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

Angiopoietin-2 exacerbates cardiac hypoxia and inflammation after myocardial infarction.

Lee SJ1, Lee CK1,2, Kang S1,2, Park I1,2, Kim YH1,2, Kim SK1,2, Hong SP1,2, Bae H1,2, He Y3, Kubota Y4, Koh GY1,2.

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Center for Vascular Research, Institute for Basic Science, Daejeon, South Korea.
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.
Cyrus Tang Hematology Center, Soochow University, Suzhou, China.
The Laboratory of Vascular Biology, School of Medicine, Keio University, Tokyo, Japan.


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.


Cardiology; Cardiovascular disease; Pericytes; Vascular Biology; endothelial cells

[Available on 2019-02-01]
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