Activation of cardiac AMPK-FGF21 feed-forward loop in acute myocardial infarction: Role of adrenergic overdrive and lipolysis byproducts

Sci Rep. 2019 Aug 14;9(1):11841. doi: 10.1038/s41598-019-48356-1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adrenergic Agents / metabolism*
  • Aged
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Angina Pectoris / blood
  • Angina Pectoris / metabolism
  • Animals
  • Catecholamines / metabolism
  • Disease Models, Animal
  • Fatty Acid-Binding Proteins / blood
  • Fatty Acids / blood
  • Female
  • Fibroblast Growth Factors / blood
  • Fibroblast Growth Factors / metabolism*
  • Humans
  • Lipolysis*
  • Male
  • Multivariate Analysis
  • Myocardial Infarction / blood
  • Myocardial Infarction / metabolism*
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Recombinant Proteins / pharmacology
  • Ribonucleotides / pharmacology
  • Time Factors
  • Troponin T / blood

Substances

  • Adrenergic Agents
  • Catecholamines
  • FABP4 protein, human
  • Fatty Acid-Binding Proteins
  • Fatty Acids
  • Recombinant Proteins
  • Ribonucleotides
  • Troponin T
  • fibroblast growth factor 21
  • Aminoimidazole Carboxamide
  • Fibroblast Growth Factors
  • AMP-Activated Protein Kinases
  • AICA ribonucleotide