Role of ferroptosis in the process of diabetes-induced endothelial dysfunction

Abstract

BACKGROUND Endothelial dysfunction, a hallmark of diabetes, is a critical and initiating contributor to the pathogenesis of diabetic cardiovascular complications. However, the underlying mechanisms are still not fully understood. Ferroptosis is a newly defined regulated cell death driven by cellular metabolism and iron-dependent lipid peroxidation. Although the involvement of ferroptosis in disease pathogenesis has been shown in cancers and degenerative diseases, the participation of ferroptosis in the pathogenesis of diabetic endothelial dysfunction remains unclear. AIM To examine the role of ferroptosis in diabetes-induced endothelial dysfunction and the underlying mechanisms. METHODS Human umbilical vein endothelial cells (HUVECs) were treated with high glucose (HG), interleukin-1β (IL-1β), and ferroptosis inhibitor, and then the cell viability, reactive oxygen species (ROS), and ferroptosis-related marker protein were tested. To further determine whether the p53-xCT (the substrate-specific subunit of system Xc - )-glutathione (GSH) axis is involved in HG and IL-1β induced ferroptosis, HUVECs were transiently transfected with p53 small interfering ribonucleic acid or NC small interfering ribonucleic acid and then treated with HG and IL-1β. Cell viability, ROS, and ferroptosis-related marker protein were then assessed. In addition, we detected the xCT and p53 expression in the aorta of db/db mice. RESULTS It was found that HG and IL-1β induced ferroptosis in HUVECs, as evidenced by the protective effect of the ferroptosis inhibitors, Deferoxamine and ferrostatin-1, resulting in increased lipid ROS and decreased cell viability. Mechanistically, activation of the p53-xCT-GSH axis induced by HG and IL-1β enhanced ferroptosis in HUVECs. In addition, a decrease in xCT and the presence of de-endothelialized areas were observed in the aortic endothelium of db/db mice. CONCLUSION Ferroptosis is involved in endothelial dysfunction and p53-xCT-GSH axis activation plays a crucial role in endothelial cell ferroptosis and endothelial dysfunction.

Exosomes derived from pioglitazone-pretreated MSCs accelerate diabetic wound healing through enhancing angiogenesis

“…It is widely accepted that disruption of local angiogenesis is a crucial limiting factor in diabetic wound healing [ 5 , 27 , 36 ]. Endothelial dysfunction seen with diabetic vascular complications results in impaired repair and abnormal angiogenesis [ 37 ]. Increasing evidence has revealed that hyperglycemia-induced impairment of endothelial cell function is an important cause of vascular dysfunction, which results in the occurrence of diabetic complications [ 38 , 39 ].…”

The Link Between Ferroptosis and Cardiovascular Diseases: A Novel Target for Treatment

“…Vascular endothelial dysfunction is thought to be one of the major causes of DCM (87). Recently, Luo et al (88) found that high glucose induces ferroptosis in human umbilical vein endothelial cells (HUVECs) and concluded that ferroptosis is involved in endothelial dysfunction via p53-xCT (the substratespecific subunit of system xc − )-GSH axis, suggesting that ferroptosis might participate in the process of DCM.…”

Ferroptosis and Its Potential Role in Metabolic Diseases: A Curse or Revitalization?

“…All of the above discoveries foreshadow that ferroptosis may participate in the development of osteoporosis, especially the devitalization of osteoblasts. Recently, a study indicated that extracellular vesicles derived from endothelial progenitor cells (EPC-EVs) satisfied the need of retarding the progress of steroid-induced osteoporosis (SIOP) by inhibiting ferroptosis, specifically by reversing the deactivation of GPX4, system Xc-and decreased cysteine levels, which is initiated by dexamethasone (Lu et al, 2019). Since these speculations are based on bioinformatics evidence, the detailed signal pathways and in vitro and in vivo experiments warrant further investigation.…”

“…Another study sustained these results. Due to the ferroptosis-induced role played by glucocorticoids in osteoblasts (Lu et al, 2019), Yang et al (2021) originally found that exosomes derived from vascular endothelial cells (EC-Exos) counteract this process both in vitro and in vivo by decreasing NCOA4 expression to suppress ferritinophagy and simultaneously targeting the Keap1-Nrf2-HO-1/NQO-1 pathway to inhibit lipid oxidation, though the specific signal has not yet been elucidated. Some drugs that target osteoporosis may actualize a ferroptotic role during the therapeutic mechanism, which, in our perspective, is reasonable to surmise, but not yet visible.…”