The protective effect of irisin against hemorrhagic injury is mediated by PI3K and p38 pathways in hemorrhage/resuscitation.

The objective of this study was to investigate whether phosphoinositide 3-kinase (PI3K) and p38 mitogen-activated kinase contribute to the protection of irisin during hemorrhage/resuscitation. Experimental groups were divided based on the different treatments during resuscitation as follows: (1) hemorrhage: adult male CD-1 mice were subjected to hemorrhage at a mean arterial blood pressure of 35-45 mm Hg for 60 minutes, followed by resuscitation with shed blood and lactated Ringer's solution (n = 13); (2) hemorrhage + irisin: receiving irisin (5 μg/kg; n = 13); (3) hemorrhage + irisin + PI3K inhibitor: receiving both Ly294002 (1 mg/kg, i.v.) and irisin (n = 6); and (4) hemorrhage + irisin + p38 inhibitor: receiving SB202190 (1 mg/kg, i.v.) and irisin (n = 6). Compared with hemorrhage/resuscitation control, irisin improved cardiac function and the recovery of hemodynamics in association with the decreased systemic interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, which were completely abrogated by PI3K or p38 inhibitions. Furthermore, the inhibition of PI3K or p38 abolished irisin-induced reduction of the inflammatory cell infiltration and terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling-positive apoptosis in the cardiac and skeletal muscles. Irisin reduced TNF-α and IL-6 expression in cardiac and skeletal muscles, which was abrogated by the inhibition of PI3K or p38. Irisin-treated hemorrhage increases the phosphorylation of PI3K and p38 in both cardiac and skeletal muscles, which was mitigated by the inhibition of PI3K or p38. PI3K and p38 play an important role in modulating the protective effect of irisin during the hemorrhage/resuscitation. SIGNIFICANCE STATEMENT: This study has identified a critical pathway in the regulation of trauma/hemorrhage by using a preclinical trauma model, in which irisin, as a hormone factor, stimulates PI3K and p38 pathways to induce protection against traumatic conditions. The study holds promise for developing a new therapeutic strategy to target irisin and its pathways related to PI3K and p38 to treat trauma and its comorbidities to reduce mortality for clinical implications.