Dimethylarginine dimethylaminohydrolase-1 transgenic mice are not protected from ischemic stroke.
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Dimethylarginine dimethylaminohydrolase-1 transgenic mice are not protected from ischemic stroke. / Leypoldt, Frank; Choe, Chi-Un; Gelderblom, Mathias; von Leitner, Eike-Christin; Atzler, Dorothee; Schwedhelm, Edzard; Gerloff, Christian; Sydow, Karsten; Böger, Rainer; Magnus, Tim.
in: PLOS ONE, Jahrgang 4, Nr. 10, 10, 2009, S. 7337.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Dimethylarginine dimethylaminohydrolase-1 transgenic mice are not protected from ischemic stroke.
AU - Leypoldt, Frank
AU - Choe, Chi-Un
AU - Gelderblom, Mathias
AU - von Leitner, Eike-Christin
AU - Atzler, Dorothee
AU - Schwedhelm, Edzard
AU - Gerloff, Christian
AU - Sydow, Karsten
AU - Böger, Rainer
AU - Magnus, Tim
PY - 2009
Y1 - 2009
N2 - BACKGROUND: Methylated arginines are endogenous analogues of L-arginine, the substrate for nitric oxide (NO) synthase. Asymmetric dimethylarginine (ADMA) interferes with NO formation, causing endothelial dysfunction. ADMA is a predictor of cardiovascular events and mortality in humans. It is eliminated primarily by enzymatic activity of dimethylarginine dimethylaminohydrolase (DDAH). METHODOLOGY/PRINCIPAL FINDINGS: We investigated whether human DDAH-1 (hDDAH-1) transgenicity protects from ischemic tissue damage in temporary middle cerebral artery occlusion (tMCAO) in mice. Infarct sizes did not significantly differ between hDDAH-1 transgenic (TG) mice and wild-type littermates (WT). As expected, ADMA plasma concentrations were significantly decreased, cerebral hDDAH expression and protein significantly increased in transgenic animals. Interestingly, neither brain tissue DDAH activity nor ADMA concentrations were different between TG and WT mice. In contrast, muscular DDAH activity was generally lower than in brain but significantly increased in TG mice. CONCLUSION/SIGNIFICANCE: Our study demonstrates that hDDAH-1 transgenic mice are not protected from ischemic cerebral tissue damage in tMCAO. This lack of protection is due to high basal cerebral DDAH activity, which is not further increasable by transgenic overexpression of DDAH.
AB - BACKGROUND: Methylated arginines are endogenous analogues of L-arginine, the substrate for nitric oxide (NO) synthase. Asymmetric dimethylarginine (ADMA) interferes with NO formation, causing endothelial dysfunction. ADMA is a predictor of cardiovascular events and mortality in humans. It is eliminated primarily by enzymatic activity of dimethylarginine dimethylaminohydrolase (DDAH). METHODOLOGY/PRINCIPAL FINDINGS: We investigated whether human DDAH-1 (hDDAH-1) transgenicity protects from ischemic tissue damage in temporary middle cerebral artery occlusion (tMCAO) in mice. Infarct sizes did not significantly differ between hDDAH-1 transgenic (TG) mice and wild-type littermates (WT). As expected, ADMA plasma concentrations were significantly decreased, cerebral hDDAH expression and protein significantly increased in transgenic animals. Interestingly, neither brain tissue DDAH activity nor ADMA concentrations were different between TG and WT mice. In contrast, muscular DDAH activity was generally lower than in brain but significantly increased in TG mice. CONCLUSION/SIGNIFICANCE: Our study demonstrates that hDDAH-1 transgenic mice are not protected from ischemic cerebral tissue damage in tMCAO. This lack of protection is due to high basal cerebral DDAH activity, which is not further increasable by transgenic overexpression of DDAH.
U2 - 10.1371/journal.pone.0007337
DO - 10.1371/journal.pone.0007337
M3 - SCORING: Zeitschriftenaufsatz
VL - 4
SP - 7337
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 10
M1 - 10
ER -
