title: The role of the FPR2/ALX receptor in atherosclerosis development and plaque stability.
abstract: OBJECTIVE
  The formyl peptide receptor (FPR) subtype FPR2/ALX transduces pro-inflammatory responses and participates in the resolution of inflammation depending on activation. The aim of the present study was to unravel the role of FPR2/ALX signalling in atherosclerosis.
  
  
  RESULTS
  Expression of FPR2/ALX was analysed in 127 human carotid atherosclerotic lesions and revealed that this receptor was expressed on macrophages, smooth muscle cells (SMCs), and endothelial cells. Furthermore, FPR2/ALX mRNA levels were significantly up-regulated in atherosclerotic lesions compared with healthy vessels. In multiple regression, age, creatinine, and clinical signs of increased cerebral ischaemia were independent predictors of FPR2/ALX expression. To provide mechanistic insights into these observations, we generated Ldlr(-/-)xFpr2(-/-) mice, which exhibited delayed atherosclerosis development and less macrophage infiltration compared with Ldlr(-/-)xFpr2(+/+) mice. These findings were reproduced by transplantation of Fpr2(-/-) bone marrow into Ldlr(-/-) mice and further extended by in vitro experiments, demonstrating a lower inflammatory state in Fpr2(-/-) macrophages. FPR2/ALX expression correlated with chemo- and cytokines in human atherosclerotic lesions and leucocytes. Finally, atherosclerotic lesions in Ldlr(-/-)xFpr2(-/-) mice exhibited decreased collagen content, and Fpr2(-/-) SMCs exhibited a profile of increased collagenase and decreased collagen production pathways.
  
  
  CONCLUSIONS
  FPR2/ALX is proatherogenic due to effects on bone marrow-derived cells, but promoted a more stable plaque phenotype through effects on SMCs. Taken together, these results suggest a dual role of FPR2/ALX signalling in atherosclerosis by way of promoting disease progression and but increasing plaque stability.
authors.affiliation: Experimental Cardiovascular Research Unit, Karolinska Institutet, Center for Molecular Medicine, L8: 03, Karolinska University Hospital, Stockholm 171 76, Sweden.
authors.forename: Marcelo H
authors.initials: MH
authors.lastname: Petri
authors.affiliation: Experimental Cardiovascular Research Unit, Karolinska Institutet, Center for Molecular Medicine, L8: 03, Karolinska University Hospital, Stockholm 171 76, Sweden.
authors.forename: Andrés
authors.initials: A
authors.lastname: Laguna-Fernández
authors.affiliation: Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Gonzalez-Diez
authors.affiliation: Experimental Cardiovascular Research Unit, Karolinska Institutet, Center for Molecular Medicine, L8: 03, Karolinska University Hospital, Stockholm 171 76, Sweden.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Paulsson-Berne
authors.affiliation: Experimental Cardiovascular Research Unit, Karolinska Institutet, Center for Molecular Medicine, L8: 03, Karolinska University Hospital, Stockholm 171 76, Sweden.
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.affiliation: Experimental Cardiovascular Research Unit, Karolinska Institutet, Center for Molecular Medicine, L8: 03, Karolinska University Hospital, Stockholm 171 76, Sweden Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden magnus.back@ki.se.
authors.forename: Magnus
authors.initials: M
authors.lastname: Bäck
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002340:Carotid Artery Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D016893:Carotid Stenosis / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C105101:FPR2 protein, human; D012333:RNA, Messenger; D044042:Receptors, Formyl Peptide; D011973:Receptors, LDL; D044067:Receptors, Lipoxin; C481578:formyl peptide receptor 2, mouse; D003094:Collagen
keywords: Formyl peptide receptors; Inflammation; Lipid mediators; Smooth muscle cells