Dimethylarginine dimethylaminohydrolase overexpression suppresses graft coronary artery disease

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. Methods and Results - In one series, donor hearts of C-H-2(bm12)KhEg (H-2(bml2)) 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 mu mol . 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.