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Background  Irisin is a newly discovered myokine that has been considered a promising candidate for the treatment of cardiovascular disease through improving endothelial function. However, little is known about the role of irisin in the progression of atherosclerosis.    Methods and Results  We used a carotid partial ligation model of apolipoprotein E–deficient mice fed on a high‐cholesterol diet to test the anti‐atherosclerosis effect of irisin. Irisin treatment significantly suppressed carotid neointima formation. It was associated with increased endothelial cell proliferation. In addition, irisin promoted human umbilical vein endothelial cell survival via upregulating microRNA126‐5p expression through the ERK signaling pathway. Inhibition of microRNA126‐5p using the microRNA126‐5p inhibitor abolished the prosurvival effect. The same results were demonstrated in vivo as the expression of microRNA126‐5p noticeably increased in ligated carotid artery after irisin treatment. Furthermore, in vivo blockade of microRNA126‐5p expression using the antagomir abolished the inhibitory effects of irisin on neointima formation, lesional lipid deposition, macrophage area, and the pro‐proliferation effects on endothelial cells.    Conclusions  Taken together, our study demonstrates that irisin significantly reduces atherosclerosis in apolipoprotein E–deficient mice via promoting endothelial cell proliferation through microRNA126‐5p, which may have a direct therapeutic effect on atherosclerotic diseases.

Irisin Inhibits Atherosclerosis by Promoting Endothelial Proliferation Through micro RNA 126‐5p