Extensive characterization of the human DDAH1 transgenic mice.
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Extensive characterization of the human DDAH1 transgenic mice. / Schwedhelm, Edzard; von Leitner, Eike-Christin; Atzler, Dorothee; Schmitz, Christine; Jacobi, Johannes; Meinertz, Thomas; Münzel, Thomas; Baldus, Stephan; Cooke, John P; Böger, Rainer; Maas, Renke; Sydow, Karsten.
in: PHARMACOL RES, Jahrgang 60, Nr. 6, 6, 2009, S. 494-502.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Extensive characterization of the human DDAH1 transgenic mice.
AU - Schwedhelm, Edzard
AU - von Leitner, Eike-Christin
AU - Atzler, Dorothee
AU - Schmitz, Christine
AU - Jacobi, Johannes
AU - Meinertz, Thomas
AU - Münzel, Thomas
AU - Baldus, Stephan
AU - Cooke, John P
AU - Böger, Rainer
AU - Maas, Renke
AU - Sydow, Karsten
PY - 2009
Y1 - 2009
N2 - PURPOSE OF THE RESEARCH: Overexpression of the human dimethylarginine dimethylaminohydrolase type 1 (hDDAH1) gene was reported to have beneficial cardiovascular effects in mice. To date, it is unclear whether these effects are related to enhanced metabolic clearance of asymmetric dimethylarginine (ADMA) and l-N(G)-mono-methyl-l-arginine (l-NMMA) or increased DDAH1 expression and activity in cardiovascular tissues of hDDAH1 transgenic mice. PRINCIPAL RESULTS: DDAH activity (DDAH1+DDAH2) was found to be markedly increased in aortic and heart tissues but unaltered in liver and kidney tissues of hDDAH1 transgenic as compared to wild-type (WT) mice. In WT mice, DDAH activity was more abundant in liver and kidney as compared to aorta and heart, suggesting a possible ceiling effect of activity which was unsurpassed by hDDAH1 overexpression. MAJOR CONCLUSIONS: Overexpression of hDDAH1 in healthy mice does not result in an improved DDAH-metabolic capacity of kidney and liver under normal, i.e. unchallenged conditions. The most likely explanation for low ADMA and l-NMMA concentrations in hDDAH1 transgenic mice is a decreased release of ADMA from aorta, heart, and possibly other organs. The protective cardiovascular effects seen in these animals may therefore be related to an improved activity of the DDAH enzyme in the cardiovascular system and not be related to improved renal and hepatic clearance of ADMA and l-NMMA.
AB - PURPOSE OF THE RESEARCH: Overexpression of the human dimethylarginine dimethylaminohydrolase type 1 (hDDAH1) gene was reported to have beneficial cardiovascular effects in mice. To date, it is unclear whether these effects are related to enhanced metabolic clearance of asymmetric dimethylarginine (ADMA) and l-N(G)-mono-methyl-l-arginine (l-NMMA) or increased DDAH1 expression and activity in cardiovascular tissues of hDDAH1 transgenic mice. PRINCIPAL RESULTS: DDAH activity (DDAH1+DDAH2) was found to be markedly increased in aortic and heart tissues but unaltered in liver and kidney tissues of hDDAH1 transgenic as compared to wild-type (WT) mice. In WT mice, DDAH activity was more abundant in liver and kidney as compared to aorta and heart, suggesting a possible ceiling effect of activity which was unsurpassed by hDDAH1 overexpression. MAJOR CONCLUSIONS: Overexpression of hDDAH1 in healthy mice does not result in an improved DDAH-metabolic capacity of kidney and liver under normal, i.e. unchallenged conditions. The most likely explanation for low ADMA and l-NMMA concentrations in hDDAH1 transgenic mice is a decreased release of ADMA from aorta, heart, and possibly other organs. The protective cardiovascular effects seen in these animals may therefore be related to an improved activity of the DDAH enzyme in the cardiovascular system and not be related to improved renal and hepatic clearance of ADMA and l-NMMA.
M3 - SCORING: Zeitschriftenaufsatz
VL - 60
SP - 494
EP - 502
JO - PHARMACOL RES
JF - PHARMACOL RES
SN - 1043-6618
IS - 6
M1 - 6
ER -