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PRECLINICAL STUDY

Dimethylarginine Dimethylaminohydrolase Promotes Endothelial Repair After Vascular Injury

Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California.

Manuscript received July 14, 2006; revised manuscript received September 22, 2006, accepted October 9, 2006.

^_* Reprint requests and correspondence: Dr. John P. Cooke, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305. (Email: john.cooke{at}stanford.edu).

Objectives: We sought to determine if a reduction in asymmetric dimethylarginine (ADMA) enhances endothelial regeneration.

Background: Asymmetric dimethylarginine is an endogenous inhibitor of nitric oxide synthase (NOS). Increased plasma levels of ADMA are associated with endothelial vasodilator dysfunction in patients with vascular disease or risk factors. Asymmetric dimethylarginine is eliminated largely by the action of dimethylarginine dimethylaminohydrolase (DDAH), which exists in 2 isoforms. Dimethylarginine dimethylaminohydrolase-1 transgenic (TG) mice manifest increased DDAH activity, reduced plasma and tissue ADMA levels, increased nitric oxide synthesis, and reduced systemic vascular resistance.

Methods: The left femoral arteries of DDAH1 TG mice and wild-type (WT) mice were injured by a straight spring wire, and regeneration of the endothelial cell (EC) monolayer was assessed. Endothelial sprouting was assayed with growth factor-reduced Matrigel.

Results: Regeneration of the EC monolayer was more complete 1 week after injury in TG mice (WT vs. TG: 40.0 ± 6.5% vs. 61.2 ± 6.4%, p < 0.05). The number of CD45 positive cells at the injured sites was reduced by 62% in DDAH TG mice (p < 0.05). Four weeks after injury, the neointima area and intima/media ratio were attenuated in DDAH TG mice (WT vs. TG: 0.049 ± 0.050 mm² vs. 0.031 ± 0.060 mm², 3.1 ± 0.5 vs. 1.7 ± 0.2, respectively, p < 0.05). Endothelial cell sprouting from vascular segments increased in TG mice (WT vs. TG: 24.3 ± 3.9 vs. 39.0 ± 2.2, p < 0.05).

Conclusions: We find for the first time an important role for DDAH in EC regeneration and in neointima formation. Strategies to enhance DDAH expression or activity might be useful in restoring the endothelial monolayer and in treating vascular disease.

Abbreviations and Acronyms   ADMA = asymmetric dimethylarginine   DDAH = dimethylarginine dimethylaminohydrolase   EC = endothelial cell   NO = nitric oxide   NOS = NO synthase   TG = DDAH transgenic mice   WT = wild-type mice

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