Dimethylarginine dimethylaminohydrolase-1 transgenic mice are not protected from ischaemic stroke due to a ceiling effect of enzymatic activity in brain

Background and Purpose: Methylated arginines are endogenous analogues of L-arginine, the substracte for NO synthase. Asymmetric dimethylarginine (ADMA) interferes with nitric oxide (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).

Methods: We investigated whether human DDAH-1 (hDDAH-1) transgenicity protects from ischemic tissue damage in temporary middle cerebral artery occlusion (tMCAO) in mice.

Results: Infarct sizes did not significantly differ between hDDAH-1 transgenic (TG) mice and wild-type littermates (WT). As expected, cerebral hDDAH expression (mRNA and Western blot) was significantly increased in transgenic animals. Interestingly, neither brain DDAH activity nor brain ADMA concentrations were different between TG and WT mice. In contrast, DDAH activity of another tissue, i.e. skeletal muscle, was lower than in brain but significantly increased in TG mice. Also, ADMA plasma concentrations were significantly decreased in TG animals.

Conclusion: Our study demonstrates that hDDAH-1 transgenic mice are not protected from ischemic cerebral tissue damage in tMCAO. This lack of protection is potentially due to a ceiling effect of already high basic cerebral DDAH activity, which is not further increasable by transgenic overexpression of hDDAH-1.