title: Activation of the vitamin D receptor selectively interferes with calcineurin-mediated inflammation: a clinical evaluation in the abdominal aortic aneurysm.
abstract: In vitro and in vivo studies attribute potent immune regulatory properties to the vitamin D receptor (VDR). Yet, it is unclear to what extend these observations translate to the clinical context of (vascular) inflammation. This clinical study evaluates the potential of a VDR agonist to quench vascular inflammation. Patients scheduled for open abdominal aneurysm repair received paricalcitol 1 μg daily during 2-4 weeks before repair. Results were compared with matched controls. Evaluation in a parallel group showed that AAA patients are vitamin D insufficient (median plasma vitamin D: 43 (30-62 (IQR)) nmol/l). Aneurysm wall samples were collected during surgery, and the inflammatory footprint was studied. The brief paricalcitol intervention resulted in a selective 73% reduction in CD4+ T-helper cell content (P<0.024) and a parallel 35% reduction in T-cell (CD3+) content (P<0.032). On the mRNA level, paricalcitol reduced expression of T-cell-associated cytokines IL-2, 4, and 10 (P<0.019). No effect was found on other inflammatory mediators. On the protease level, selective effects were found for cathepsin K (P<0.036) and L (P<0.005). Collectively, these effects converge at the level of calcineurin activity. An effect of the VDR agonist on calcineurin activity was confirmed in a mixed lymphocyte reaction. In conclusion, brief course of the VDR agonist paricalcitol has profound effects on local inflammation via reduced T-cell activation. The anti-inflammatory potential of VDR activation in vitamin D insufficient patients is highly selective and appears to be mediated by an effect on calcineurin-mediated responses.
authors.affiliation: Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Arend Jan
authors.initials: AJ
authors.lastname: Nieuwland
authors.affiliation: Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Vivianne Bc
authors.initials: VB
authors.lastname: Kokje
authors.affiliation: Department Surgery, Jeroen Bosch Ziekenhuis, Den Bosch, The Netherlands.
authors.forename: Olivier H
authors.initials: OH
authors.lastname: Koning
authors.affiliation: Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jaap F
authors.initials: JF
authors.lastname: Hamming
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Karoly
authors.identifier: 0000-0002-1228-4245
authors.initials: K
authors.lastname: Szuhai
authors.affiliation: Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frans H J
authors.initials: FH
authors.lastname: Claas
authors.affiliation: Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jan H N
authors.initials: JH
authors.lastname: Lindeman
mesh_terms: D000368:Aged; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004872:Ergocalciferols / Q000494:pharmacology*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000819:agonists*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004872:Ergocalciferols; D018836:Inflammation Mediators; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C579457:VDR protein, human; C084656:paricalcitol; D019703:Calcineurin