Exercise hormone irisin mitigates endothelial barrier dysfunction and microvascular leakage–related diseases
Jianbin Bi, Jia Zhang, Yifan Ren, Zhaoqing Du, Yuanyuan Zhang, Chang Liu, Yawen Wang, Lin Zhang, Zhihong Shi, Zheng Wu, Yi Lv, Rongqian Wu
Jianbin Bi, Jia Zhang, Yifan Ren, Zhaoqing Du, Yuanyuan Zhang, Chang Liu, Yawen Wang, Lin Zhang, Zhihong Shi, Zheng Wu, Yi Lv, Rongqian Wu
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Research Article Cell biology Vascular biology

Exercise hormone irisin mitigates endothelial barrier dysfunction and microvascular leakage–related diseases

Abstract

Increased microvascular leakage is a cardinal feature of many critical diseases. Regular exercise is associated with improved endothelial function and reduced risk of cardiovascular disease. Irisin, secreted during exercise, contributes to many health benefits of exercise. However, the effects of irisin on endothelial function and microvascular leakage remain unknown. In this study, we found that irisin remarkably strengthened endothelial junctions and barrier function via binding to integrin αVβ5 receptor in LPS-treated endothelial cells. The beneficial effect of irisin was associated with suppression of the Src–MLCK–β-catenin pathway, activation of the AMPK-Cdc42/Rac1 pathway, and improvement of mitochondrial function. In preclinical models of microvascular leakage, exogenous irisin improved pulmonary function, decreased lung edema and injury, suppressed inflammation, and increased survival. In ARDS patients, serum irisin levels were decreased and inversely correlated with disease severity and mortality. In conclusion, irisin enhances endothelial barrier function and mitigates microvascular leakage–related diseases.

Authors

Jianbin Bi, Jia Zhang, Yifan Ren, Zhaoqing Du, Yuanyuan Zhang, Chang Liu, Yawen Wang, Lin Zhang, Zhihong Shi, Zheng Wu, Yi Lv, Rongqian Wu

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Figure 3

Irisin enhanced endothelial cell barrier function via binding to integrin αVβ5 receptor and suppression of P-Src (Y416)/P-MLCK (Y464)/P–β-catenin (Y142) pathway.

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Irisin enhanced endothelial cell barrier function via binding to integri...
Irisin (250 μg/kg, i.v.) and cilengitide trifluoroacetate (20 mg/kg, i.v.) were given by i.v. administration immediately after LPS administration intratracheally (2 mg/kg). Vehicle group of mice was given equivalent amounts of saline. Lungs were harvested 24 hours after LPS administration. HMVECs were treated with 10 nM irisin and 20 μM cilengitide trifluoroacetate immediately after 500 ng/mL LPS administration. (A) Immunofluorescence colocalization of intergrin αVβ5 and irisin at 2 hours after LPS and irisin treatment in HMVECs. Scale bar: 10 μm. (B) Co-IP of irisin and integrin αVβ5 at 24 hours after LPS-induced microvascular leakage. (C) Relative permeability of FITC-labeled albumin 2 hours after LPS, irisin, and cilengitide trifluoroacetate treatment in HMVECs. (D) Phalloidin and VE-cadherin staining for assessing cytoskeletal remodeling and adherens junction integrity. Scale bar: 10 μm. Asterisks in the Phalloidin and VE-cadherin staining represents gaps between the cell. (E) Gap areas in the total areas. (F and G) Total cells and protein levels in BALF in LPS-induced microvascular leakage. (H) Water content of lungs in LPS-induced microvascular leakage. (I–L) Western blot analysis of phosphorylation of Src, MLCK, and β-catenin at Tyr416, Tyr464, Tyr142, respectively. *P < 0.05 versus the sham group, #P < 0.05 versus the LPS or CLP group. (M–P) Western blot analysis of phosphorylation of Src, MLCK, and β-catenin after treatment with cilengitide trifluoroacetate. *P < 0.05 versus the LPS group, #P < 0.05 versus the irisin group; n = 6 per group, mean ± SEM. One-way ANOVA was used to analyze the differences between groups.