{"title":"Irisin alleviates steroid-induced vascular dysfunction by regulating the αVβ5-c-Abl-Caveolin-1 signaling pathway","authors":"Lijun Fang , Wenqiang Li , Hua Zhao , Wei Wang , Hongmei Gao , Pengqi Wang , Xinzhi Zhang , Ruijuan Lv , Feng Xu , Jiazheng Chen , Linmao Lyu , Yuguo Chen","doi":"10.1016/j.bcp.2025.116870","DOIUrl":null,"url":null,"abstract":"<div><div>Steroid-induced avascular necrosis of the femoral head (SANFH) is a progressive degenerative disease of the hip, primarily due to glucocorticoid (GC)-induced endothelial cell (EC) injury and compromised blood supply. Irisin is an EC-protective mytokine whose receptor is the integrin αVβ5. Caveolin-1 (CAV-1), a major component of caveolae, causes endothelial dysfunction when phosphorylated. However, the role of irisin and CAV-1 in SANFH remains unclear. In our study, irisin levels decreased but CAV-1 phosphorylation increased in human and mouse SANFH samples. Intraperitoneal irisin injection (250 μg/kg daily) notably reduced GC-induced osteonecrosis, vascular abnormalities, and CAV-1 phosphorylation in SANFH mice. In cultured ECs, GC induced CAV-1 phosphorylation by activating c-Abl via the glucocorticoid receptor, and irisin inhibited GC-induced phosphorylation of c-Abl and CAV-1 via the integrin αVβ5. Inhibition of integrin αVβ5 also abolished the protective effects of irisin on ERK and eNOS signalling, viability, angiogenesis, and migration in ECs. Therefore, our findings indicate that irisin has a protective role against vascular dysfunction in SANFH, possibly mediated by the inhibition of GC-triggered c-Abl-CAV-1 phosphorylation through integrin αVβ5. These findings provide insights into the potential therapeutic applications of irisin in SANFH.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116870"},"PeriodicalIF":5.3000,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemical pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0006295225001327","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
Steroid-induced avascular necrosis of the femoral head (SANFH) is a progressive degenerative disease of the hip, primarily due to glucocorticoid (GC)-induced endothelial cell (EC) injury and compromised blood supply. Irisin is an EC-protective mytokine whose receptor is the integrin αVβ5. Caveolin-1 (CAV-1), a major component of caveolae, causes endothelial dysfunction when phosphorylated. However, the role of irisin and CAV-1 in SANFH remains unclear. In our study, irisin levels decreased but CAV-1 phosphorylation increased in human and mouse SANFH samples. Intraperitoneal irisin injection (250 μg/kg daily) notably reduced GC-induced osteonecrosis, vascular abnormalities, and CAV-1 phosphorylation in SANFH mice. In cultured ECs, GC induced CAV-1 phosphorylation by activating c-Abl via the glucocorticoid receptor, and irisin inhibited GC-induced phosphorylation of c-Abl and CAV-1 via the integrin αVβ5. Inhibition of integrin αVβ5 also abolished the protective effects of irisin on ERK and eNOS signalling, viability, angiogenesis, and migration in ECs. Therefore, our findings indicate that irisin has a protective role against vascular dysfunction in SANFH, possibly mediated by the inhibition of GC-triggered c-Abl-CAV-1 phosphorylation through integrin αVβ5. These findings provide insights into the potential therapeutic applications of irisin in SANFH.
期刊介绍:
Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics.
The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process.
All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review.
While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.