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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 12

Genetic deletion or blocking antibody of Angpt2 ameliorates infarct size and adverse cardiac remodeling after myocardial ischemia.

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Genetic deletion or blocking antibody of Angpt2 ameliorates infarct size...
Adult WT or Angpt2iΔ/Δ mice were subject to MI, I/R, or sham procedure, and hearts were analyzed at 3 weeks after the procedure. (A) Diagram depicting preparation of animals and experimental schedules. Fc or α-Angpt2 (20 mg/kg, intraperitoneally) was administered to WT or Angpt2iΔ/Δ mice at 6 hours after MI, followed by repeated injections of the same dose at 1-week intervals. (B and C) Images and comparisons of infarction area. n = 5–6, each group. Scale bars: 1 mm. (D and E) Images and comparisons of cardiac fibrosis represented by fibronectin+ area. n = 6, each group. Scale bars: 1 mm. (F and G) Images and comparisons of cardiac systolic function evaluated by echocardiography. n = 6, each group. (C, E, and G) Comparisons of indicated parameters. *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. (H–J) Fc or α-Angpt2 (20 mg/kg, intraperitoneally) was administered to WT mice at 6 hours after I/R, followed by repeated injections of the same dose at 1 week intervals. Images of cardiac fibrosis determined by Masson trichrome stain and comparisons of indicated parameters. n = 6, each group. Scale bars: 1 mm. *P < 0.05 versus WT, Mann-Whitney U test. Error bars represent mean ± SD.
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