Abstract：
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.
摘要：
动脉粥样硬化,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展中起着重要的作用。在这种慢性炎症环境中，我们的目的是通过体内和体外试验研究PCSK9是否可以通过降低ECs中组织因子的表达来缓解动脉粥样硬化的进展.在体内,我们研究了PCSK9抑制对饮食喂养的ApoE-/-小鼠动脉粥样硬化病变形成的预防作用。结果表明，抑制PCSK9可以显著下调ECs组织因子（TF）的蛋白表达，减少动脉粥样硬化斑块面积。体外，我们将人脐静脉内皮细胞（HUVECs）与脂多糖（LPS）孵育。我们发现PCSK9抑制剂在mRNA和蛋白质水平上都抑制了LPS诱导的TF升高，并且PCSK9抑制剂也抑制了TLR4/NF-κB途径。关于颈动脉狭窄患者的血浆样本，我们还证明TF的表达与PCSK9的表达呈正相关。因此，除了调节脂质代谢，通过TLR4/NF-κB通路调节内皮细胞TF的表达可能是PCSK9促进动脉粥样硬化性颈动脉狭窄的潜在机制。
