Diosgenin suppresses ALOX5 expression through Histone acetyltransferase KAT2A-mediated H3K27ac modification to attenuate macrophage ferroptosis and foam cell formation in atherosclerosis.
TL;DR
Diosgenin attenuated macrophage ferroptosis and foam cell formation in AS at least in part by suppressing ALOX5 expression through KAT2A-mediated H3K27ac modification, which provides new therapeutic targets for AS treatment.
Abstract
Background
Diosgenin is a steroidal saponin derived from plants, and it exhibits anti-atherogenic properties. Our research objective is to explore the link between macrophage ferroptosis and foam cell formation, and explore the effect and mechanism of Diosgenin on inhibiting Atherosclerosis (AS) by regulating ferroptosis.
Methods
ApoE-/- mouse models of AS were constructed. Histological analysis of atherosclerotic lesions in aortic root was performed. Plasma levels of TC, TG, HDL-C, and LDL-C were assessed. ELISA detected IL-1β, IL-6, and TNF-α levels in serum. Expressions of ALOX5 and KAT2A were detected by RT-qPCR, Western blot and Immunofluorescence staining. CCK-8 was used to detect cell viability. Levels of MDA, GSH, SOD, 4-HNE, LDH and iron content were measured in macrophages by commercial kits. Chromatin immunoprecipitation (ChIP) and luciferase reporter assay were used to assess the binding of KAT2A and H3K27ac enrichment at the ALOX5 promoter.
Results
Diosgenin reduced AS lesions and inhibited macrophage ferroptosis in ApoE- /- mice. The inhibitory effects of Diosgenin on foam cell formation were reversed by Erastin treatment. ALOX5 was discovered as a downstream mediator influenced by Diosgenin. Knocking down ALOX5 reversed ox-LDL-induced foam cell formation. The upregulation of ALOX5 negated Diosgenin's inhibitory impact on ox-LDL-induced macrophage ferroptosis. There was a positive correlation and interaction between KAT2A and ALOX5, a relationship also attenuated by Diosgenin. KAT2A promoted ALOX5 expression, and this effect was accompanied by increased H3K27ac enrichment and KAT2A binding at the ALOX5 promoter, suggesting that KAT2A may enhance ALOX5 expression through H3K27ac modification.
Conclusion
Diosgenin attenuated macrophage ferroptosis and foam cell formation in AS at least in part by suppressing ALOX5 expression through KAT2A-mediated H3K27ac modification, which provides new therapeutic targets for AS treatment.