Hydroxysafflor yellow A inhibits endothelial cell ferroptosis in diabetic atherosclerosis mice by regulating miR-429/SLC7A11
Jianjie Rong, Chuanyong Li, Qiang Zhang, Guangfeng Zheng, Weijian Fan, Zhichang Pan, Shuming Shi
Abstract
Context Ferroptosis may play an essential role in lipid peroxidation and endothelial dysfunction of aortic endothelial cells (ECs) in type 2 diabetes mellitus (T2DM) with atherosclerosis (AS). Hydroxysafflor yellow A (HSYA) has shown substantial antioxidant stress and anti-ferroptosis.Objective This study confirms whether HSYA improves symptoms in a mouse model of T2DM/AS and elucidates the underlying mechanisms.Materials and methods ApoE-/- mice were fed with high fat combined with 30 mg/kg streptozotocin to establish a T2DM/AS model. Then mice were treated with intraperitoneal injections of 2.25 mg/kg HSYA for 12 weeks. Human Umbilical Vein Endothelial cells (HUVEC) induced by 33.3 mM d-glucose +100 μg/mL ox-LDL were used to construct a high lipid and high glucose cell model treated with 25 μM HSYA. The changes in oxidative stress- and ferroptosis-related markers were detected, and the regulatory effect of HSYA on the miR-429/SLC7A11 was also verified. Normal ApoE-/- mice or HUVEC cells were used as the control group.Results HSYA effectively reduced atherosclerotic plaque formation in the T2DM/AS mouse model and inhibited HUVEC ferroptosis, such as upregulating GSH-Px, SLC7A11 and GPX4, but inhibited ACSL4. Furthermore, HSYA also downregulated the expression of miR-429, which further regulated SLC7A11 expression. After miR-429 mimic or SLC7A11 siRNA transfection in the HUVEC, the antioxidative stress and anti-ferroptosis effects of HSYA were significantly abolished.Conclusions HSYA is expected to become an important health drug to prevent the occurrence and development of T2DM/AS.