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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 October 8, 2018
Citation Information: J Clin Invest. 2018;128(11):5018-5033. https://doi.org/10.1172/JCI99659.
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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 8

Angpt2 plays a substantial role in proinflammatory macrophage polarization in ischemic heart.

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Angpt2 plays a substantial role in proinflammatory macrophage polarizati...
Adult WT or Angpt2iΔ/Δ mice were subject to MI or sham procedure, hearts were harvested at 7 days after MI, and indicated molecules in heart sections at the infarct border were detected by immunostaining. (A) Diagram depicting generation of Angpt2iΔ/Δ mice and their experiment schedule. (B) Images of expression of iNOS, CD206, MHC II, and Arg-1 in CD68+ macrophages. Scale bars: 50 μm. (C) Comparisons of indicated parameters. n = 5–6, each group. *P < 0.025. Kruskal-Wallis test followed by Mann-Whitney U test for post hoc pairwise comparisons. Significance was adjusted for multiple comparisons using Bonferroni’s method. Error bars represent mean ± SD. (D) Diagram depicting the experiment schedule for integrin α5β1 inhibitor treatment (ATN-161, 30 mg/kg, intraperitoneal injection) after MI. (E and F) Images and comparisons of iNOS expression in CD68+ macrophages. n = 4–5, each group. Scale bars: 100 μm. *P < 0.05, Mann-Whitney U test. Error bars represent mean ± SD.

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