Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 301 Middle Yanchang Road, Shanghai 200072, China.
Oxid Med Cell Longev. 2022 Apr 25;2022:2350857. doi: 10.1155/2022/2350857. eCollection 2022.
Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cerebral ischemia injury via regulating the level of asymmetric dimethylarginine (ADMA). This study is aimed at exploring the effect of adiponectin resistance on ADMA-induced neuronal loss in ischemic stroke (IS) and the underlying mechanism. DDAH1 knockout (DDAH1) and wild-type (DDAH1) rats underwent middle cerebral artery occlusion/reperfusion (MCAO/R). Plasma and brain adiponectin levels and the expressions of adiponectin receptor 1 (APR1), adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1), adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK were determined after 24 h, 3 days, and 7 days. Neurological behavior, infarct volume, and adiponectin signaling were evaluated using adiponectin peptide or AdipoRon. The levels of reactive oxygen species (ROS) and Forkhead box O1 (FOXO1) (a transcription factor for APR1) were also assessed. An oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in primary neurons. DDAH1 was overexpressed in neurons, after which FOXO1 expression, ROS production, adiponectin resistance, and cell viability were detected. DDAH1 rats showed no significant difference in adiponectin level in either plasma or brain after MCAO/R in DDAH1 rats, but downregulated APR1 expression and suppressed adiponectin signaling were observed. AdipoRon, but not adiponectin peptide, attenuated the neurological deficits and adiponectin resistance in DDAH1 rats. ROS accumulation and phosphorylated FOXO1 expression also increased with DDAH1 depletion. Following DDAH1 overexpression, decreased cell viability and inhibited adiponectin signaling induced by OGD/R were alleviated in primary neurons, accompanied by reduced ROS production and phosphorylated FOXO1 expression. Our study elucidated that in IS, DDAH1 protected against adiponectin resistance in IS via the ROS/FOXO1/APR1 pathway.
二甲基精氨酸二甲胺水解酶 1（DDAH1）通过调节非对称二甲基精氨酸（ADMA）的水平来保护大脑免受缺血性损伤。本研究旨在探讨脂联素抵抗对缺血性中风（IS）中 ADMA 诱导的神经元丢失的影响及其潜在机制。DDAH1 敲除（DDAH1）和野生型（DDAH1）大鼠进行大脑中动脉闭塞/再灌注（MCAO/R）。在 24 小时、3 天和 7 天后，测定血浆和脑组织中脂联素水平以及脂联素受体 1（APR1）、衔接蛋白、磷酸酪氨酸相互作用 PH 结构域和亮氨酸拉链 1（APPL1）、腺苷单磷酸激活蛋白激酶（AMPK）和磷酸化 AMPK 的表达。用脂联素肽或 AdipoRon 评估神经行为、梗死体积和脂联素信号。还评估了活性氧（ROS）和叉头框 O1（FOXO1）（APR1 的转录因子）的水平。在原代神经元中建立了氧葡萄糖剥夺/再氧合（OGD/R）模型。在神经元中过表达 DDAH1，然后检测 FOXO1 表达、ROS 产生、脂联素抵抗和细胞活力。在 DDAH1 大鼠中，MCAO/R 后 DDAH1 大鼠血浆或脑组织中脂联素水平无明显差异，但下调 APR1 表达并抑制脂联素信号。AdipoRon 而非脂联素肽可减轻 DDAH1 大鼠的神经功能缺损和脂联素抵抗。随着 DDAH1 的消耗，ROS 积累和磷酸化 FOXO1 的表达也增加。过表达 DDAH1 后，原代神经元中由 OGD/R 引起的细胞活力降低和抑制的脂联素信号得到缓解，同时伴随着 ROS 产生和磷酸化 FOXO1 表达减少。我们的研究表明，在 IS 中，DDAH1 通过 ROS/FOXO1/APR1 通路防止 IS 中的脂联素抵抗。
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