Nicotinamide phosphoribosyltransferase regulates cell survival through NAD+ synthesis in cardiac myocytes.
Nicotinamide phosphoribosyltransferase regulates cell survival through NAD+ synthesis in cardiac myocytes.
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DOI：
10.1161/circresaha.109.203703
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发表时间：
2009-08-28
影响因子：
20.1
通讯作者：
Sadoshima J
中科院分区：
文献类型：
--
作者：
Hsu CP;Oka S;Shao D;Hariharan N;Sadoshima J
NAD+ 不仅作为细胞呼吸的辅助因子，而且还作为 NAD+ 依赖性酶（例如 Sirt1）的底物。细胞 NAD+ 合成受到从头途径和挽救途径的调节。烟酰胺磷酸核糖转移酶 (Nampt) 是挽救途径中的限速酶。在这里，我们研究了Nampt在介导心肌细胞NAD+合成中的作用以及Nampt在体内心脏中的功能。心脏中Nampt的表达因缺血、缺血/再灌注和压力超负荷而显着降低。 Nampt 的上调显着增加了 NAD+ 和 ATP 浓度，而 Nampt 的下调则显着降低了它们。 Nampt 的下调会增加 caspase 3 裂解、细胞色素 c 释放和 TUNEL 阳性细胞，这些细胞在 Bcl-xL 存在下受到抑制，但不会增加发夹 2 阳性细胞，表明内源性 Nampt 负向调节细胞凋亡，但不负向调节坏死。 Nampt 的下调也会损害自噬通量，表明内源性 Nampt 正向调节自噬。转基因小鼠心脏中 Nampt 的特异性过度表达增加了心脏中 NAD+ 的含量，防止了 Nampt 的下调，并减少了心肌梗死的范围和响应长期缺血和缺血/再灌注的细胞凋亡。 Nampt 关键性地调节 NAD+ 和 ATP 含量，从而通过抑制心肌细胞凋亡和刺激自噬通量来介导细胞存活。防止 Nampt 下调可抑制心肌缺血和再灌注引起的心肌损伤。这些结果表明 Nampt 是心肌细胞能量状态和存活的重要看门人。
NAD+ acts not only as a co-factor for cellular respiration, but also as a substrate for NAD+-dependent enzymes, such as Sirt1. The cellular NAD+ synthesis is regulated by both the de novo and the salvage pathways. Nicotinamide phosphoribosyltransferase (Nampt) is a rate-limiting enzyme in the salvage pathway. Here we investigated the role of Nampt in mediating NAD+ synthesis in cardiac myocytes and the function of Nampt in the heart in vivo. Expression of Nampt in the heart was significantly decreased by ischemia, ischemia/reperfusion and pressure overload. Upregulation of Nampt significantly increased NAD+ and ATP concentrations, while downregulation of Nampt significantly decreased them. Downregulation of Nampt increased caspase 3 cleavage, cytochrome c release, and TUNEL positive cells, which were inhibited in the presence of Bcl-xL, but did not increase hairpin 2 positive cells, suggesting that endogenous Nampt negatively regulates apoptosis but not necrosis. Downregulation of Nampt also impaired autophagic flux, suggesting that endogenous Nampt positively regulates autophagy. Cardiac specific overexpression of Nampt in transgenic mice increased NAD+ content in the heart, prevented downregulation of Nampt and reduced the size of myocardial infarction and apoptosis in response to prolonged ischemia and ischemia/reperfusion. Nampt critically regulates NAD+ and ATP contents, thereby playing an essential role in mediating cell survival by inhibiting apoptosis and stimulating autophagic flux in cardiac myocytes. Preventing downregulation of Nampt inhibits myocardial injury in response to myocardial ischemia and reperfusion. These results suggest that Nampt is an essential gatekeeper of energy status and survival in cardiac myocytes.