This Article Full Text Full Text (PDF) All Versions of this Article: 112/11/1549    most recent CIRCULATIONAHA.105.537670v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tanaka, M. Articles by Cooke, J. P. Search for Related Content PubMed PubMed Citation Articles by Tanaka, M. Articles by Cooke, J. P. Related Collections Animal models of human disease Coronary circulation Endothelium/vascular type/nitric oxide

(Circulation. 2005;112:1549-1556.)
© 2005 American Heart Association, Inc.

Coronary Heart Disease

Dimethylarginine Dimethylaminohydrolase Overexpression Suppresses Graft Coronary Artery Disease

Masashi Tanaka, MD^*; Karsten Sydow, MD^*; Feny Gunawan, BA; Johannes Jacobi, MD; Phil S. Tsao, PhD; Robert C. Robbins, MD; John P. Cooke, MD, PhD

From the Department of Cardiothoracic Surgery (M.T., F.G., R.C.R.) and the Department of Cardiovascular Medicine (K.S., J.J., P.S.T., J.P.C.), Stanford University Medical Center, Stanford, Calif.

Correspondence to John P. Cooke, MD, PhD, Division of Cardiovascular Medicine, Stanford University School of Medicine, Falk Cardiovascular Research Center, 300 Pasteur Dr, Stanford, CA 94305-5406. E-mail john.cooke{at}stanford.edu

Received September 8, 2004;de novo received February 2, 2005; revision received May 28, 2005; accepted June 6, 2005.

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^bm12KhEg (H-2^bm12) wild-type (WT) mice were heterotopically transplanted into C57BL/6 (H-2^b) 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 µmol · 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.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				Z. Wang, W. H. W. Tang, L. Cho, D. M. Brennan, and S. L. Hazen Targeted Metabolomic Evaluation of Arginine Methylation and Cardiovascular Risks: Potential Mechanisms Beyond Nitric Oxide Synthase Inhibition Arterioscler Thromb Vasc Biol, September 1, 2009; 29(9): 1383 - 1391. [Abstract] [Full Text] [PDF]

				M. Hu, D. Watson, G. Y. Zhang, N. Graf, Y. M. Wang, M. Sartor, B. Howden, J. Fletcher, and S. I. Alexander Long-Term Cardiac Allograft Survival across an MHC Mismatch after "Pruning" of Alloreactive CD4 T Cells J. Immunol., May 15, 2008; 180(10): 6593 - 6603. [Abstract] [Full Text] [PDF]

				K. Hasegawa, S. Wakino, S. Tatematsu, K. Yoshioka, K. Homma, N. Sugano, M. Kimoto, K. Hayashi, and H. Itoh Role of Asymmetric Dimethylarginine in Vascular Injury in Transgenic Mice Overexpressing Dimethylarginie Dimethylaminohydrolase 2 Circ. Res., July 20, 2007; 101(2): e2 - e10. [Abstract] [Full Text] [PDF]

				M. C. Stuhlinger, E. Conci, B. J. Haubner, E.-M. Stocker, J. Schwaighofer, J. P. Cooke, P. S. Tsao, O. Pachinger, and B. Metzler Asymmetric Dimethyl L-Arginine (ADMA) is a critical regulator of myocardial reperfusion injury Cardiovasc Res, July 15, 2007; 75(2): 417 - 425. [Abstract] [Full Text] [PDF]

				A. M. Wilson, R. Harada, N. Nair, N. Balasubramanian, and J. P. Cooke L-Arginine Supplementation in Peripheral Arterial Disease: No Benefit and Possible Harm Circulation, July 10, 2007; 116(2): 188 - 195. [Abstract] [Full Text] [PDF]

				J. T. Kielstein and C. Zoccali A New Perspective for the Treatment of Renal Diseases? J. Am. Soc. Nephrol., May 1, 2007; 18(5): 1365 - 1367. [Full Text] [PDF]

				H. Konishi, K. Sydow, and J. P. Cooke Dimethylarginine Dimethylaminohydrolase Promotes Endothelial Repair After Vascular Injury J. Am. Coll. Cardiol., March 13, 2007; 49(10): 1099 - 1105. [Abstract] [Full Text] [PDF]