Angiopoietin-2 exacerbates cardiac hypoxia and inflammation after myocardial infarction

J Clin Invest. 2018 Nov 1;128(11):5018-5033. doi: 10.1172/JCI99659. Epub 2018 Oct 8.

Abstract

Emerging evidence indicates that angiopoietin-2 (Angpt2), a well-recognized vascular destabilizing factor, is a biomarker of poor outcome in ischemic heart disease. However, its precise role in postischemic cardiovascular remodeling is poorly understood. Here, we show that Angpt2 plays multifaceted roles in the exacerbation of cardiac hypoxia and inflammation after myocardial ischemia. Angpt2 was highly expressed in endothelial cells at the infarct border zone after myocardial infarction (MI) or ischemia/reperfusion injury in mice. In the acute phase of MI, endothelial-derived Angpt2 antagonized Angpt1/Tie2 signaling, which was greatly involved in pericyte detachment, vascular leakage, increased adhesion molecular expression, degradation of the glycocalyx and extracellular matrix, and enhanced neutrophil infiltration and hypoxia in the infarct border area. In the chronic remodeling phase after MI, endothelial- and macrophage-derived Angpt2 continuously promoted abnormal vascular remodeling and proinflammatory macrophage polarization through integrin α5β1 signaling, worsening cardiac hypoxia and inflammation. Accordingly, inhibition of Angpt2 either by gene deletion or using an anti-Angpt2 blocking antibody substantially alleviated these pathological findings and ameliorated postischemic cardiovascular remodeling. Blockade of Angpt2 thus has potential as a therapeutic option for ischemic heart failure.

Keywords: Cardiology; Cardiovascular disease; Pericytes; Vascular Biology; endothelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-1 / genetics
  • Angiopoietin-1 / metabolism
  • Angiopoietin-2 / antagonists & inhibitors
  • Angiopoietin-2 / genetics
  • Angiopoietin-2 / metabolism*
  • Animals
  • Antibodies, Blocking / pharmacology
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Inflammation / drug therapy
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Myocardial Infarction / drug therapy
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism*
  • Myocardial Infarction / pathology
  • Receptor, TIE-2 / genetics
  • Receptor, TIE-2 / metabolism
  • Receptors, Vitronectin / genetics
  • Receptors, Vitronectin / metabolism
  • Signal Transduction*
  • Vascular Remodeling / drug effects
  • Vascular Remodeling / genetics

Substances

  • Angiopoietin-1
  • Angiopoietin-2
  • Angpt1 protein, mouse
  • Antibodies, Blocking
  • Receptors, Vitronectin
  • integrin alphavbeta1
  • Receptor, TIE-2
  • Tek protein, mouse

Grant support

This study was supported by the Institute of Basic Science (IBS-R025-D1-2015, G.Y.K.) funded by the Ministry of Science, ICT and Future Planning, Republic of Korea.