Nicotinamide phosphoribosyltransferase regulates cell survival through nad+ synthesis in cardiac myocytes

Chiao Po Hsu, Shinichi Oka, Dan Shao, Nirmala Hariharan, Junichi Sadoshima

Research output: Contribution to journalArticle

175 Scopus citations

Abstract

Rationale: NAD+ acts not only as a cofactor 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. Objective: Here we investigated the role of Nampt in mediating NAD+ synthesis in cardiac myocytes and the function of Nampt in the heart in vivo. Methods and Results: 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, whereas 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)481-491
Number of pages11
JournalCirculation Research
Volume105
Issue number5
DOIs
StatePublished - Aug 28 2009
Externally publishedYes

Keywords

  • Apoptosis
  • Myocardial ischemia
  • NAD

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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