Department of Neurology, The First Hospital of Qiqihar, Qiqihar 161005, Heilongjiang, China.
Department of Rheumatology, The First Hospital of Qiqihar, Qiqihar 161005, Heilongjiang, China.
J Stroke Cerebrovasc Dis. 2024 May;33(5):107668. doi: 10.1016/j.jstrokecerebrovasdis.2024.107668. Epub 2024 Feb 27.
Stroke is a major cause of death and severe disability, and there remains a substantial need for the development of therapeutic agents for neuroprotection in acute ischemic stroke (IS) to protect the brain against damage before and during recanalization. Caveolin-1 (CAV1), an integrated protein that is located at the caveolar membrane, has been reported to exert neuroprotective effects during IS. Nevertheless, the mechanism remains largely unknown. Here, we explored the upstream modifiers of CAV1 in IS.
E3 ubiquitin ligases of CAV1 that are differentially expressed in IS were screened using multiple databases. The transcription factor responsible for the dysregulation of E3 ubiquitin-protein ligase synoviolin (SYVN1) in IS was predicted and verified. Genetic manipulations by lentiviral vectors were applied to investigate the effects of double-strand-break repair protein rad21 homolog (RAD21), SYVN1, and CAV1 in a middle cerebral artery occlusion (MCAO) mouse model and mouse HT22 hippocampal neurons induced by oxygen-glucose deprivation (OGD).
SYVN1 was highly expressed in mice with MCAO, and knockdown of SYVN1 alleviated IS injury in mice, as evidenced by limited infarction volume, the lower water content in the brain, and repressed apoptosis and inflammatory response. RAD21 inhibited the transcription of SYVN1, thereby reducing the ubiquitination modification of CAV1. Overexpression of RAD21 elicited a neuroprotective role as well in mice with MCAO and HT22 induced with OGD, which was overturned by SYVN1.
Transcriptional repression of SYVN1 by RAD21 alleviates IS in mice by reducing ubiquitination modification of CAV1.
中风是死亡和严重残疾的主要原因，因此仍然需要开发治疗急性缺血性中风（IS）的神经保护剂，以在再通前和再通期间保护大脑免受损伤。小窝蛋白-1（CAV1）是一种位于小窝膜的整合蛋白，据报道在 IS 期间具有神经保护作用。然而，其机制在很大程度上仍不清楚。在这里，我们探讨了 IS 中小窝蛋白-1 的上游修饰物。
使用多个数据库筛选 IS 中差异表达的 CAV1 的 E3 泛素连接酶。预测并验证了负责 IS 中 E3 泛素蛋白连接酶 synoviolin（SYVN1）失调的转录因子。通过慢病毒载体进行遗传操作，以研究双链断裂修复蛋白 rad21 同源物（RAD21）、SYVN1 和 CAV1 在大脑中动脉闭塞（MCAO）小鼠模型和氧葡萄糖剥夺（OGD）诱导的小鼠 HT22 海马神经元中的作用。
SYVN1 在 MCAO 小鼠中高表达，SYVN1 的敲低减轻了小鼠的 IS 损伤，表现为梗死体积有限、脑含水量降低、凋亡和炎症反应受到抑制。RAD21 抑制 SYVN1 的转录，从而减少 CAV1 的泛素化修饰。RAD21 在 MCAO 小鼠和 OGD 诱导的 HT22 中过表达也具有神经保护作用，但被 SYVN1 逆转。
RAD21 通过降低 CAV1 的泛素化修饰，抑制 SYVN1 的转录，从而减轻了小鼠的 IS。
