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Background: Homocysteine is an independent risk factor of atheroslceorsis, characterized by the formation of macrophage-derived foam cells. Liver X receptor alpha (LXRα) can keep cholesterol homeostasis, while proprotein convertase subtilisin/kexin 9(PCSK9), a lipid metabolism regulatory protein whose inhibitor can markedly attenuate LDL-C. Therefore, this study aims to discuss the potential mechanism that involving LXRα and PCSK9 in the homocysteine-induced dyslipidemia in macrophages.
Methods: Six weeks old ApoE-/- mice were randomly received a control or methionine (2%) diet. The levels of plasma homocysteine and lipids and HE, Oil red O and Masson staining of aortic valve sections were performed after 16 weeks. Meanwhile, THP-1 macrophages challenged by homocysteine at 0, 50, 100, 200 μmol/L with ox-LDL. Foam cells were observed by Oil Red O staining and intracellular lipid profiles were quantified. RT-qPCR and Western blot were performed to analyze the expressions of LXRα, ABCA1, ABCG1 and PCSK9. LXRα agonist (T0901317) was used to verify the above again. Furthermore, expressions of SIRT1 and SIRT6 were analyzed to discuss the underlying epigenetics mechanisms.
Results: In vivo study, hyperhomocysteine and increased atherosclerotic lesions area were observed in methionine group. In vitro study, increased homocysteine promoted the cholesterol accumulation in foam cells. Besides, the mRNA and protein of LXRα, ABCA1 and ABCG1 were lower than the control group (P<0.01), while the PCSK9 expression was higher than the control group (P<0.01) in a dose-dependent manner. However, T0901317 reversed the effects of homocysteine on cholesterol accumulation and the increased expression of PCSK9(P<0.05). The expressions of SIRT1 and SIRT6 also decreased in a dose-dependent manner (P<0.01).
Conclusions: Homocysteine promotes the formation of atherosclerotic plaque and foam cells through inhibiting LXRα-ABCA1/ABCG1 pathway and activating PCSK9. Histone deacetylation might be the potential epigenetics mechanism regulating LXRα and PCSK9, which may provide a new insight to the scientific research and clinical intervention of atheroslcerosis.
Poster Hall, Hall C
Saturday, March 18, 2017, 9:45 a.m.-10:30 a.m.
Session Title: From Diet to Drugs: Mechanistic Insight Into Ischemic Heart Disease
Abstract Category: 1. Acute and Stable Ischemic Heart Disease: Basic
Presentation Number: 1202-299
- 2017 American College of Cardiology Foundation