OBJECTIVE: 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, among vascular cells, 
PCSK9 is expressed in smooth muscle cells (SMCs) but not in endothelial cells, 
macrophages and monocytes. PCSK9 was also detectable in human atherosclerotic 
plaques. Conditioned media from SMCs significantly reduced LDLR expression in 
human macrophage and in the macrophage cell line J774. Co-culture experiments 
also demonstrated the influence of SMCs on LDLR expression in J774. PCSK9 
released from SMCs directly regulated LDLR expression in macrophages as 
demonstrated by retroviral overexpression or knockdown of PCSK9 with small 
interfering RNA and by using recombinant PCSK9. Moreover, the proteolytic 
activity of PCSK9 was not required for LDLR downregulation since cultured media 
containing either the catalytic inactive PCSK9 or PCSK9 WT had a similar effect 
on LDLR in J774. Finally, conditioned media from SMCs affected β-VLDL 
cholesterol uptake and PCSK9 expression reduced both LDLR and LDL uptake in 
J774.
CONCLUSIONS: Taken together our data indicate that PCSK9 secreted by human SMCs 
is functionally active and capable of reducing LDLR expression in macrophages. A 
possible direct role for this protein in foam cell formation and atherogenesis 
is suggested.