Jin Ping, Ma Juan, Wu Peng, Yan Ru, Bian Yitong, Jia Shaobin, Zheng Qiangsun, Ma Xueping
Department of Cardiology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi, China.
Heart Centre & Department of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan Ningxia, China.
Biochem Pharmacol. 2025 Sep;239:117031. doi: 10.1016/j.bcp.2025.117031. Epub 2025 Jun 4.
Atherosclerosis (AS) is a persistent inflammatory disorder marked by vulnerable plaques, which increase the likelihood of cardiovascular incidents. This study explored the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the development of vulnerable plaques triggered by hyperhomocysteinemia (HHcy), with a focus on lipid metabolism, and inflammation. Apolipoprotein E knockout (ApoE) mice were fed a methionine-rich diet to induce HHcy. PCSK9 inhibition via SBC-115076 significantly improved plaque stability. HHcy upregulated PCSK9 levels, and hinder cholesterol efflux by downregulating the ATP-binding cassette transporters ABCA1 and ABCG1. In contrast, no significant effects were noted on low-density lipoprotein receptor (LDLR), cluster of differentiation 36 (CD36), or scavenger receptor class B type I (SR-BI). Inhibition of PCSK9 led to the restoration of ABCA1 and ABCG1, thereby facilitating an increase in cholesterol efflux. Furthermore, PCSK9 inhibition reduced HHcy-induced increase of proinflammatory cytokines, including interleukin-1beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). In vitro, mouse peritoneal macrophages (MPMs) exposed to HHcy presented reduced ABCA1 and ABCG1, whereas LDLR, CD36, and SR-BI remained unaffected. PCSK9 knockout reversed these changes. Additionally, HHcy upregulated expression of proinflammatory cytokines, along with the activation of Toll-like receptor 4 (TLR4) /nuclear factor kappa B (NF-κB) pathway. PCSK9 inhibition reduced the production of these cytokines and mitigated the activation of the TLR4/NF-κB pathway, confirming its role in macrophage inflammation. These findings reveal that PCSK9 exacerbates HHcy-related AS by impairing cholesterol efflux and promoting inflammation. PCSK9 inhibitors may offer a dual therapeutic approach for stabilizing plaques and reducing cardiovascular risk in patients with HHcy.
动脉粥样硬化（AS）是一种以易损斑块为特征的持续性炎症性疾病，易损斑块会增加心血管事件的发生可能性。本研究探讨了前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）在高同型半胱氨酸血症（HHcy）引发的易损斑块形成过程中的作用，重点关注脂质代谢和炎症。给载脂蛋白E基因敲除（ApoE）小鼠喂食富含蛋氨酸的饮食以诱导HHcy。通过SBC - 115076抑制PCSK9可显著改善斑块稳定性。HHcy上调PCSK9水平，并通过下调ATP结合盒转运蛋白ABCA1和ABCG1来阻碍胆固醇外流。相比之下，对低密度脂蛋白受体（LDLR）、分化簇36（CD36）或I型清道夫受体B类（SR - BI）未观察到显著影响。抑制PCSK9导致ABCA1和ABCG1恢复，从而促进胆固醇外流增加。此外，抑制PCSK9可降低HHcy诱导的促炎细胞因子增加，包括白细胞介素 - 1β（IL - 1β）、白细胞介素 - 6（IL - 6）、肿瘤坏死因子 - α（TNF - α）和单核细胞趋化蛋白 - 1（MCP - 1）。在体外，暴露于HHcy的小鼠腹腔巨噬细胞（MPM）中ABCA1和ABCG1减少，而LDLR、CD36和SR - BI未受影响。敲除PCSK9可逆转这些变化。此外，HHcy上调促炎细胞因子的表达，并激活Toll样受体4（TLR4）/核因子κB（NF - κB）通路。抑制PCSK9可减少这些细胞因子的产生，并减轻TLR4/NF - κB通路的激活，证实了其在巨噬细胞炎症中的作用。这些发现表明，PCSK9通过损害胆固醇外流和促进炎症来加重HHcy相关的AS。PCSK9抑制剂可能为稳定斑块和降低HHcy患者的心血管风险提供一种双重治疗方法。
