Apelin regulates FoxO3 translocation to mediate cardioprotective responses to myocardial injury and obesity

Sci Rep. 2015 Nov 6;5:16104. doi: 10.1038/srep16104.

Abstract

The increasing incidence of obesity accentuates the importance of identifying mechanisms and optimal therapeutic strategies for patients with heart failure (HF) in relation to obesity status. Here, we investigated the association between plasma level of apelin, an adipocyte-derived factor, and clinicopathological features of obese and non-obese patients with HF. We further explored potential regulatory mechanisms of cardiac cell fate responses in conditions combining myocardial injury and obesity. In a prospective, cross-sectional study involving patients with HF we show that obese patients (BMI ≥ 30 kg/m(2)) have higher left ventricular ejection fraction (LVEF) and greater levels of plasma apelin (p < 0.005) than non-obese patients (< 30 kg/m(2)), independently of ischemic etiology. In a mouse model combining ischemia-reperfusion (I/R) injury and high-fat diet (HFD)-induced obesity, we identify apelin as a novel regulator of FoxO3 trafficking in cardiomyocytes. Confocal microscopy analysis of cardiac cells revealed that apelin prevents nuclear translocation of FoxO3 in response to oxygen deprivation through a PI3K pathway. These findings uncover apelin as a novel regulator of FoxO3 nucleocytoplasmic trafficking in cardiac cells in response to stress and provide insight into its potential clinical relevance in obese patients with HF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Aged
  • Animals
  • Cardiotonic Agents / metabolism*
  • Cells, Cultured
  • Cross-Sectional Studies
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Female
  • Forkhead Transcription Factors / metabolism*
  • Heart Failure
  • Humans
  • Intercellular Signaling Peptides and Proteins / blood
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardium / metabolism
  • Myocytes, Cardiac / metabolism
  • Obesity / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Prospective Studies
  • Rats
  • Ventricular Function, Left / physiology

Substances

  • Cardiotonic Agents
  • Forkhead Transcription Factors
  • Intercellular Signaling Peptides and Proteins
  • Phosphatidylinositol 3-Kinases