Role of Human Epicardial Adipose Tissue-Derived miR-92a-3p in Myocardial Redox State

J Am Coll Cardiol. 2023 Jul 25;82(4):317-332. doi: 10.1016/j.jacc.2023.05.031.

Abstract

Background: Visceral obesity is directly linked to increased cardiovascular risk, including heart failure.

Objectives: This study explored the ability of human epicardial adipose tissue (EAT)-derived microRNAs (miRNAs) to regulate the myocardial redox state and clinical outcomes.

Methods: This study screened for miRNAs expressed and released from human EAT and tested for correlations with the redox state in the adjacent myocardium in paired EAT/atrial biopsy specimens from patients undergoing cardiac surgery. Three miRNAs were then tested for causality in an in vitro model of cardiomyocytes. At a clinical level, causality/directionality were tested using genome-wide association screening, and the underlying mechanisms were explored using human biopsy specimens, as well as overexpression of the candidate miRNAs and their targets in vitro and in vivo using a transgenic mouse model. The final prognostic value of the discovered targets was tested in patients undergoing cardiac surgery, followed up for a median of 8 years.

Results: EAT miR-92a-3p was related to lower oxidative stress in human myocardium, a finding confirmed by using genetic regulators of miR-92a-3p in the human heart and EAT. miR-92a-3p reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase-derived superoxide (O2.-) by targeting myocardial expression of WNT5A, which regulated Rac1-dependent activation of NADPH oxidases. Finally, high miR-92a-3p levels in EAT were independently related with lower risk of adverse cardiovascular events.

Conclusions: EAT-derived miRNAs exert paracrine effects on the human heart. Indeed miR-92a-3p suppresses the wingless-type MMTV integration site family, member 5a/Rac1/NADPH oxidase axis and improves the myocardial redox state. EAT-derived miR-92a-3p is related to improved clinical outcomes and is a rational therapeutic target for the prevention and treatment of obesity-related heart disease.

Keywords: Wnt5a signaling; epicardial adipose tissue; microRNAs; myocardial NADPH oxidase activity; myocardial oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Genome-Wide Association Study*
  • Humans
  • Mice
  • Mice, Transgenic
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Myocardium / metabolism
  • Oxidation-Reduction

Substances

  • MicroRNAs