Dimethylarginine dimethylaminohydrolase-1 transgenic mice are not protected from ischemic stroke.
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).


RESULTS
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.


CONCLUSIONS
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.
Leypoldt
Frank
F
Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Choe
Chi-Un
CU
Gelderblom
Mathias
M
von Leitner
Eike-Christin
EC
Atzler
Dorothee
D
Schwedhelm
Edzard
E
Gerloff
Christian
C
Sydow
Karsten
K
Böger
Rainer H
RH
Magnus
Tim
T
D000581:Amidohydrolases / Q000235:genetics*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology; D005838:Genotype; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D007511:Ischemia / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D020521:Stroke / Q000235:genetics* / Q000517:prevention & control*
D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase