P3773
Homocysteine accelerates lipid accumulation in macrophages and atherosclerotic lesions via PCSK9-mediated ABCA1/ABCG1-dependent cholesterol efflux

Extract

Background: Atherosclerosis is characterized by excessive lipid accumulation and chronic inflammation in the arterial wall, and is a major cause and pathological basis of arteriosclerotic cardiovascular diseases (ASCVD). Homocysteine (Hcy) is an independent risk factor of atherosclerosis, and the pro-atherogenic mechanism is multiple and complicated, such as macrophage apoptosis, inflammation, endoplasmic reticulum stress and dslipidemia in macrophages, etc. Our previous study showed that Hcy promoted lipid accumulation by inhibiting ABCA1/ABCG1-dependent cholesterol efflux in macrophages. Proprotein convertase subtilisin/kexin 9 (PCSK9) is a new target for the prophylaxis and treatment of ASCVD, and its inhibitor can largely decrease LDL and improve the prognosis of cardiovascular events. However, the effects of PCSK9 in Hcy induced atherosclerosis remains unknown.

Purpose: To investigate the potential role of PCSK9 in the Hcy accelerated lipid accumulation and atherosclerotic lesions, and to clarify the underlying mechanisms by using PCSK9 special antagonist-SBC115076.

Methods: THP-1 macrophages were incubated with different concentrations (50,100,200 μmol/L) or exposing time (6, 12, 24, 48 h) of Hcy. Oil Red O staining and NBD-labeled cholesterol were used to assess the lipid accumulation and cholesterol efflux. Meanwhile, 36 male ApoE-/- mice were divided into three groups for 20 weeks: control group (AC), methionine diet group (AHM) and treatment group (methionine diet plus SBC115076, AHS). Plasma hcy and lipid levels were detected, and atheroslcerotic lesions and lipid accumulation in plaque were analyzed by H&E and ORO staining. Real-time PCR and Western blot were performed to examine expression of mRNA and protein.