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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 3

Angpt2 destabilizes endothelial integrity of ischemic heart by antagonizing Angpt1/Tie2 signaling.

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Angpt2 destabilizes endothelial integrity of ischemic heart by antagoniz...
Adult WT, Angpt1iΔ/Δ (A1ΔU), or Angpt2iΔEC (A2ΔE) mice were subjected to MI or sham procedure, and hearts were harvested at 3 days after MI. (A and B) Images and comparisons of Angpt1 expression in heart of Angpt1-GFP mice at 3 days after sham or MI procedure. Each region marked by a box demonstrating the expression of Angpt1 in myocardium is magnified in the right corner. Scale bars: 500 μm. n = 4–5. (C) Diagram depicting generation of Angpt1iΔ/Δ or Angpt2iΔEC mice and experiment schedule. (D and E) Immunofluorescence images and quantification show the decrease in pTie2 in border zone ECs after MI; pTie2 level was lower in Angpt1iΔ/Δ mice, but higher in Angpt2iΔEC mice compared with WT. Scale bars: 100 μm. n = 5–6, each time point. *P < 0.01, Kruskal-Wallis test followed by Mann-Whitney U test for post hoc pairwise comparisons. (F and G) Images and comparisons of NG2+ pericyte (PC) coverage on ECs at the border zone. Direction of arrow indicates the border zone closer to infarct area. Dashed lines distinguish PChi/Angpt2lo region from PClo/Angpt2hi region at the infarct border. PC coverage was compared between the ECs within high Angpt2 expression zone (A2hi) and low Angpt2 expression zone (A2lo). n = 4, each group. Scale bars: 100 μm. *P < 0.05 versus A2lo zone, Mann-Whitney U test. (H and I) Images and comparisons of NG2+ PC coverage onto ECs at the border zone. n = 5–6, each group. Scale bars: 50 μm. *P < 0.025, Kruskal-Wallis test followed by Mann-Whitney U test for post hoc pairwise comparisons (WT versus sham and WT versus Angpt2iΔEC). (J and K) Temporal changes of relative expression of Tie1 in the ECs of infarct border. n = 5–6, each time point. Scale bars: 50 μm. *P < 0.05 versus sham, Mann-Whitney U test. Error bars represent mean ± SD.

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