Inhibition of acid-sensing receptor GPR4 attenuates neuronal ferroptosis via RhoA/YAP signaling in a rat model of subarachnoid hemorrhage

作者：Qiuguang He, You Zhou, Lei Wu, Lei Huang, Ye Yuan, Jerry Flores, Xu Luo, Yihao Tao, Xionghui Chen, Hideki Kanamaru, Siyuan Dong, Shiyi Zhu, Qian Yu, Mingyang Han, Prativa Sherchan, Jiani Li, Jiping Tang, Zongyi Xie, John H. Zhang · 发表于：Free Radical Biology and Medicine · 年份：2024 · DOI：10.1016/j.freeradbiomed.2024.10.273 · 被引用次数：12 · 研究领域：Intracerebral and Subarachnoid Hemorrhage Research、Ion Transport and Channel Regulation、Cancer, Hypoxia, and Metabolism

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) is a devastating stroke, in which acidosis is one of detrimental complications. The extracellular pH reduction can activate G protein-coupled receptor 4 (GPR4) in the brain. Yet, the extent to which proton-activated GPR4 contributes to the early brain injury (EBI) post-SAH remains largely unexplored. Ferroptosis, iron-dependent programmed cell death, has recently been shown to contribute to EBI. We aimed to investigate the effects of GPR4 inhibition on neurological deficits and neuronal ferroptosis after SAH in rats. METHODS: A total 253 Sprague Dawley (SD) male rats (weighing 275-330g) were utilized in this study. SAH was induced by endovascular perforation. NE-52-QQ57 (NE), a selective antagonist of GPR4 was administered intraperitoneally 1-h post-SAH. To explore the mechanisms, RhoA activator U-46619 and YAP activator PY-60 were delivered intracerebroventricularly. Short- and long-term neurobehavior, SAH grading, Western blot assay, ELISA assay, immunofluorescence staining, and transmission electron microscopy was performed post-SAH. RESULTS: Following SAH, there was an upregulation of GPR4 expression in neurons. GPR4 inhibition by NE improved both short-term and long-term neurological outcomes post-SAH. NE also reduced neuronal ferroptosis, as evidenced by decreased lipid peroxidation products 4HNE and MDA levels in brain tissues, and reduced mitochondrial shrinkage, increased mitochondria crista and decreased membrane...