Iron deficiency promotes aortic media degeneration by activating endoplasmic reticulum stress-mediated IRE1 signaling pathway

Aortic dissection (AD) is a macrovascular disease which is pathologically characterized by aortic media degeneration (AMD). Our team's previous research found that iron deficiency (ID) promoted the formation of AMD through presentative research. In this study, we aimed to investigate the underlying mechanism of ID promoting AMD formation. The human aortic tissues were harvested from AD patients and organ donors. ApoE-/- mice were simultaneously given AngII infusion and low-iron feed to investigate the relationship between ID and AD. The IRE1-XBP1-CHOP signal axis of endoplasmic reticulum (ER) stress was selectively inhibited with 4μ8C. Iron contents were detected by Perls staining. The expression of iron metabolism and ER stress-relative proteins were analyzed by IF and western blotting. Apoptosis rates of aortic tissue and ASMCs were detected by TUNEL staining and flow cytometry, and ROS content was also measured by the flow cytometry. ID was accompanied by ER stress in patients with AD. Among the three signaling pathways of ER stress in ID-induced AMD, proteins of IRE1, PERK and ATF6 signaling pathways were up-regulated by 2.65 times, 1.14 times and 1.24 times, respectively. ID was positively related to ER stress, mitochondrial oxidative stress and aortic media apoptosis in vivo and in vitro assays, while 4μ8C reversed the severity of ER stress and AMD. ID could activate ER stress by eliciting mitochondrial oxidative stress to activate the IRE1-XBP1-CHOP signaling pathway in the ER, which accelerated the apoptosis of ASMCs in aortic media, thus promoting the formation of AMD.