Dimethylarginine dimethylaminohydrolase promotes endothelial repair after vascular injury

TY - JOUR

T1 - Dimethylarginine dimethylaminohydrolase promotes endothelial repair after vascular injury

AU - Konishi, Hakuoh

AU - Sydow, Karsten

AU - Cooke, John P

PY - 2007/3/13

Y1 - 2007/3/13

N2 - 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.

AB - 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.

KW - Amidohydrolases/metabolism

KW - Animals

KW - Arginine/analogs & derivatives

KW - Cell Proliferation

KW - Disease Models, Animal

KW - Endothelium, Vascular/drug effects

KW - Enzyme Induction

KW - Femoral Artery/injuries

KW - Humans

KW - Immunohistochemistry

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Neovascularization, Physiologic/physiology

KW - Nitric Oxide/physiology

KW - Probability

KW - Random Allocation

KW - Sensitivity and Specificity

KW - Species Specificity

KW - Vascular Diseases/drug therapy

U2 - 10.1016/j.jacc.2006.10.068

DO - 10.1016/j.jacc.2006.10.068

M3 - SCORING: Journal article

C2 - 17349891

VL - 49

SP - 1099

EP - 1105

JO - J AM COLL CARDIOL

JF - J AM COLL CARDIOL

SN - 0735-1097

IS - 10

ER -