title: Synergistic therapeutic vascular cytoprotection against complement-mediated injury induced via a PKCα-, AMPK-, and CREB-dependent pathway.
abstract: Endothelial injury and dysfunction precede accelerated arterial disease in allograft vasculopathy and systemic autoimmune diseases and involve pathogenic Abs and complement. Recent reports suggest that switching to rapamycin from calcineurin antagonists reduces posttransplant vasculopathy and prolongs survival following cardiac transplantion. The majority of these patients also receive statin therapy. We examined potential mechanisms underlying this protective response in human endothelial cells and identified synergy between rapamycin and atorvastatin. Mechanistically, atorvastatin and rapamycin activated a protein kinase Cα, AMP-activated kinase, and CREB-dependent vasculoprotective pathway, which induced decay-accelerating factor (DAF) promoter activity via binding to the cAMP response element, mutation of which attenuated promoter activity. This response significantly increased endothelial cell surface DAF and enhanced protection against complement-mediated injury. Synergy with rapamycin was reproduced by simvastatin, whereas combining atorvastatin with cyclosporine or mycophenolate in place of rapamycin was ineffective. Importantly, synergy was reproduced in vivo, in which only atorvastatin and rapamycin therapy in combination was sufficient to induce DAF on murine aortic endothelium. We believe this pathway represents an important therapeutically inducible vasculoprotective mechanism for diseases mediated by pathogenic Abs and complement, including posttransplant vasculopathy and systemic lupus erythematosus. Although our study focuses on the vascular endothelium, the findings are likely to be broadly applicable, given the diverse cellular expression of DAF.
authors.affiliation: Vascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, W12 ONN, United Kingdom;
authors.forename: Shahir S
authors.initials: SS
authors.lastname: Hamdulay
authors.forename: Bufei
authors.initials: B
authors.lastname: Wang
authors.forename: Damien
authors.initials: D
authors.lastname: Calay
authors.forename: Allan P
authors.initials: AP
authors.lastname: Kiprianos
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cole
authors.forename: Odile
authors.initials: O
authors.lastname: Dumont
authors.forename: Nicola
authors.initials: N
authors.lastname: Dryden
authors.forename: Anna M
authors.initials: AM
authors.lastname: Randi
authors.forename: Clare C
authors.initials: CC
authors.lastname: Thornton
authors.forename: Fahad
authors.initials: F
authors.lastname: Al-Rashed
authors.forename: Caroline
authors.initials: C
authors.lastname: Hoong
authors.forename: Aamir
authors.initials: A
authors.lastname: Shamsi
authors.forename: Zilei
authors.initials: Z
authors.lastname: Liu
authors.forename: Vijay R
authors.initials: VR
authors.lastname: Holla
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Boyle
authors.forename: Dorian O
authors.initials: DO
authors.lastname: Haskard
authors.forename: Justin C
authors.initials: JC
authors.lastname: Mason
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000069059:Atorvastatin; D018958:CD55 Antigens / Q000378:metabolism; D003167:Complement Activation / Q000187:drug effects / Q000502:physiology; D003165:Complement System Proteins / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D020123:Sirolimus / Q000008:administration & dosage*
chemical_list: D018958:CD55 Antigens; D017362:Cyclic AMP Response Element-Binding Protein; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D011758:Pyrroles; D003165:Complement System Proteins; D000069059:Atorvastatin; D011493:Protein Kinase C; D055372:AMP-Activated Protein Kinases; D020123:Sirolimus