Jin Ping, Gao Dengfeng, Cong Guangzhi, Yan Ru, Jia Shaobin
Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Heart Center and Cardiovascular Institute, General Hospital of Ningxia Medical University, Yinchuan, China.
Front Cardiovasc Med. 2021 Oct 1;8:746989. doi: 10.3389/fcvm.2021.746989. eCollection 2021.
Homocysteine (Hcy) has been established as an independent risk factor for atherosclerosis, and the involvement of hyperhomocysteinemia (HHcy) in atherosclerotic lesions is complex. Proprotein convertase subtilisin kexin 9 (PCSK9) has vital importance in lipid metabolism, and its inhibitors have intense lipid-lowering and anti-atherosclerotic effects. However, the underlying effect of PCSK9 on HHcy-accelerated dyslipidemia of macrophages is still uncertain. The purpose of this study was to investigate the potential role of PCSK9 in Hcy-induced lipid accumulation and atherosclerotic lesions. , gene and protein expressions were assessed by real-time quantitative PCR and western blot in THP-1 macrophages with Hcy incubation. Lipid accumulation and cholesterol efflux were evaluated with Hcy treatment. SBC-115076 was used to examine the role of PCSK9 in ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1)-dependent cholesterol efflux. , lesion area, lipid deposition and collagen contents were determined in aortas of ApoE mice under a methionine diet. SBC-115076 was subcutaneously injected to explore the potential effects of PCSK9 inhibition on alleviating the severity of HHcy-related atherosclerotic lesions. In THP-1 macrophages, Hcy dose- and time-dependently promoted PCSK9 gene and protein levels without regulating the translation of Low-density lipoprotein receptor (LDLR). SBC-115076 used to inhibit PCSK9 largely alleviated lipid accumulation and reversed the cholesterol efflux to apolipoprotein-I(apoA-I) and high-density lipoprotein (HDL) mediated by ABCA1 and ABCG1. In ApoE mice, methionine diet induced HHcy caused larger lesion area and more lipid accumulation in aortic roots. SBC-115076 reduced atherosclerotic severity by reducing the lesion area and lipid accumulation and increasing expressions of ABCA1 and ABCG1 in macrophages from atherosclerotic plaque. In addition, SBC-115076 decreased plasma Hcy level and lipid profiles significantly. PCSK9 promoted lipid accumulation via inhibiting cholesterol efflux mediated by ABCA1 and ABCG1 from macrophages and accelerated atherosclerotic lesions under HHcy treatment. Inhibiting PCSK9 may have anti-atherogenic properties in HHcy-accelerated atherosclerosis.
同型半胱氨酸（Hcy）已被确认为动脉粥样硬化的独立危险因素，高同型半胱氨酸血症（HHcy）参与动脉粥样硬化病变的过程较为复杂。前蛋白转化酶枯草溶菌素9（PCSK9）在脂质代谢中至关重要，其抑制剂具有强效的降脂和抗动脉粥样硬化作用。然而，PCSK9对HHcy加速巨噬细胞脂质代谢异常的潜在影响仍不明确。本研究旨在探讨PCSK9在Hcy诱导的脂质蓄积和动脉粥样硬化病变中的潜在作用。通过实时定量PCR和蛋白质印迹法评估经Hcy孵育的THP-1巨噬细胞中的基因和蛋白表达。用Hcy处理评估脂质蓄积和胆固醇流出情况。使用SBC-115076研究PCSK9在ATP结合盒转运体A1和G1（ABCA1和ABCG1）依赖性胆固醇流出中的作用。测定蛋氨酸饮食下ApoE小鼠主动脉的病变面积、脂质沉积和胶原含量。皮下注射SBC-115076以探究抑制PCSK9对减轻HHcy相关动脉粥样硬化病变严重程度的潜在作用。在THP-1巨噬细胞中，Hcy剂量和时间依赖性地促进PCSK9基因和蛋白水平，而不调节低密度脂蛋白受体（LDLR）的翻译。用于抑制PCSK9的SBC-115076在很大程度上减轻了脂质蓄积，并逆转了由ABCA1和ABCG1介导的向载脂蛋白-I（apoA-I）和高密度脂蛋白（HDL）的胆固醇流出。在ApoE小鼠中，蛋氨酸饮食诱导的HHcy导致主动脉根部病变面积更大、脂质蓄积更多。SBC-115076通过减小病变面积和脂质蓄积以及增加动脉粥样硬化斑块中巨噬细胞ABCA1和ABCG1的表达来降低动脉粥样硬化严重程度。此外，SBC-115076显著降低血浆Hcy水平和血脂谱。PCSK9通过抑制巨噬细胞中ABCA1和ABCG1介导的胆固醇流出促进脂质蓄积，并在HHcy处理下加速动脉粥样硬化病变。抑制PCSK9在HHcy加速的动脉粥样硬化中可能具有抗动脉粥样硬化特性。
