Irisin在调节组织应激、心脏功能和炎症方面起着重要作用。最近发现整合素αvβ5是一种irisin受体，用以发挥其生理功能。尚不清楚整合素αvβ5是否能够调控irisin在调节出血生理反应中的功能。本研究旨在探讨整合素αvβ5是否对irisin在出血反应中的影响起到贡献。 通过将平均动脉血压维持在35-45mmHg的水平1小时，然后行2小时复苏来诱导小鼠出血。给予irisin（50ng/kg）以评估其在出血中的药理效应。同时与irisin一起给予整合素αvβ5的抑制剂Cilengitide，或RGD对照（1mg/kg）。在另一组小鼠中，通过使用CRSIPR/Cas-9基因编辑，用纳米颗粒递送整合素β5 sgNRA进行整合素β5的基因敲低，然后检测irisin诱导的保护效应。使用超声心动图和股动脉导管测量心功能和血流动力学。使用酶联免疫吸附测定法（ELISA）测量全身细胞因子释放。使用组织学分析确定心肌、骨骼肌和肺组织的损伤情况。使用末端脱氧核苷酸转移ase dUTP终端标记（TUNEL）评估组织中的凋亡情况。 出血导致骨骼肌整合素αvβ5的降低，并抑制心脏功能和血流动力学的恢复。irisin治疗显著改善了心脏功能，而Cilengitide或整合素β5敲低会使这种效应消失。此外，irisin显著抑制了心肌和骨骼肌中肿瘤坏死因子-α（TNF-α）和白细胞介素-1（IL-1）的释放、肌肉水肿和炎症细胞浸润，而这种效应会被Cilengitide或整合素β5敲低所减弱。irisin可减少心肌、骨骼肌和肺组织中的凋亡，而抑制整合素αvβ5或敲低整合素β5将减弱这种效应。 整合素αvβ5在irisin调节出血期间的保护效应中起着重要作用。 © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Irisin plays an important role in regulating tissue stress, cardiac function, and inflammation. Integrin αvβ5 was recently identified as a receptor for irisin to elicit its physiologic function. It remains unknown whether integrin αvβ5 is required for irisin's function in modulating the physiologic response to hemorrhage. The objective of this study is to examine if integrin αvβ5 contributes to the effects of irisin during the hemorrhagic response.Hemorrhage was induced in mice by achieving a mean arterial blood pressure of 35-45 mmHg for one hour, followed by two hours of resuscitation. Irisin (50 ng/kg) was administrated to assess its pharmacologic effects in hemorrhage. Cilengitide, a cyclic Arg-Gly-Asp peptide (cRGDyK) which is an inhibitor of integrin αvβ5, or control RGD (1 mg/kg) was administered with irisin. In another cohort of mice, the irisin-induced protective effect was examined after knocking down integrin β5 with nanoparticle delivery of integrin β5 sgNRA using CRSIPR/Cas-9 gene editing. Cardiac function and hemodynamics were measured using echocardiography and femoral artery catheterization, respectively. Systemic cytokine releases were measured using Enzyme-linked immunosorbent assay (ELISA). Histological analyses were used to determine tissue damage in myocardium, skeletal muscles, and lung tissues. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was carried out to assess apoptosis in tissues.Hemorrhage induced reduction of integrin αvβ5 in skeletal muscles and repressed recovery of cardiac performance and hemodynamics. Irisin treatment led to significantly improved cardiac function, which was abrogated by treatment with Cilengitide or knockdown of integrin β5. Furthermore, irisin resulted in a marked suppression of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), muscle edema, and inflammatory cells infiltration in myocardium and skeletal muscles, which was attenuated by Cilengitide or knockdown of integrin β5. Irisin-induced reduction of apoptosis in the myocardium, skeletal muscles, and lung, which were attenuated by either the inhibition of integrin αvβ5, or knockdown of integrin β5.Integrin αvβ5 plays an important role for irisin in modulating the protective effect during hemorrhage.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.