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, extrahepatic tissues significantly contribute to PCSK9 production and, potentially, local regulation of LDL receptor expression. Methods and results: In the present study w e show that, among vascular cells, PCSK9 is expressed in smooth muscle cells (SMCs) but not in endothelial cells, macrophages and monocytes. PCSK9 w as 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 knockdow n of PCSK9 w ith small interfering RNA and by using recombinant PCSK9. Moreover, the proteolytic activity of PCSK9 w as not required for LDLR dow nregulation 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 b-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.

Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels / N. Ferri, G. Tibolla, A. Pirillo, F. Cipollone, A. Mezzetti, S. Pacia, A. Corsini, A.L. Catapano. ((Intervento presentato al 80. convegno EAS Congress tenutosi a Milano nel 2012.

Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels

N. Ferri
Primo
;
G. Tibolla;A. Pirillo;A. Corsini;A.L. Catapano
Ultimo
2012

Abstract

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, extrahepatic tissues significantly contribute to PCSK9 production and, potentially, local regulation of LDL receptor expression. Methods and results: In the present study w e show that, among vascular cells, PCSK9 is expressed in smooth muscle cells (SMCs) but not in endothelial cells, macrophages and monocytes. PCSK9 w as 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 knockdow n of PCSK9 w ith small interfering RNA and by using recombinant PCSK9. Moreover, the proteolytic activity of PCSK9 w as not required for LDLR dow nregulation 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 b-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.
LDLR ; VLDL ; smooth muscle cells ; macrophages ; PCSK9
Settore BIO/14 - Farmacologia
Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels / N. Ferri, G. Tibolla, A. Pirillo, F. Cipollone, A. Mezzetti, S. Pacia, A. Corsini, A.L. Catapano. ((Intervento presentato al 80. convegno EAS Congress tenutosi a Milano nel 2012.
Conference Object
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/237210
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact