Irisin Lowers Blood Pressure by Improvement of Endothelial Dysfunction via AMPK‐Akt‐eNOS‐NO Pathway in the Spontaneously Hypertensive Rat

BACKGROUND Exercise is a major nonpharmacological treatment for hypertension, but its underlying mechanisms are still not completely elucidated. Irisin, a polypeptide containing 112 amino acids, which is secreted mainly by skeletal muscle cells during exercise, exerts a protective role in metabolic diseases, such as diabetes mellitus and obesity. Because of the close relationship between irisin and metabolic diseases, we hypothesized that irisin may play a role in the regulation of blood pressure. METHODS AND RESULTS Blood pressures of male Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) were monitored through the carotid artery. Our study found that acute intravenous injection of irisin reduced blood pressure in SHRs, but not WKY rats. Irisin, by itself, had no direct vasorelaxing effect in phenylephrine-preconstricted mesenteric arteries from SHRs. However, irisin augmented the acetylcholine-induced vasorelaxation in mesenteric arteries from SHRs that could be reversed by Nω-nitro-l-arginine-methyl ester (L-NAME; 100 μmol/L), indicating a role of nitric oxide (NO) in this action. Indeed, irisin increased NO production and phosphorylation of endothelial nirtic oxide synthase (eNOS) in endothelial cells. 5'-AMP-activated protein kinase (AMPK) was involved in the vasorelaxing effect of irisin because compound C (20 μmol/L), an AMPK inhibitor, blocked the irisin-mediated increase in phosphorylation of eNOS and protein kinase B (Akt) in endothelial cells and vasodilation in mesenteric arteries. CONCLUSIONS We conclude that acute administration of irisin lowers blood pressure of SHRs by amelioration of endothelial dysfunction of the mesenteric artery through the AMPK-Akt-eNOS-NO signaling pathway.