Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, PR China.
Biochem Pharmacol. 2024 Jul;225:116314. doi: 10.1016/j.bcp.2024.116314. Epub 2024 May 24.
Atherosclerosis, a chronic inflammatory disease, is the most relevant cause of carotid artery stenosis. Vascular endothelial cells (ECs) play a significant role in the development of atherosclerosis. In this chronic inflammatory environment, we aimed to investigate whether PCSK9 could mitigate atherosclerosis progression by reducing tissue factor expression in ECs via in vivo and in vitro assays. In vivo, we investigated the effect of PCSK9 inhibition on preventing atherosclerotic lesion formation in ApoE mice fed a western diet. The results showed that inhibiting PCSK9 could significantly downregulate the protein expression of tissue factor (TF) in ECs to reduce the area of atherosclerotic plaques. In vitro, we incubated human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS). We found that LPS-induced TF elevation was suppressed by a PCSK9 inhibitor at both the mRNA and protein levels and that the TLR4/NF-κB pathway was also suppressed by a PCSK9 inhibitor. With respect to plasma samples from patients with carotid artery stenosis, we also demonstrated that the expression of TF was positively correlated with that of PCSK9. Thus, in addition to regulating lipid metabolism, the regulation of endothelial cell TF expression through the TLR4/NF-κB pathway may be a potential mechanism of PCSK9 in promoting atherosclerotic carotid stenosis.
动脉粥样硬化是一种慢性炎症性疾病，是颈动脉狭窄最相关的原因。血管内皮细胞（ECs）在动脉粥样硬化的发生发展中起重要作用。在这种慢性炎症环境中，我们旨在通过体内和体外研究来探讨 PCSK9 是否可以通过降低 ECs 中的组织因子（TF）表达来减轻动脉粥样硬化的进展。在体内，我们研究了 PCSK9 抑制对喂食西方饮食的 ApoE 小鼠预防动脉粥样硬化病变形成的影响。结果表明，抑制 PCSK9 可以显著下调 ECs 中组织因子（TF）的蛋白表达，从而减少动脉粥样硬化斑块的面积。在体外，我们用脂多糖（LPS）孵育人脐静脉内皮细胞（HUVECs）。我们发现 LPS 诱导的 TF 升高可被 PCSK9 抑制剂在 mRNA 和蛋白水平上抑制，TLR4/NF-κB 途径也可被 PCSK9 抑制剂抑制。对于颈动脉狭窄患者的血浆样本，我们也证明了 TF 的表达与 PCSK9 的表达呈正相关。因此，除了调节脂质代谢外，TLR4/NF-κB 途径调节内皮细胞 TF 表达可能是 PCSK9 促进动脉粥样硬化性颈动脉狭窄的潜在机制。
