PCSK9 aggravated carotid artery stenosis in ApoE-/- mice by promoting the expression of tissue factors in endothelial cells via the TLR4/NF-κB pathway

• Published in: Biochemical pharmacology Vol. 225; p. 116314
• Main Authors: Peng, Chao, Li, Jian, Chen, Yan, Zhang, Heng-rui, Li, Tian-xing, Jiang, Yu-hang, Yang, Xin-yu, Zhao, Yan
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.07.2024
• Subjects: Animals; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Atherosclerosis; Carotid artery stenosis; Carotid Stenosis - metabolism; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Female; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Knockout, ApoE; NF-kappa B - metabolism; PCSK9 Inhibitors; Proprotein Convertase 9 - genetics; Proprotein Convertase 9 - metabolism; Proprotein convertase subtilisin/kexin type 9; Signal Transduction - physiology; Thromboplastin - biosynthesis; Thromboplastin - genetics; Thromboplastin - metabolism; Tissue factor; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; LDL-C; Tissue factor; PCSK9; Proprotein convertase subtilisin/kexin type 9; LPS; Endothelial cells; TF; ECs; CAS; ND; Atherosclerosis; PL; Carotid artery stenosis; HUVECs; CID
• ISSN: 0006-2952; 1873-2968; 1873-2968
• DOI: 10.1016/j.bcp.2024.116314

[Display omitted] 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.