Department of Plastic Surgery, Rhode Island Hospital, Brown University, USA.
Boston University, Boston, MA, USA.
Exp Mol Pathol. 2023 Dec;134:104869. doi: 10.1016/j.yexmp.2023.104869. Epub 2023 Sep 27.
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 (0.5 μg/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 RGDS (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 sgRNA 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.
鸢尾素在调节组织应激、心脏功能和炎症方面发挥着重要作用。整合素 αvβ5 最近被鉴定为鸢尾素发挥其生理功能的受体。目前尚不清楚整合素 αvβ5 是否是鸢尾素调节出血时生理反应所必需的。本研究旨在探讨整合素 αvβ5 是否有助于鸢尾素在出血反应中的作用。
通过将平均动脉血压降至 35-45mmHg 持续 1 小时，然后再复苏 2 小时，诱导小鼠出血。给予鸢尾素（0.5μg/kg）以评估其在出血中的药理作用。给予西利那肽（一种整合素 αvβ5 的抑制剂，即环状精氨酸-甘氨酸-天冬氨酸肽（cRGDyK））或对照 RGDS（1mg/kg）与鸢尾素一起给药。在另一批小鼠中，使用 CRSIPR/Cas-9 基因编辑，通过整合素β5 sgRNA 的纳米颗粒递送敲低整合素β5，检查鸢尾素诱导的保护作用。使用超声心动图和股动脉导管分别测量心功能和血液动力学。使用酶联免疫吸附试验（ELISA）测量全身细胞因子释放。进行末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）以评估组织中的细胞凋亡。
出血诱导骨骼肌中整合素 αvβ5 的减少，并抑制心脏功能和血液动力学的恢复。鸢尾素治疗导致心脏功能显著改善，而用西利那肽或敲低整合素β5 治疗则阻断了这一作用。此外，鸢尾素显著抑制肿瘤坏死因子-α（TNF-α）和白细胞介素-1（IL-1）、肌肉水肿和心肌及骨骼肌中的炎症细胞浸润，而用西利那肽或敲低整合素β5 治疗则减弱了这一作用。鸢尾素诱导的心肌、骨骼肌和肺组织细胞凋亡减少，而用抑制整合素 αvβ5 或敲低整合素β5 则减弱了这一作用。
整合素 αvβ5 在调节鸢尾素在出血时的保护作用中起重要作用。
