Irisin improves endothelial function in obese mice through the AMPK-eNOS pathway

Abstract

Sun X. Irisin improves endothelial function in obese mice through the AMPK-eNOS pathway. Am J Physiol Heart Circ Physiol 309: H1501-H1508, 2015. First published September 14, 2015 doi:10.1152/ajpheart.00443.2015.-Irisin is a novel hormone secreted by myocytes. Lower levels of irisin are independently associated with endothelial dysfunction in obese subjects. The objective of this study was to explore whether irisin exerts a direct vascular protective effect on endothelial function in high-fat-diet-induced obese mice. Male C57BL/6 mice were given chow or a high-fat diet with or without treatment with irisin. Aortic endothelial function was determined by measuring endothelium-dependent vasodilatation (EDV). Nitric oxide (NO) in the aorta was determined. The effect of irisin on the levels of AMP-activated protein kinase (AMPK), Akt, and endothelial NO synthase (eNOS) phosphorylation in endothelial cells was determined. Human umbilical vein endothelial cells were used to study the role of irisin in the AMPK-eNOS pathway. Acetylcholine-stimulated EDV was significantly lower in obese mice compared with control mice. Treatment of obese mice with irisin significantly enhanced EDV and improved endothelial function. This beneficial effect of irisin was partly attenuated in the presence of inhibitors of AMPK, Akt, and eNOS. Treatment of obese mice with irisin enhanced NO production and phosphorylation of AMPK, Akt, and eNOS in endothelial cells. These factors were also enhanced by irisin in human umbilical vein endothelial cells in vitro. Suppression of AMPK expression by small interfering RNA blocked irisin-induced eNOS and Akt phosphorylation and NO production. We have provided the first evidence that irisin improves endothelial function in aortas of high-fat-diet-induced obese mice. The mechanism for this protective effect is related to the activation of the AMPK-eNOS signaling pathway. irisin; endothelial function; nitric oxide; obesity NEW & NOTEWORTHYIrisin improved endothelial function in aortas of high-fat-dietinduced obese mice. The mechanism for the protective effect of irisin is related to activation of the AMP-activated protein kinase-endothelial nitric oxide synthase signaling pathway.

Irisin Regulates Heme Oxygenase-1/Adiponectin Axis in Perivascular Adipose Tissue and Improves Endothelial Dysfunction in Diet-Induced Obese Mice

“…Mice in the NC group were fed a normal chow diet and mice in the other two groups were fed a HFD (493 kcal 100 g –1 ) [18]. Mice in the irisin group were given recombinant irisin (0.5 μg/g/day; Phoenix Pharmaceuticals, Inc., Burlingame, CA, USA) by intraperitoneal injection daily [12, 14]. The other two groups were given physiological saline as control.…”

“…Zhu et al [10] showed that irisin improves endothelial dysfunction in diet-induced diabetic mice. In our previous study, serum irisin levels were found to be reduced in obese patients compared with non-obese subjects and that treatment of obese mice with irisin improves endothelial dysfunction by the AMP kinase (AMPK)–endothelial NO synthase (eNOS) signaling pathway [11, 12]. These findings suggest that irisin has the ability to improve endothelial dysfunction.…”

Thirty Years of Saying NO

“…Modified from Zhao et al 29 (Copyright ©2015, The Authors). α indicates α-adrenergic receptor; 5HT, serotonin (5-hydroxytryptamine); 5HT1d, serotoninergic (5 hydroxytryptamine) receptor 1D subtypes; ACh, acetylcholine; Ang 1-7 , angiotensin [1][2][3][4][5][6][7] ; AdipoR, adiponectin receptor; AVP, arginine vasopressin; B, kinin receptor; E, epinephrine; EP4, prostaglandin E 2 -receptor 4; ER, nongenomic estrogen receptor; ET, endothelin-1; ETb, endothelin-receptor B subtypes; GLP, glucagon-like peptide-1, glucagon-like peptide receptor; GPR55, G-protein-coupled receptor 55; H, histaminergic receptor; HDL, high-density lipoproteins; IP, prostacyclin receptor; IR 1 , insulin receptor; M, muscarinic receptor; Mas, Mas receptor; MC, melanocortin receptor; NE, norepinephrine; P, purinergic receptor; PAR, protease activated receptor; PGE 2 in a nongenomic manner on G-protein-coupled receptors), glucagon-like peptide-1, high-density lipoproteins (HDL; associating with sphingosine 1 -phosphate), insulin (by activating the PI3K/Akt pathway), irisin 52 (an autacoid/hormone secreted by myocytes), melanocortin (α-melanocyte-stimulating hormone), oxytocin, secretoneurin, 79 and vasopressin. 15 Likewise, aggregating platelets (Figure 2) release adenine nucleotides (in particular, ADP) and 5-hydroxytryptamine (serotonin), which induce endothelium-dependent relaxations.…”

“…This beneficial impact of exercise on endothelial vasomotor regulation, resulting from repeated augmentations in blood flow, is explained by several long-term effects of increases in shear stress that include: (1) upregulation of tyrosine kinase c-Src increasing the expression and activation (by phosphorylation) of eNOS; (2) increased production of transforming growth factor-β and subsequent activation of Krüppel-like factor-2, which promotes eNOS gene transcription; (3) upregulation of longevity-associated bactericidal permeability increasing fold-containing-family-B-member-4, the activation of which promotes the phosphorylation of eNOS at Ser1177; (4) production of endogenous hydrogen peroxide, which activates calcium/calmodulin-dependent PK II leading to activation of, on the one hand, janus kinase II upregulating eNOS expression/presence (see Reduced Protein Presence section of this article) and, on the other hand, of kinases (including Akt, AMPK, and ERK1/2), which increase phosphorylation at Ser1177 and hence activate eNOS; (5) increased production of irisin 52 ; and (6) improved mitochondrial biogenesis/function thereby permitting greater metabolic capacity (including glycolysis and oxidative phosphorylation) and preventing mitochondrial ROS formation.…”

“…With aging, with dietary unbalance (eg, high salt intake, hypercholesterolemia, and hypovitaminosis D), with exposure to deleterious environmental factors (active and passive smoking, chronic exposure to air pollution) and under pathological conditions such as obesity (with exaggerated release of deleterious adipokines [eg, chemerin, leptin, 93 lipocalin-2, and resistin] from inflamed fat, in particular, in perivascular adipose tissues, and reduced secretion of irisin from myocytes), 52 93 cortisol, progesterone, or testosterone), atherosclerosis, endothelial regeneration after injury (eg, angioplasty and heart transplantation), immunodeficiency and certain inflammatory situations (eg, rheumatoid arthritis), the eNOS-NO system becomes dysfunctional. 12,14,15 When comparing NO-mediated responses between preparations of control, aged, and diseased animals or humans, examining only responses to strong stimuli for NO production (eg, acetylcholine, bradykinin or shear stress) is not necessarily indicative of endothelial normality because the parallel use of less efficacious endothelium-dependent dilators (α 2 -adrenergic agonists, insulin, or serotonin) may reveal an obvious endothelial dysfunction.…”