Irisin attenuates oxidized low‐density lipoprotein impaired angiogenesis through AKT/mTOR/S6K1/Nrf2 pathway

Abstract

It is known that irisin increases total body energy expenditure, decreases body weight, and enhances insulin sensitivity. Although previous studies have demonstrated that irisin induces vascular endothelial cell (EC) angiogenesis, the molecular mechanisms underlying irisin‐induced angiogenesis under conditions reflecting atherosclerosis are not known. The aim of the present study is to investigate whether irisin could inhibit oxidized low‐density lipoprotein (oxLDL) impaired angiogenesis. We investigated the effect of irisin on angiogenesis in vitro by evaluating cell viability, cell migration, and the capacity to form capillary‐like tubes using human umbilical vein endothelial cells and human microvascular endothelial cells (HUVECs and HMEC‐1) that were treated with oxLDL. We also evaluated the effects of irisin on angiogenesis in vivo by Matrigel plug angiogenesis assay and in a chicken embryo membrane (CAM) model. Our results demonstrated that irisin increased oxLDL‐treated EC viability as well as migration and tube formation. Moreover, oxLDL inhibited angiogenic response in vivo, both in the Matrigel plug angiogenesis assay and in the CAM model, and was attenuated by irisin. Furthermore, irisin decreased apoptosis, inflammatory cytokines, and intracellular reactive oxygen species (ROS) levels in oxLDL‐treated EC. In addition, we found that irisin upregulated pAkt/mTOR/Nrf2 in oxLDL‐treated EC. Both mTOR/Nrf2 shRNA and LY294002 could inhibit the protective effect of irisin. Taken together these results, they suggested that irisin attenuates oxLDL‐induced vascular injury by activating the Akt/mTOR/Nrf2 pathway. Our findings suggest that irisin attenuates oxLDL‐induced blood vessel injury.

Potential Applications of NRF2 Modulators in Cancer Therapy

“…Depletion of NRF2 decreases the levels of HIF-1a, which in turn causes reduction of blood vessels formation through regulation of VEGF in rat gastric epithelial cells, glioblastoma and colon cancer xenograft models [177][178][179]. In recent studies, it was reported that regulation of VEGF by NRF2 also depends on PI3K/AKT/mTOR pathways in endothelial cells [180,181]. These data suggest that both proliferative and pro-angiogenic effects of PI3K/AKT/mTOR and NRF2 pathways cooperate in favor of cancer cells.…”

Irisin and Incretin Hormones: Similarities, Differences, and Implications in Type 2 Diabetes and Obesity

“…The induction of autophagy has been proposed as a mechanism though which irisin exerts these beneficial effects [112,114,115], as block of the autophagic flux has been identified as a possible cause of cardiomyocyte apoptosis and cardiac hypertrophy. In addition, the activation of AKT [108,111,116] and AMPK [15,109,114] could represent key signaling steps in the cardio-protective effects of irisin. Moreover, irisin could also promote cardiac progenitor cell-induced myocardial repair and functional improvement in an infarcted heart [117].…”

“…Furthermore, in vitro studies conducted on human umbilical vein endothelial cells (HUVECs) or human microvascular endothelial cells (HMEC-1) have shown the irisin's ability to exert proangiogenic effects through activation of the ERK-regulated proliferation signaling pathway [106,[126][127][128], to prevent apoptosis induced by high fat, high glucose, or advanced glycation end products [128][129][130] and to counteract the impairment of angiogenesis by oxidized low-density lipoprotein (LDL) [116]. Interestingly, irisin could also improve endothelial function by increasing the number of endothelial progenitor cells (EPCs) in peripheral blood of diabetic mice and by improving the function of bone marrowderived EPCs in diabetic mice via the PI3K-AKT-eNOS pathway [131].…”

Irisin: A New Code Uncover the Relationship of Skeletal Muscle and Cardiovascular Health During Exercise

“…In addition, irisin treatment (0.5 μg/g body weight/day) inhibits the formation of carotid neointima, alleviates aortic inflammation and apoptosis and significantly reduces atherosclerosis in ApoEdeficient mice fed with high cholesterol diet (Zhang et al, 2016a). In the cell model of atherosclerosis, the application of irisin can improve the survival of ECs, promote their migration and tube forming capacity and inhibit apoptosis, proinflammatory cytokine secretion, and reactive oxygen species (ROS) production via pAkt/mTOR/nuclear factor E2-related factor-2 (Nrf2) pathway (Zhang et al, 2019).…”