title: Long term stabilization of expanding aortic aneurysms by a short course of cyclosporine A through transforming growth factor-beta induction.
abstract: Abdominal aortic aneurysms (AAAs) expand as a consequence of extracellular matrix destruction, and vascular smooth muscle cell (VSMC) depletion. Transforming growth factor (TGF)-beta 1 overexpression stabilizes expanding AAAs in rat. Cyclosporine A (CsA) promotes tissue accumulation and induces TGF -beta1 and, could thereby exert beneficial effects on AAA remodelling and expansion. In this study, we assessed whether a short administration of CsA could durably stabilize AAAs through TGF-beta induction. We showed that CsA induced TGF-beta1 and decreased MMP-9 expression dose-dependently in fragments of human AAAs in vitro, and in animal models of AAA in vivo. CsA prevented AAA formation at 14 days in the rat elastase (diameter increase: CsA: 131.9±44.2%; vehicle: 225.9±57.0%, P = 0.003) and calcium chloride mouse models (diameters: CsA: 0.72±0.14 mm; vehicle: 1.10±0.11 mm, P = .008), preserved elastic fiber network and VSMC content, and decreased inflammation. A seven day administration of CsA stabilized formed AAAs in rats seven weeks after drug withdrawal (diameter increase: CsA: 14.2±15.1%; vehicle: 45.2±13.7%, P = .017), down-regulated wall inflammation, and increased αSMA-positive cell content. Co-administration of a blocking anti-TGF-beta antibody abrogated CsA impact on inflammation, αSMA-positive cell accumulation and diameter control in expanding AAAs. Our study demonstrates that pharmacological induction of TGF-beta1 by a short course of CsA administration represents a new approach to induce aneurysm stabilization by shifting the degradation/repair balance towards healing.
authors.affiliation: CNRS EAC7054, Centre de Recherches Chirurgicales Dominique Chopin, Faculty of Medicine, Paris-Est University, Créteil, France.
authors.forename: Jianping
authors.initials: J
authors.lastname: Dai
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Michineau
authors.forename: Grégory
authors.initials: G
authors.lastname: Franck
authors.forename: Pascal
authors.initials: P
authors.lastname: Desgranges
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Becquemin
authors.forename: Marianne
authors.initials: M
authors.lastname: Gervais
authors.forename: Eric
authors.initials: E
authors.lastname: Allaire
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002122:Calcium Chloride; D016572:Cyclosporine / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D010196:Pancreatic Elastase; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; D004549:Elastin; D010196:Pancreatic Elastase; D020780:Matrix Metalloproteinase 9; D002122:Calcium Chloride