Dimethylarginine dimethylamino hydrolase-1 (DDAH-1) as an indirect regulator of nitric oxide (NO) metabolism, its role in hypoxic preconditioning (HPC) and ischemic tolerance (IT) of ischemic stroke has still been unknown and needs to be elucidated. Herein, DDAH-1 knock-out (KO) and wild-type (WT) rats underwent HPC and middle cerebral artery occlusion/reperfusion (MCAO/R) model. After 24 h, neurological severity scores, TTC staining and TUNEL assay were used to evaluate neurological damages. To explore the mechanism, the expression of hypoxia inducible factor (HIF-1α) and its target genes were assessed by Western blot and RT-qPCR. NO and ADMA contents were also tested. In addition, supplementation of l-arginine to DDAH-1 KO rats was used to explore the role of DDAH-1 in regulating NO. After HPC the ischemic outcome improved in both KO and WT rats, while KO rats showed attenuated IT exhibiting less expression of HIF-1α and its target genes, lower NO but higher ADMA content. The supplement of l-arginine to KO rats partly alleviated neurological damages accompanied with higher expression of HIF-1α. To sum up, DDAH-1 could regulate the level of NO and enhance IT following HPC and MCAO model via activating the expression of HIF-1α and its target genes.

中文翻译：

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经由HIF-1靶基因的DDAH-1可改善缺氧预处理和大脑中动脉闭塞-再灌注后的脑缺血耐受性。

二甲基精氨酸二甲基氨基水解酶-1（DDAH-1）作为一氧化氮（NO）代谢的间接调节剂，其在缺血性卒中的低氧预适应（HPC）和缺血耐受性（IT）中的作用仍是未知的，需要阐明。在此，对DDAH-1敲除（KO）和野生型（WT）大鼠进行了HPC和大脑中动脉闭塞/再灌注（MCAO / R）模型。24小时后，使用神经系统严重程度评分，TTC染色和TUNEL法评估神经系统损伤。通过Western blot和RT-qPCR检测缺氧诱导因子（HIF-1α）及其靶基因的表达，探讨其机制。还测试了NO和ADMA含量。此外，还向DDAH-1 KO大鼠补充了L-精氨酸，以探讨DDAH-1在调节NO中的作用。HPC后，KO和WT大鼠的缺血结局均得到改善，而KO大鼠的IT衰减显示HIF-1α及其靶基因的表达较少，NO较低，但ADMA含量较高。向KO大鼠补充L-精氨酸可部分缓解神经损伤，并伴有HIF-1α的高表达。综上所述，遵循HPC和MCAO模型，DDAH-1可以通过激活HIF-1α及其靶基因的表达来调节NO水平并增强IT。