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

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 13

Schematic diagram depicting the roles of Angpt2 in exacerbating cardiac hypoxia and inflammation after myocardial ischemia.

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Schematic diagram depicting the roles of Angpt2 in exacerbating cardiac ...
Myocardial ischemia induces disintegration of endothelial barrier, abnormal vascular remodeling, robust inflammatory responses, and ECM disorganization, and these pathological changes can be effectively mitigated by Angpt2 blockade. Mechanistically, in ECs, the increase in Angpt2 expression is directly regulated by FOXO1, which antagonizes Tie2 signaling and consequently attenuates PI3K/Akt signaling and enhances NF-κB p65 and FOXO1 expression. Thus, increased FOXO1 transcriptional activity forms a positive feedback loop with Angpt2 and exerts a sustained effect on ECs, leading to destabilization and remodeling. Pericyte detachment and EC destabilization presumably due to attenuated PI3K/Akt signaling exacerbate vascular leakage. Enhanced activity of NF-κB p65 augments endothelial expression of heparanase and adhesion molecules, further promoting inflammatory cell recruitment and ECM disorganization. In addition, Angpt2/integrin α5β1 signaling promotes abnormal vascular remodeling through FAK phosphorylation, resulting in chronic hypoxia. In macrophages, the Angpt2/integrin α5β1/ERK–signaling pathway plays an important role in proinflammatory macrophage polarization in autocrine and paracrine manners. These exacerbating roles of Angpt2 in cardiac hypoxia and inflammation after myocardial ischemia eventually trigger deterioration of cardiac structure and function, leading to heart failure.