Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
PLoS One. 2009 Oct 7;4(10):e7337. doi: 10.1371/journal.pone.0007337.
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.
甲基精氨酸是内源性 L-精氨酸类似物，是一氧化氮合酶（NOS）的底物。不对称二甲基精氨酸（ADMA）干扰 NO 的形成，导致内皮功能障碍。ADMA 是人类心血管事件和死亡率的预测因子。它主要通过二甲基精氨酸二甲氨基水解酶（DDAH）的酶活性来消除。
方法/主要发现：我们研究了人类 DDAH-1（hDDAH-1）转基因是否能保护小鼠短暂性大脑中动脉闭塞（tMCAO）引起的缺血性组织损伤。hDDAH-1 转基因（TG）小鼠和野生型同窝仔（WT）之间的梗塞面积没有显著差异。正如预期的那样，转基因动物的血浆 ADMA 浓度显著降低，大脑 hDDAH 表达和蛋白显著增加。有趣的是，转基因和 WT 小鼠之间的脑组织 DDAH 活性和 ADMA 浓度没有差异。相比之下，肌肉 DDAH 活性通常低于大脑，但在 TG 小鼠中显著增加。
结论/意义：我们的研究表明，hDDAH-1 转基因小鼠在 tMCAO 中不能免受缺血性脑损伤。这种保护作用的缺失是由于基础大脑 DDAH 活性较高，而 DDAH 的转基因过表达不能进一步增加。
