title: Vitamin D receptor is expressed within human carotid plaques and correlates with pro-inflammatory M1 macrophages.
abstract: The role of Vitamin D system in cardiovascular diseases remains controversial. Here, we investigated whether intraplaque levels of vitamin D receptor (VDR) predicted major adverse cardiovascular events (MACEs) at 18month-follow-up and correlated with macrophage subsets in 164 patients undergoing endarterectomy for carotid stenosis. In human carotid plaque portions upstream and downstream the blood flow, VDR, lipid, collagen, as well as macrophage subsets were determined. Human primary monocytes were then differentiated in vitro to M1 and M2 macrophages and treated with 1,25(OH)2D3. Intraplaque VDR positively correlated with total and M1 macrophages. According to the result of ROC curve analysis, downstream portions of plaques having high VDR expression were characterized by increased M1 macrophages. Kaplan-Meier analysis showed that the risk of MACEs was greater in patients having low downstream VDR levels (8.2% vs. 1.3%; p=0.005). Cox proportional hazard regression analyses confirmed that MACE risk decreased with increasing downstream VDR (adjusted HR 0.78 [95% CI 0.62-0.98]; p=0.032). In vitro, VDR expression was prevalent in M1, but not M2. Incubation of M1 macrophages with 1,25(OH)2D3, increased VDR expression and suppressed toll-like receptor 4 expression. These results suggest that low intraplaque VDR expression predict MACEs in patients with carotid stenosis potentially involving M1 macrophages.
authors.affiliation: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy. Electronic address: federico.carbone@edu.unige.it.
authors.forename: Federico
authors.initials: F
authors.lastname: Carbone
authors.affiliation: Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Satta
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, 64 Avenue de la Roseraie, 1211 Geneva, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burger
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, 64 Avenue de la Roseraie, 1211 Geneva, Switzerland.
authors.forename: Aline
authors.initials: A
authors.lastname: Roth
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, 64 Avenue de la Roseraie, 1211 Geneva, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lenglet
authors.affiliation: Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pagano
authors.affiliation: Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lescuyer
authors.affiliation: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Bertolotto
authors.affiliation: Vascular and Endovascular Surgery Unit, Department of Surgery, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Largo Benzi 10, 16100 Genoa, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Spinella
authors.affiliation: Vascular and Endovascular Surgery Unit, Department of Surgery, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Largo Benzi 10, 16100 Genoa, Italy.
authors.forename: Bianca
authors.initials: B
authors.lastname: Pane
authors.affiliation: Vascular and Endovascular Surgery Unit, Department of Surgery, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Largo Benzi 10, 16100 Genoa, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Palombo
authors.affiliation: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy; IRCCS AOU San Martino - IST, Largo Benzi 10, 16100 Genoa, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Pende
authors.affiliation: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy; IRCCS AOU San Martino - IST, Largo Benzi 10, 16100 Genoa, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Dallegri
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, Department of Medical Specialties, University of Geneva, 64 Avenue de la Roseraie, 1211 Geneva, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.affiliation: Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vuilleumier
authors.affiliation: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy; IRCCS AOU San Martino - IST, Largo Benzi 10, 16100 Genoa, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
mesh_terms: D000368:Aged; D002117:Calcitriol / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000209:etiology; D016893:Carotid Stenosis / Q000473:pathology*; D002454:Cell Differentiation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000378:metabolism; D010865:Pilot Projects; D016016:Proportional Hazards Models; D018167:Receptors, Calcitriol / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D018167:Receptors, Calcitriol; D051197:Toll-Like Receptor 4; D002117:Calcitriol
keywords: Atherosclerosis; Macrophage; Major adverse cardiovascular events; Vitamin D; Vitamin D receptor