Angiopoietin-2 exacerbates cardiac hypoxia and inflammation after myocardial infarction

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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 alpha(5)beta(1) 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.
Publisher
AMER SOC CLINICAL INVESTIGATION INC
Issue Date
2018-11
Language
English
Article Type
Article
Keywords

ENDOTHELIAL GROWTH-FACTOR; MACROPHAGE POLARIZATION; MESENCHYMAL TRANSITION; CLINICAL-APPLICATIONS; CARDIOGENIC-SHOCK; RECEPTOR TIE-2; HEART-FAILURE; DISEASE; CELLS; ANGIOGENESIS

Citation

JOURNAL OF CLINICAL INVESTIGATION, v.128, no.11, pp.5018 - 5033

ISSN
0021-9738
DOI
10.1172/JCI99659
URI
http://hdl.handle.net/10203/246887
Appears in Collection
MSE-Journal Papers(저널논문)
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