Abstract
Fibroblast growth factor 21 (FGF21) is a metabolic hormone having anti-oxidative and anti-hypertrophic effects. However, the regulation of FGF21 expression during acute myocardial infarction (AMI) remains unclear. We tested blood samples from 50 patients with AMI and 43 patients with stable angina pectoris (sAP) for FGF21, fatty acid binding protein 4 (FABP4), a protein secreted from adipocytes in response to adrenergic lipolytic signal, and total and individual fatty acids. Compared with sAP patients, AMI patients had higher serum FGF21 levels on admission, which were significantly correlated with peak FABP4 and saturated fatty acids (SFAs) but not with peak levels of cardiac troponin T. In mice, myocardial ischemia rapidly induced FGF21 production by the heart, which accompanied activation of AMP-activated protein kinase (AMPK)-dependent pathway. Like AICAR, an activator of AMPK, catecholamines (norepinephrine and isoproterenol) and SFAs (palmitate and stearate) significantly increased FGF21 production and release by cardiac myocytes via AMPK activation. Recombinant FGF21 induced its own expression as well as members of down-stream targets of AMPK involved in metabolic homeostasis and mitochondrial biogenesis in cardiac myocytes. These findings suggest that adrenergic overdrive and resultant adipose tissue lipolysis induce cardiac AMPK-FGF21 feed-forward loop that potentially provides cardioprotection against ischemic damage.
Highlights
Myocardial ischemia induces a cellular process leading to adverse ventricular remodeling and serious arrhythmias and potential healing of damaged myocardium at least partly through the induction of the heart-derived paracrine/autocrine factors that promote cytoprotection[1]
We compared the time course of serum levels of Fibroblast growth factor 21 (FGF21), fatty acid binding protein 4 (FABP4, known as adipocyte P217) which is a byproduct of adipose tissue lipolysis stimulated by catecholamine[18,19], free fatty acids (FFAs), and cardiac troponin T after onset of acute myocardial infarction (AMI), and measured 24 distinct species of fatty acids to determine the potential mechanisms of induction of FGF21
We found that myocardial FGF21 production and release as well as activation of AMPK-FGF21 axis by heart are robustly induced upon myocardial ischemia in mice, and that activation of AMPK is required for catecholamine- and saturated fatty acids (SFAs)-induced FGF21 expression in cardiac myocytes
Summary
Myocardial ischemia induces a cellular process leading to adverse ventricular remodeling and serious arrhythmias and potential healing of damaged myocardium at least partly through the induction of the heart-derived paracrine/autocrine factors that promote cytoprotection[1]. We compared the time course of serum levels of FGF21, fatty acid binding protein 4 (FABP4, known as adipocyte P2 (aP2)17) which is a byproduct of adipose tissue lipolysis stimulated by catecholamine[18,19], FFA, and cardiac troponin T (cTnT) after onset of AMI, and measured 24 distinct species of fatty acids to determine the potential mechanisms of induction of FGF21. We tested if AMP-activated protein kinase (AMPK), which plays a major role in cellular metabolic homeostasis[20], acts as an upstream regulator and as a downstream target of FGF21 in cardiac myocytes. This study provides new insight into the role of AMPK-FGF21 feed-forward loop in the cardioprotective response upon acute myocardial ischemia where excessive adrenergic activation and lipolysis take place
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