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

Abstract

BackgroundExercise 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 ResultsBlood 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.ConclusionsWe 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.

Activation of AMP‐activated protein kinase by metformin ablates angiotensin II‐induced endoplasmic reticulum stress and hypertension in mice in vivo

“…This finding is consistent with our previous study which demonstrated that AMPK acted as a physiological suppressor of ER stress by maintaining SERCA activity and intracellular Ca 2+ homeostasis in endothelial cells (Dong et al , ). In addition, AMPK activation by irisin, a polypeptide containing 112 amino acids, secreted mainly by skeletal muscle cells during exercise, has been shown to lower BP in spontaneously hypertensive rats by improving NO bioactivity and endothelial cell function (Fu et al , ). This has been mechanistically attributed to the higher NO release by enhancing the phosphorylation and activation of endothelial NOS (eNOS) at Ser 1177 and Ser 633 (Chen et al , ; Zhang et al , ) and by blocking NO inactivation by reactive oxygen species (Deng et al , ).…”

Tetrahydroxystilbene Glycoside Improves Microvascular Endothelial Dysfunction and Ameliorates Obesity-Associated Hypertension in Obese ZDF Rats Via Inhibition of Endothelial Autophagy

“…The endothelium secretes various vasoconstrictors and vasodilators. The imbalance between the vasodilator NO and vasoconstrictor endothelin-1 in the endothelium contributes to endothelial dysfunction and increased peripheral vascular resistance and, subsequently, to hypertension [28-30]. …”

Adropin and irisin in arterial hypertension, diabetes mellitus and chronic kidney disease

“…A higher level of NO improved endothelial function. 17 Another study focused on correlations between irisin and AH in pregnant and preeclamptic women. The researchers used ELISA kits to analyze the level of irisin in the blood.…”