MiR-221-3p targets Hif-1α to inhibit angiogenesis in heart failure

Lab Invest. 2021 Jan;101(1):104-115. doi: 10.1038/s41374-020-0450-3. Epub 2020 Sep 1.

Abstract

Angiogenesis is involved in ischemic heart disease as well as the prognosis of heart failure (HF), and endothelial cells are the main participants in angiogenesis. In this study, we found that miR-221-3p is highly expressed in vascular tissue, especially in endothelial cells, and increased miR-221-3p was observed in heart tissue of HF patients and transverse aortic constriction (TAC)-induced HF mice. To explore the role of miR-221-3p in endothelial cells, microRNA (miRNA) mimics and inhibitors were employed in vitro. Overexpression of miR-221-3p inhibited endothelial cell proliferation, migration, and cord formation in vitro, while inhibition of miR-221-3p showed the opposite effect. Anti-argonaute 2 (Ago2) coimmunoprecipitation, dual-luciferase reporter assay, and western blotting were performed to verify the target of miR-221-3p. Hypoxia-inducible factor-1α (HIF-1α) was identified as a miR-221-3p target, and the adverse effects of miR-221-3p on endothelial cells were alleviated by HIF-1α re-expression. In vivo, a mouse model of hindlimb ischemia (HLI) was developed to demonstrate the effect of miR-221-3p on angiogenesis. AntagomiR-221-3p increased HIF-1α expression and promoted angiogenesis in mouse ischemic hindlimbs. Using the TAC model, we clarified that antagomiR-221-3p improved cardiac function in HF mice by promoting cardiac angiogenesis. Furthermore, serum miR-221-3p was detected to be negatively correlated with heart function in chronic heart failure (CHF) patients. Our results conclude that miR-221-3p inhibits angiogenesis of endothelial cells by targeting HIF-1α and that inhibition of miR-221-3p improves cardiac function of TAC-induced HF mice. Furthermore, miR-221-3p might be a potential prognostic marker of HF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endothelial Cells / physiology
  • Gene Expression Regulation
  • HEK293 Cells
  • Heart Failure / metabolism*
  • Hindlimb / blood supply
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism*
  • Neovascularization, Physiologic*

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MIRN221 microRNA, human
  • MIRN221 microRNA, mouse
  • MicroRNAs