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 4

Irisin restored endothelial barrier function by activation of AMPK-Rac1/Cdc42 signaling.

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Irisin restored endothelial barrier function by activation of AMPK-Rac1/...
HMVECs were treated with 10 nM irisin immediately after 500 ng/mL LPS administration. (A–D) Western blot analysis of activation of adenosine monophosphate–activated protein kinase (AMPK), as well as Rac1 and Cdc42 activation assays in irisin- and control-treated HMVECs. (E and F) Western blot analysis of activation of AMPK in cilengitide trifluoroacetate- and control-treated HMVECs after 500 ng/mL LPS and 10 nM irisin administration. (G–I) Rac1 and Cdc42 activation assays in irisin- and LPS-treated HMVECs transfected with nonspecific siRNA or AMPK siRNA. (J) Phalloidin and VE-cadherin staining in HMVECs. Scale bar: 10 μm. Asterisks in the Phalloidin and VE-cadherin staining represents gaps between the cells. (K) Gap areas in the total areas. (L) TER. (M) Relative permeability of FITC-labeled albumin. n = 6 per group, mean ± SEM, *P < 0.05 versus the sham group or the LPS + irisin group. #P < 0.05 versus the LPS or LPS + irisin group. The t test was used to analyze the differences between 2 groups (K and M), and 1-way ANOVA was used to analyze the differences among 3 or more groups (B–D, F, H, and I).