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Angiopoietin-2 exacerbates cardiac hypoxia and inflammation after myocardial infarction
Seung-Jun Lee, … , Yoshiaki Kubota, Gou Young Koh
Seung-Jun Lee, … , Yoshiaki Kubota, Gou Young Koh
Published November 1, 2018; First published October 8, 2018
Citation Information: J Clin Invest. 2018;128(11):5018-5033. https://doi.org/10.1172/JCI99659.
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Categories: Research Article Cardiology Vascular biology

Angiopoietin-2 exacerbates cardiac hypoxia and inflammation after myocardial infarction

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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.

Authors

Seung-Jun Lee, Choong-kun Lee, Seok Kang, Intae Park, Yoo Hyung Kim, Seo Ki Kim, Seon Pyo Hong, Hosung Bae, Yulong He, Yoshiaki Kubota, Gou Young Koh

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Figure 1

Angpt2 is highly expressed in ECs of the border zone after MI.

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Angpt2 is highly expressed in ECs of the border zone after MI.
Adult WT ...
Adult WT mice were subject to MI or sham procedure (Sh), hearts were harvested at indicated time points, and indicated molecules in heart sections were detected by immunostaining. (A and B) Images for Angpt2 in ECs at the infarct border. Scale bars: 500 μm (A); 20 μm (B). (C and D) Temporal changes of Angpt2 in border zone ECs at indicated day after MI. n = 6, each time point. Each box region is magnified below. Scale bars: 100 μm. *P < 0.05 versus sham, Mann-Whitney U test. (E and F) Images and comparisons of Angpt2 expression in ECs at the infarct border of Angpt2-EGFP mice. Box region is magnified at right. n = 5, each group. Scale bars: 100 μm. *P < 0.05 versus sham, Mann-Whitney U test. Error bars represent mean ± SD.
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ISSN: 0021-9738 (print), 1558-8238 (online)

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