title: Dimethylarginine dimethylaminohydrolase overexpression suppresses graft coronary artery disease.
abstract: BACKGROUND
  Graft coronary artery disease (GCAD) is the leading cause of death after the first year of heart transplantation. The reduced bioavailability of endothelium-derived nitric oxide (NO) may play a role in endothelial vasodilator dysfunction and the structural changes that are characteristic of GCAD. A potential contributor to endothelial pathobiology is asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor. We hypothesized that lowering ADMA concentrations by dimethylarginine dimethylaminohydrolase (DDAH) overexpression in the recipient might suppress GCAD and long-term immune responses in murine cardiac allografts.
  
  
  RESULTS
  In one series, donor hearts of C-H-2(bm12)KhEg (H-2(bm12)) wild-type (WT) mice were heterotopically transplanted into C57BL/6 (H-2b) transgenic mice overexpressing human DDAH-I or WT littermates and procured after 4 hours of reperfusion (WT and DDAH-I recipients, n=6 each). In a second series, donor hearts were transplanted into DDAH-I-transgenic or WT mice and procured 30 days after transplantation (n=7 each). In DDAH-I recipients, plasma ADMA concentrations were lower, in association with reduced myocardial generation of superoxide anion (WT versus DDAH-I, 465.7+/-79.8 versus 173.4+/-32.3 micromol.L(-1).mg(-1).h(-1); P=0.02), inflammatory cytokines, adhesion molecules, and chemokines. GCAD was markedly reduced in cardiac allografts of DDAH-I-transgenic recipients as assessed by luminal narrowing (WT versus DDAH, 79+/-2% versus 33+/-7%; P<0.01), intima-media ratio (WT versus DDAH, 1.1+/-0.1 versus 0.5+/-0.1; P<0.01), and the percentage of diseased vessels (WT versus DDAH, 100+/-0% versus 62+/-10%; P<0.01).
  
  
  CONCLUSIONS
  Overexpression of DDAH-I attenuated oxidative stress, inflammatory cytokines, and GCAD in murine cardiac allografts. The effect of DDAH overexpression may be mediated by its reduction of plasma and tissue ADMA concentrations.
authors.affiliation: Department of Cardiothoracic Surgery, Stanford University Medical Center, Stanford, CA, USA.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tanaka
authors.forename: Karsten
authors.initials: K
authors.lastname: Sydow
authors.forename: Feny
authors.initials: F
authors.lastname: Gunawan
authors.forename: Johannes
authors.initials: J
authors.lastname: Jacobi
authors.forename: Phil S
authors.initials: PS
authors.lastname: Tsao
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
authors.forename: John P
authors.initials: JP
authors.lastname: Cooke
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D003324:Coronary Artery Disease / Q000209:etiology* / Q000517:prevention & control*; D016207:Cytokines / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D016027:Heart Transplantation / Q000009:adverse effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009205:Myocarditis / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000378:metabolism; D009994:Osmolar Concentration; D011184:Postoperative Period; D011247:Pregnancy; D013481:Superoxides / Q000037:antagonists & inhibitors; D013997:Time Factors; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000581:Amidohydrolases; C059999:dimethylargininase