Irisin protects against atherosclerosis in ApoE-/- mice by suppressing the migration of vascular smooth muscle cell via PI3K-Akt-cofilin.

Irisin, a myokine secreted by the skeletal muscles during exercise, exerts atheroprotective effects. However, the precise molecular mechanisms that underlie these effects remain incompletely elucidated. This study aimed to investigate the effect of irisin on atherosclerosis and vascular smooth muscle cell (VSMC) migration, and to explore the role of cofilin-mediated cytoskeletal remodeling in the atheroprotective effect of irisin. In vivo, irisin was administered to high-fat diet-fed ApoE^-/- mice. Dyslipidemia in these mice was alleviated by irisin treatment. Atherosclerotic lesion assessment via Oil Red O staining, Masson's trichrome staining, and alpha-smooth muscle actin (a-SMA) immunofluorescence staining revealed that irisin significantly attenuated atherosclerotic plaque burden, necrotic core size, and VSMC area within the aortic tissue of ApoE^-/- mice. However, the atheroprotective effect of irisin was partially reversed when ApoE^-/- mice were cotreated with an integrin αVβ5 inhibitor. In vitro, irisin supplementation decreased platelet-derived growth factor (PDGF)-induced VSMC migration, determined by wound healing assay and transwell migration assay. Furthermore, irisin treatment reversed the elevated expression of p-PI3K and p-Akt as well as the decreased expression of p-cofilin observed both in the aorta of ApoE^-/- mice and in PDGF-stimulated VSMCs. The effects of irisin on p-PI3K, p-Akt, and p-cofilin expression were partially blocked by cotreatment with an integrin αVβ5 inhibitor or PI3K activator. The decreased expression of p-cofilin in PDGF-stimulated VSMCs was partially blocked by PI3K inhibitor. Systemic irisin administration confers protection against atherosclerosis in ApoE^-/- mice. Mechanistically, this beneficial effect involves suppression of the PI3K-Akt signaling pathway, which modulates cofilin-mediated cytoskeletal remodeling to regulate VSMC migration.