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/m2) have higher left ventricular ejection fraction (LVEF) and greater levels of plasma apelin (p < 0.005) than non-obese patients (< 30 kg/m2), 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.
Highlights
Obesity-related processes and cardiac I/R-induced damage has been shown recently[9,10]
We provide the first line of evidence that in obese patients with heart failure (HF) greater apelin levels are associated with the higher LVEF independently of ischemic etiology
Our results suggest that prevention of I/R-induced FoxO3 nuclear translocation by apelin is associated with activation of survival pathways and cardioprotection in obese mice after ischemic injury
Summary
Obesity-related processes and cardiac I/R-induced damage has been shown recently[9,10]. The forkhead box O (FoxO) family of transcription factors plays a fundamental role in the regulation of mitochondrial activity and cellular responses to oxidative stress. FoxO acts as transcriptional activators governing a variety of vital cellular processes including cell survival, apoptosis, metabolism, DNA repair and resistance to oxidative stress. Additional work in animal models of age-dependent oxidative stress responses demonstrated that up-regulation of FoxO3 in the heart and adipose tissue is associated with activation of cellular antioxidant systems[15]. Trafficking of FoxO between the nucleus and the cytoplasm plays a decisive role in stress-related regulation of cell death/cell survival. Given the fundamental role of FoxO3 in cardiovascular and metabolic homeostasis, the function and fine-tuned regulation of its subcellular distribution is critical for the future development of specific and effective cardioprotective therapeutics in clinical situations combining obesity and myocardial damage. The role of apelin in conditions combining myocardial infarction and obesity remains to be determined
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