Effect of PCSK9 on Vascular Smooth Muscle Cell Functions: A New Player in Atherosclerosis

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a secretory serine protease that plays multiple biological functions in the regulation of physiological and pathological processes. PCSK9 inhibitors decrease the circulating LDL-cholesterol level with well-known preventive and therapeutic effects on atherosclerosis (AS). Still, increasing evidence shows that the direct impact of PCSK9 on the vascular wall also plays an important role in atherosclerotic progression. Compared with other vascular cells, a large proportion of PCSK9 is originated from vascular smooth muscle cells (VSMC). Therefore, defining the effect of VSMC-derived PCSK9 on response changes, such as phenotypic switch, apoptosis, autophagy, inflammation, foam cell formation, and calcification of VSMC, helps us better understand the "pleiotropic" effects of VSMC on the atherosclerotic process. In addition, our understanding of the mechanisms of PCSK9 controlling VSMC functions in vivo is far from enough. This review aims to holistically evaluate and analyze the current state of our knowledge regarding PCSK9 actions affecting VSMC functions and its mechanism in atherosclerotic lesion development. A mechanistic understanding of PCSK9 effects on VSMC will further underpin the success of a new therapeutic strategy targeting AS.