px-478 and Atherosclerosis

To elucidate the key regulator responsible for autophagy and ferroptosis, and if specific pharmacological inhibitor of upregulated gene exerted the pro-autophagic and anti-ferroptotic effect on macrophage to alleviate the atherosclerosis.. Autophagy and ferroptosis were evaluated in atherosclerotic lesions and THP-1 macrophages exposed to ox-LDL. Autophagy/ferroptosis-related differentially expressed genes (DEGs) in atherosclerosis were identified by bioinformatic analysis of GSE97210 dataset, and were validated in atherosclerotic cells and tissues. The efficacy and mechanism of pharmacological inhibition of the validated DEGs on alleviating atherosclerosis were explored in vivo and in vitro.. Atherosclerotic lesions were characterized by autophagy inhibition and ferroptosis activation in macrophages. The crosslink between autophagy and ferroptosis were demonstrated. Ox-LDL induced THP-1 macrophage foam cell formation, autophagy dysfunction, and ferroptosis occurrence. Rapamycin ameliorated and, conversely, erastin deteriorated the effect of ox-LDL on THP-1 macrophages. Eleven autophagy/ferroptosis-related DEGs were identified in atherosclerosis vs. normal. The up-regulated expression of HIF-1α was verified in atherosclerotic lesions and THP-1 macrophages induced by ox-LDL. HIF-1α inhibitor PX-478 restored autophagy function, depressed ferroptosis, and reduced lipid accumulation in ox-LDL induced THP-1 macrophage. Autophagy inhibitor 3-MA obviously abrogated the pro-autophagic, anti-ferroptotic, and anti-atherosclerotic effects of PX-478. PX-478 treatment down-regulated HIF-1α expression and reduced atherosclerotic plaques in the mice model.. Autophagy is inhibited, ferroptosis is activated, and crosslink occurs between autophagy and ferroptosis during atherosclerosis. HIF-1α, an upregulated DEG between atherosclerosis and normal, co-regulates autophagy and ferroptosis. HIF-1α inhibitor PX-478 attenuates foam cell formation and lessens atherosclerosis by enhancing autophagy and depressing ferroptosis in macrophages.

Topics: Animals; Atherosclerosis; Autophagy; Ferroptosis; Hypoxia; Lipoproteins, LDL; Macrophages; Mice; Signal Transduction

Hypoxia inducible factor 1α (HIF1α) plays a critical role in atherosclerosis as demonstrated in endothelial-targeted HIF1α -deficient mice. However, it has not been shown if specific pharmacological inhibitors of HIF1α can be used as potential drugs for atherosclerosis. PX-478 is a selective inhibitor of HIF1α, which was used to reduce cancer and obesity in animal models. Here, we tested whether PX-478 can be used to inhibit atherosclerosis.. PX-478 treatment reduced atherosclerotic plaque burden in the aortic trees in both mouse models, while plaque burden in the aortic sinus was reduced in the AAV-PCSK9 mouse model, but not in the ApoE. These results suggest that PX-478 is a potential anti-atherogenic drug, which targets vascular endothelium and hepatic cholesterol pathways.

Topics: Animals; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Disease Models, Animal; Endothelial Cells; Hypoxia; Mice; Mice, Inbred C57BL; Mice, Knockout; Mustard Compounds; Phenylpropionates; Plaque, Atherosclerotic; Proprotein Convertase 9