Background: Atherosclerosis is a chronic disease, with smoking being an independent risk factor. Irisin, a factor produced by myocytes, is expected to treat smoking-related arteriosclerosis, however its specific mechanism remains unclear.
Methods: Forty Apoe-/- mice with nicotine intervention were involved in this study. The atherosclerotic lesions, smooth muscle cell proliferation, and macrophage infiltration induced by nicotine, and the corresponding changes caused by the administration of irisin, were obtained. The integrin αVβ5 inhibitor, cilengitide, was included to determine the cell entry pathway of irisin. Proteins and mRNA levels of phosphatidylinositol 3-kinase (PI3K) and downstreams were detected to clarify the specific molecular mechanism of irisin activity.
Results: H&E staining and Masson staining showed that nicotine could aggravate the intensity of atherosclerosis in mice, and Irisin could reverse the thickening of the vascular media induced by nicotine. Immunohistochemical staining of CD68 and α-SMA suggested that Irisin could inhibit nicotine-mediated macrophage infiltration and smooth muscle cell proliferation. The protective effect of Irisin was partially reduced after the administration of cilengitide, confirming that Irisin enters cells through multiple ways, including integrin αvβ5. Nicotine was confirmed to activate the PI3K pathway to promote media thickening, while Irisin can inhibit the activation of the PI3K pathway, thus playing its anti-atherosclerosis role. Irisin was further observed to reverse nicotine-mediated P27 down-regulation.
Conclusions: Irisin was found to inhibit nicotine-mediated medium thickening, smooth muscle cell proliferation, macrophage infiltration, and atherosclerosis progression via the integrin αVβ5/PI3K/P27 pathway.
Keywords: Irisin; PI3K; atherosclerosis; integrin αVβ5; nicotine.
2021 Annals of Translational Medicine. All rights reserved.