Critical Role of LOX-1-PCSK9 Axis in the Pathogenesis of Atheroma Formation and Its Instability

Cardiovascular disease (CVD) is a major contributor to annual deaths globally. Atherosclerosis is a prominent risk factor for CVD. Although significant developments have been recently made in the prevention and treatment, the molecular pathology of atherosclerosis remains unknown. Interestingly, the recent discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) introduced a new avenue to explore the molecular pathogenesis and novel management strategies for atherosclerosis. Initial research focussed on the PCSK9-mediated degradation of low density lipoprotein receptor (LDLR) and subsequent activation of pro-inflammatory pathways by oxidised low density lipoprotein (ox-LDL). Recently, PCSK9 and lectin-like oxidised low-density lipoprotein receptor-1 (LOX-1) were shown to positively amplify each other pro-inflammatory activity and gene expression in endothelial cells, macrophages and vascular smooth muscle cells. In this literature review, we provide insight into the reciprocal relationship between PCSK9 and LOX-1 in the pathogenesis of atheroma formation and plaque instability in atherosclerosis. Further understanding of the LOX-1-PCSK9 axis possesses tremendous translational potential to design novel management approaches for atherosclerosis. Cardiovascular disease (CVD) is a major contributor to annual deaths globally. Atherosclerosis is a prominent risk factor for CVD. Although significant developments have been recently made in the prevention and treatment, the molecular pathology of atherosclerosis remains unknown. Interestingly, the recent discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) introduced a new avenue to explore the molecular pathogenesis and novel management strategies for atherosclerosis. Initial research focussed on the PCSK9-mediated degradation of low density lipoprotein receptor (LDLR) and subsequent activation of pro-inflammatory pathways by oxidised low density lipoprotein (ox-LDL). Recently, PCSK9 and lectin-like oxidised low-density lipoprotein receptor-1 (LOX-1) were shown to positively amplify each other pro-inflammatory activity and gene expression in endothelial cells, macrophages and vascular smooth muscle cells. In this literature review, we provide insight into the reciprocal relationship between PCSK9 and LOX-1 in the pathogenesis of atheroma formation and plaque instability in atherosclerosis. Further understanding of the LOX-1-PCSK9 axis possesses tremendous translational potential to design novel management approaches for atherosclerosis.