Expression and secretion of PCSK9 from cultured smooth muscle cells: evidence for a direct role in atherogenesis

Proprotein convertase subtilisin kexin type 9 (PCSK9) is an important regulator of hepatic 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. In the present study we show, by RT-PCR analysis of RNA isolated from cultured vascular cells, that PCSK9 is expressed in smooth muscle cells (SMCs) and fibroblasts, but not in endothelial cells, macrophages and monocytes. By Western blot and immunohistochemical analysis PCSK9 was also detectable in human atherosclerotic plaques. Interestingly, PCSK9 was induced by PDGF-BB in cultured SMCs. Retroviral overexpression of PCSK9 in SMCs and knockdown of PCSK9 by small interfering RNA demonstrated that PCSK9 released from SMCs reduced LDLR expression in the macrophage cell line J774, leading to a significant reduction of cholesterol uptake from \uf062-VLDL. Moreover, SMCs overexpressing PCSK9 significantly increased their migratory potential 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 accumulation in atherosclerotic plaques. Finally, SMCs overexpressing PCSK9 show a faster proliferative rate in response to PDGF-BB. Taken together, PCSK9 secreted by human aortic SMCs is functionally active and capable to reduce LDLR expression in macrophages and to influence SMC proliferation and migration, suggesting a possible role in atherogenesis