Nampt Potentiates Antioxidant Defense in Diabetic Cardiomyopathy.
Nampt Potentiates Antioxidant Defense in Diabetic Cardiomyopathy.
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DOI：
10.1161/circresaha.120.317943
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发表时间：
2021-06-25
影响因子：
20.1
通讯作者：
Sadoshima J
中科院分区：
文献类型：
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作者：
Oka SI;Byun J;Huang CY;Imai N;Ralda G;Zhai P;Xu X;Kashyap S;Warren JS;Alan Maschek J;Tippetts TS;Tong M;Venkatesh S;Ikeda Y;Mizushima W;Kashihara T;Sadoshima J
糖尿病性心肌病伴随着NADH的产生增加，主要是通过脂肪酸的氧化和随后的氧化应激的增加。烟酰胺磷酸核糖基转移酶（Nampt）是NAD+合成挽救途径的限速酶，在糖尿病性心肌病的发展中所起的作用尚不清楚。我们研究了内源性和外源性Nampt在高脂肪饮食（HFD）消耗和氧化应激背景下糖尿病性心肌病发展过程中的作用。食用HFD可上调内源性Nampt，在心脏特异性过表达Nampt的转基因小鼠中，HFD诱导的心脏舒张功能障碍、纤维化、细胞凋亡和促炎信号均得到缓解。通过抑制NAD激酶（NADK）抑制NADP(H)的产生，可以消除这些小鼠舒张功能障碍的缓解。在食用HFD的情况下，Nampt过表达降低GSSG/GSH比值、硫氧还蛋白1 （Trx1）靶点、二酪氨酸的氧化以及包括神经酰胺和二甘油酯在内的有毒脂质的积累。Nampt过表达不仅上调心脏和培养心肌细胞中的NAD+，还上调NADP+和NADPH，从而刺激GSH和Trx1系统，减轻HFD消耗引起的心脏氧化应激。在培养的心肌细胞中，NADK下调后，nampt诱导的NADPH上调被消除，而NAD+的上调则未被消除。在培养的心肌细胞中，Nampt过表达以nadk依赖的方式减弱h2o2诱导的Prdx1和mTOR的氧化抑制。Nampt过表达也能减轻h2o2诱导的细胞死亡，这一作用部分被抑制NADK、Trx1或GSH合成所消除。相反，在Nampt+/−小鼠中，氧化应激和糖尿病性心肌病的发生加剧了对HFD消耗的反应。nampt介导的NAD+的产生部分通过nadph依赖的还原系统来防止氧化应激，从而减轻糖尿病性心肌病在HFD消耗后的发展。
Diabetic cardiomyopathy is accompanied by increased production of NADH, predominantly through oxidation of fatty acids and consequent increases in oxidative stress. The role of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme of the salvage pathway of NAD+ synthesis, in the development of diabetic cardiomyopathy is poorly understood. We investigated the role of endogenous and exogenous Nampt during the development of diabetic cardiomyopathy in response to high fat diet (HFD) consumption and in the context of oxidative stress. HFD consumption upregulated endogenous Nampt, and HFD-induced cardiac diastolic dysfunction, fibrosis, apoptosis and pro-inflammatory signaling were alleviated in transgenic mice with cardiac-specific overexpression of Nampt. The alleviation of diastolic dysfunction observed in these mice was abolished by inhibition of NADP(H) production via NAD kinase (NADK) inhibition. Nampt overexpression decreased the GSSG/GSH ratio, oxidation of thioredoxin 1 (Trx1) targets, dityrosine, and the accumulation of toxic lipids, including ceramides and diglycerides, in the presence of HFD consumption. Nampt overexpression upregulated not only NAD+ but also NADP+ and NADPH in the heart and in cultured cardiomyocytes, which in turn stimulated the GSH and Trx1 systems and alleviated oxidative stress in the heart induced by HFD consumption. In cultured cardiomyocytes, Nampt-induced upregulation of NADPH was abolished in the presence of NADK knockdown, whereas that of NAD+ was not. Nampt overexpression attenuated H2O2-induced oxidative inhibition of Prdx1 and mTOR in an NADK-dependent manner in cultured cardiomyocytes. Nampt overexpression also attenuated H2O2-induced cell death, an effect that was partly abolished by inhibition of NADK, Trx1 or GSH synthesis. In contrast, oxidative stress and the development of diabetic cardiomyopathy in response to HFD consumption were exacerbated in Nampt+/− mice. Nampt-mediated production of NAD+ protects against oxidative stress in part through the NADPH-dependent reducing system, thereby alleviating the development of diabetic cardiomyopathy in response to HFD consumption.