PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9 SECRETED BY CULTURED SMOOTH MUSCLE CELLS REDUCES MACROPHAGES LOW DENSITY LIPOPROTEIN RECEPTOR LEVELS AND FACILITATES SMOOTH MUSCLE CELL MIGRATION

Introduction. Proprotein convertase subtilisin kexin type 9 (PCSK9) is an important regulator of hepatic low-density lipoprotein (LDL)-cholesterol levels. Although PCSK9 is mainly of hepatic origin, extra-hepatic tissues significantly contribute to PCSK9 production and, potentially, local regulation of LDL receptor expression. Methods and results. In the present study we show that PCSK9 is expressed in smooth muscle cells (SMCs) and fibroblasts, but not in endothelial cells, macrophages and monocytes. PCSK9 was also detectable in human atherosclerotic plaques. Conditioned media from SMC affected LDLR expression and cholesterol uptake from \uf062-VLDL in the macrophage cell line J774. Co-cultured experiments also demonstrated the influence of SMCs on LDLR expression in J774. By retroviral overexpression or knockdown with small interfering RNA, we demonstrated that PCSK9 released from SMCs directly regulated LDLR expression in J774. Stimulation of SMCs with PDGF-BB induces both PCSK9 expression and SMC migration. PCSK9 overexpression significantly increased SMC migration in response to PDGF-BB, while PCSK9 knock down led to a significant reduction of cell migration, suggesting a possible effect of PCSK9 on SMC motility. Conclusions. Taken together our data indicate that PCSK9 secreted by human aortic SMCs is functionally active and capable to reduce LDLR expression in macrophages and to influence SMC migration, suggesting a possible role for this protein in atherogenesis