our results show that NAD⁺ redox imbalance to regulate acetylation and phosphorylation is a critical mediator of the progression of diabetic cardiomyopathy and suggest the therapeutic potential for diabetic cardiomyopathy by harnessing NAD⁺ metabolism.

中文翻译：

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心脏中 NAD+ 氧化还原失衡加剧糖尿病性心肌病

背景：糖尿病是心力衰竭的危险因素，可促进心功能不全。^{糖尿病组织与烟酰胺腺嘌呤二核苷酸（NAD +}）氧化还原失衡有关；^{然而，NAD +}氧化还原失衡导致糖尿病性心肌病的假设尚未得到检验。^{本研究使用 NAD +}氧化还原平衡发生改变的小鼠模型来检验这一假设。方法：链脲佐菌素在小鼠中诱导糖尿病应激。心脏功能通过超声心动图测量。收集心脏和血浆样本用于生化、组织学和分子分析。两个具有改变的 NAD ^{+的小鼠模型}使用氧化还原状态（1，Ndufs4 [NADH：泛醌氧化还原酶亚基 S4] 敲除，cKO，和 2，NAMPT [烟酰胺磷酸核糖基转移酶] 转基因小鼠，NMAPT）。结果：糖尿病应激导致心脏功能障碍并降低 NAD + /NADH 比率^（氧化/减少野生型小鼠中烟酰胺腺嘌呤二核苷酸的比例）。^{心脏 NAD +} /NADH 比率降低且无基线功能障碍的小鼠，即 cKO 小鼠，受到慢性糖尿病应激的挑战。cKO 心脏中的NAD ⁺氧化还原失衡加剧了收缩（缩短分数：27.6% 对 4 周时的 36.9%，男性队列P <0.05）和舒张功能障碍（峰值舒张速度的早期与晚期比率：0.99 对 1.20，P<0.05) 的糖尿病小鼠在两种性别中。胶原蛋白水平和纤维化转录本以及细胞外基质依赖性通路在糖尿病 cKO 心脏中没有显示变化，这表明心功能障碍加剧是由于心肌细胞功能障碍。NAD ⁺氧化还原失衡促进超氧化物歧化酶 2 乙酰化、蛋白质氧化、肌钙蛋白 I S150 磷酸化和糖尿病 cKO 心脏的能量受损。重要的是，通过 NAMPT提高心脏 NAD ^{+水平使 NAD +}氧化还原平衡正常化，减轻心脏功能障碍（缩短分数：cKO 中 40.2% 对 24.8%：NAMPT 对 cKO，P <0.05；峰值舒张速度的早期与晚期比率： 1.32 对 1.04，P<0.05)，并逆转糖尿病小鼠的致病机制。结论：我们的结果表明，NAD ⁺氧化还原失衡调节乙酰化和磷酸化是糖尿病心肌病进展的关键介质，并表明通过利用 NAD + 代谢治疗糖尿病心肌病^的潜力.