Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism.
Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism.
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阿霉素通过内皮型一氧化氮合酶依赖性机制对实验性缺血性卒中的神经血管保护作用。
DOI：
10.1016/j.redox.2021.102197
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发表时间：
2021-11-22
期刊：
影响因子：
11.4
通讯作者：
Candelario-Jalil E
中科院分区：
文献类型：
--
作者：
Yang C;Lavayen BP;Liu L;Sanz BD;DeMars KM;Larochelle J;Pompilus M;Febo M;Sun YY;Kuo YM;Mohamadzadeh M;Farr SA;Kuan CY;Butler AA;Candelario-Jalil E
Adropin 是一种高度保守的肽，已被证明可以保护内皮屏障功能。血脑屏障（BBB）破坏是脑缺血的关键病理事件。然而，阿德罗平对缺血性中风结局的影响仍有待探索。假设adropin通过维持BBB完整性发挥神经保护作用，我们利用功能丧失和获得功能遗传方法结合合成adropin肽的药物治疗，研究了adropin在中风病理学中的作用。使用组织学、MRI 以及一系列感觉运动和认知测试对缺血性中风小鼠进行长期解剖和功能结果评估。脑缺血降低了大脑和血浆中的内源性adropin水平。 Adropin 治疗或转基因 adropin 过度表达可显着减少缺血性中风的年轻和老年小鼠的脑损伤并改善长期感觉运动和认知功能。相比之下，无论性别如何，adropin 的基因缺失都会加剧缺血性脑损伤。从机制上讲，adropin 治疗可减少 BBB 损伤、紧密连接蛋白降解、基质金属蛋白酶 9 活性、氧化应激以及中性粒细胞向缺血脑的浸润。 Adropin 显着增加内皮一氧化氮合酶 (eNOS)、Akt 和 ERK1/2 的磷酸化。虽然 adropin 疗法对野生型小鼠具有显着的保护作用，但它未能减少 eNOS 缺陷动物的脑损伤，这表明 eNOS 是 adropin 对中风的保护作用所必需的。这些数据提供了第一个因果证据，表明阿德罗平通过 eNOS 依赖性机制在中风中发挥神经血管保护作用。我们认为阿德洛平是一种新型神经保护肽，具有改善中风结果的潜力。缺血性中风会降低大脑和血浆中的内源性阿降蛋白水平。 Adropin 治疗可改善年轻和老年小鼠的中风结果。 Adropin 基因缺失会加剧中风损伤。阿德罗品可预防中风引起的血脑屏障破坏。从机制上讲，adropin 通过 eNOS 依赖性途径减少中风损伤。
Adropin is a highly-conserved peptide that has been shown to preserve endothelial barrier function. Blood-brain barrier (BBB) disruption is a key pathological event in cerebral ischemia. However, the effects of adropin on ischemic stroke outcomes remain unexplored. Hypothesizing that adropin exerts neuroprotective effects by maintaining BBB integrity, we investigated the role of adropin in stroke pathology utilizing loss- and gain-of-function genetic approaches combined with pharmacological treatment with synthetic adropin peptide. Long-term anatomical and functional outcomes were evaluated using histology, MRI, and a battery of sensorimotor and cognitive tests in mice subjected to ischemic stroke. Brain ischemia decreased endogenous adropin levels in the brain and plasma. Adropin treatment or transgenic adropin overexpression robustly reduced brain injury and improved long-term sensorimotor and cognitive function in young and aged mice subjected to ischemic stroke. In contrast, genetic deletion of adropin exacerbated ischemic brain injury, irrespective of sex. Mechanistically, adropin treatment reduced BBB damage, degradation of tight junction proteins, matrix metalloproteinase-9 activity, oxidative stress, and infiltration of neutrophils into the ischemic brain. Adropin significantly increased phosphorylation of endothelial nitric oxide synthase (eNOS), Akt, and ERK1/2. While adropin therapy was remarkably protective in wild-type mice, it failed to reduce brain injury in eNOS-deficient animals, suggesting that eNOS is required for the protective effects of adropin in stroke. These data provide the first causal evidence that adropin exerts neurovascular protection in stroke through an eNOS-dependent mechanism. We identify adropin as a novel neuroprotective peptide with the potential to improve stroke outcomes. Ischemic stroke decreases endogenous adropin levels in the brain and plasma. Adropin treatment improves stroke outcomes in young and aged mice. Adropin genetic deletion exacerbates stroke injury. Stroke-induced blood-brain barrier disruption is prevented by adropin. Mechanistically, adropin reduces stroke damage through an eNOS-dependent pathway.
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