Zhang Jie, Li Yiyi, Wang Chao, Wang Yaya, Zhang Yangyang, Huang Liqin, Zhang Zhaohui
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
Front Mol Neurosci. 2020 Feb 6;13:16. doi: 10.3389/fnmol.2020.00016. eCollection 2020.
Lysophosphatidic acid is a small extracellular signaling molecule, which is elevated in pathological conditions such as ischemic stroke and traumatic brain injury (TBI). LPA regulates the survival of neurons in various diseases. However, the molecular mechanisms underlying LPA-induced neuronal death remain unclear. Here we report that LPA activates LPA1 and LPA2 receptors, and the downstream MAPK pathway to induce the apoptosis of PC12 cells through mitochondrial dysfunction. LPA elicits the activation of ERK1/2, p38, and JNK pathways, decreases the expression of Bcl2, promotes the translocation of Bax, and enhances the activation of caspase-3, resulting in mitochondrial dysfunction and cell apoptosis. This process can be blocked by LPA1 receptor antagonist and LPA2 receptor antagonist and MAPK pathway inhibitors. Our results indicate that LPA1 receptor, LPA2 receptor and MAPK pathway play a critical role in LPA-induced neuronal injury. LPA receptors and MAPK pathways may be novel therapeutic targets for ischemic stroke and TBI, where excessive LPA signaling exist.
溶血磷脂酸是一种小的细胞外信号分子，在缺血性中风和创伤性脑损伤（TBI）等病理状况下会升高。溶血磷脂酸在多种疾病中调节神经元的存活。然而，溶血磷脂酸诱导神经元死亡的分子机制仍不清楚。在此我们报告，溶血磷脂酸激活溶血磷脂酸1型（LPA1）和溶血磷脂酸2型（LPA2）受体以及下游的丝裂原活化蛋白激酶（MAPK）途径，通过线粒体功能障碍诱导PC12细胞凋亡。溶血磷脂酸引发细胞外信号调节激酶1/2（ERK1/2）、p38和应激活化蛋白激酶（JNK）途径的激活，降低Bcl2的表达，促进Bax的易位，并增强半胱天冬酶-3的激活，导致线粒体功能障碍和细胞凋亡。这一过程可被LPA1受体拮抗剂、LPA2受体拮抗剂和MAPK途径抑制剂阻断。我们的结果表明，LPA1受体、LPA2受体和MAPK途径在溶血磷脂酸诱导的神经元损伤中起关键作用。溶血磷脂酸受体和MAPK途径可能是存在过度溶血磷脂酸信号传导的缺血性中风和TBI的新型治疗靶点。
