title: PCSK9 regulates the chemokine receptor CCR2 on monocytes.
abstract: Monocyte migration is a key element in atherosclerosis. LDL-C facilitates monocyte migration via induction of CCR2. PCSK9 regulates cell surface expression of the LDL-R and is expressed in vascular smooth muscle cells (VSMCs). The present study was done to investigate the regulation of PCSK9 in VSMCs and its impact on monocyte function.
  
  
  
  PCSK9 mRNA and protein levels were upregulated in VSMCs by the TLR-4 ligand LPS, whereas TGF-β or angiotensin II had no effect. Induction of PCSK9 was selectively inhibited by TLR-4 blockade and further downstream by the SAPK/JNK-inhibitor SP600125, whereas inhibitors of ERK1/2, p38 or PI3-kinase pathways had no effect. Incubation of monocytes in conditioned media from LPS-stimulated VSMCs resulted in a significant reduction of LDL-R levels on monocytes, comparable to the effects of recombinant PCSK9. LDL-C increased monocyte CCR2 expression, which augmented monocyte migration towards MCP-1. This LDL-C dependent monocyte chemotaxis was inhibited by supernatants from LPS-stimulated VSMCs, similar to recombinant PCSK9 and a specific LDL-R blocking antibody.
  
  
  
  PCSK9 is regulated in VSMCs by TLR-4 - SAPK/JNK signaling, a pathway important in inflammation and metabolism. VSMC-derived PCSK9 reduces monocyte LDL-R expression, affecting LDL-C/LDL-R-mediated CCR2-expression on monocytes, which is crucial to cell motility and atherogenesis.
authors.affiliation: Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Germany; Institute of Pharmacology and Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Germany; DHZK (German Center for Cardiovascular Research) Partner Site Berlin, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Grune
authors.affiliation: Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Meyborg
authors.affiliation: Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Germany; Master's Program Molecular Medicine, Charité-UniversitätsmedizinBerlin, Germany.
authors.forename: Taisiya
authors.initials: T
authors.lastname: Bezhaeva
authors.affiliation: DHZK (German Center for Cardiovascular Research) Partner Site Berlin, Germany; Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Kappert
authors.affiliation: Department for Internal Medicine I, Brandenburg Clinic, Brandenburg Medical School, Germany; Center for Cardiovascular Research, Richard-Thoma-Laboratories, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Hillmeister
authors.affiliation: Institute of Pharmacology and Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Germany; DHZK (German Center for Cardiovascular Research) Partner Site Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
authors.affiliation: Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Germany; DHZK (German Center for Cardiovascular Research) Partner Site Berlin, Germany; Department of Cardiology / Virchow-Campus, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
authors.affiliation: Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Germany. Electronic address: stawowy@dhzb.de.
authors.forename: Philipp
authors.initials: P
authors.lastname: Stawowy
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000276:immunology; D000071449:Proprotein Convertase 9 / Q000276:immunology*; D017207:Rats, Sprague-Dawley; D054390:Receptors, CCR2 / Q000032:analysis / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: D008070:Lipopolysaccharides; D054390:Receptors, CCR2; D051197:Toll-Like Receptor 4; C472125:PCSK9 protein, human; C510804:PCSK9 protein, rat; D000071449:Proprotein Convertase 9
keywords: Atherosclerosis; Inflammation; Monocytes; PCSK9; TLR-4; Vascular smooth muscle cells