title: Cardiac signaling molecules and plasma biomarkers after cardiac transplantation: impact of tacrolimus versus cyclosporine.
abstract: BACKGROUND
  We investigated cardiac proinflammatory, mitogenic, and apoptotic signaling events, and plasma biomarkers of inflammation and oxidative stress in de novo adult cardiac transplant (CTX) patients receiving tacrolimus (TAC) or cyclosporine A (CsA).
  
  
  METHODS
  One hundred CTX recipients were randomized 1:1 to TAC/CsA in a prospective, randomized open-label multicenter study. Biomarkers of inflammation, immunity, oxidative stress, and cardiac signaling underlying growth and inflammation (extracellular signal-related kinase 1/2, p38 mitogen-activated protein kinase, mitogen-activated protein kinase kinases [MEK] 1/2 and 3/6, c-Src), and apoptosis and survival (c-Jun NH2-terminal kinases [JNK], Bax/Bcl2, Akt) were assessed at 2, 4, 12, 26, and 52 weeks post-CTX. Plasma from healthy controls (n = 30) and tissue from explanted non-failing hearts (n = 6) were used as controls.
  
  
  RESULTS
  Biomarkers of inflammation/immunity (interleukin -6 and -18, soluble intercellular adhesion molecule, E-selectin, monocyte chemoattractant protein-1, osteopontin, fibrinogen, N-terminal prohormone brain natriuretic peptide, high-sensitive C-reactive protein) and oxidative stress (thiobarbituric acid reactive substances, nitrotyrosine) were increased, and antioxidant capacity was (glutathione/glutathione disulfide) decreased in patients vs healthy controls (p < 0.05). Phosphorylation of mitogen-activated protein kinases and Akt was increased, and Bax/Bcl was decreased in transplanted vs non-transplanted hearts. Except for plasma fibrinogen, which was lower in TAC vs. CsA, (p = 0.01), there were no significant differences in parameters studied between TAC vs CsA immunoprophylaxis.
  
  
  CONCLUSIONS
  De novo CTX recipients exhibit significant sub-clinical inflammation and oxidative stress that persists 12 months after transplantation. Associated with this is activation of myocardial growth and inflammatory signaling and decreased apoptosis. Our findings suggest that CTX is an inflammatory condition associated with oxidative stress and myocardial growth regardless of CsA or TAC immunoprophylaxis and independently of rejection status.
authors.affiliation: Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada. Electronic address: m_white@icm-mhi.com.
authors.forename: Michel
authors.initials: M
authors.lastname: White
authors.forename: Bernard
authors.initials: B
authors.lastname: Cantin
authors.forename: Haissam
authors.initials: H
authors.lastname: Haddad
authors.forename: Jon A
authors.initials: JA
authors.lastname: Kobashigawa
authors.forename: Heather
authors.initials: H
authors.lastname: Ross
authors.forename: Michel
authors.initials: M
authors.lastname: Carrier
authors.forename: Peter W
authors.initials: PW
authors.lastname: Pflugfelder
authors.forename: Debra
authors.initials: D
authors.lastname: Isaac
authors.forename: Renzo
authors.initials: R
authors.lastname: Cecere
authors.forename: Lucette
authors.initials: L
authors.lastname: Whittom
authors.forename: Imtiaz S
authors.initials: IS
authors.lastname: Ali
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.forename: Adrienne
authors.initials: A
authors.lastname: Groulx
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood*; D019040:E-Selectin / Q000097:blood; D005260:Female; D005978:Glutathione / Q000097:blood; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000097:blood*; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects*; D011446:Prospective Studies; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016207:Cytokines; D019040:E-Selectin; C573420:ICAM1 protein, human; D007166:Immunosuppressive Agents; D017392:Thiobarbituric Acid Reactive Substances; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine; D020929:Mitogen-Activated Protein Kinase Kinases; D005978:Glutathione; D016559:Tacrolimus
keywords: biomarkers; immunosuppression; inflammation; signal transduction; transplantation