Dimethylarginine dimethylaminohydrolase promotes endothelial repair after vascular injury
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Dimethylarginine dimethylaminohydrolase promotes endothelial repair after vascular injury. / Konishi, Hakuoh; Sydow, Karsten; Cooke, John P.
in: J AM COLL CARDIOL, Jahrgang 49, Nr. 10, 13.03.2007, S. 1099-1105.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -