Tat-SynGAP 通过抑制 MST1/JNK 信号通路促进血管生成和卒中后恢复。
Tat-SynGAP improves angiogenesis and post-stroke recovery by inhibiting MST1/JNK signaling.
机构信息
Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210008, China; Nanjing Drum Tower Clinical College of Xuzhou Medical University, Nanjing 210008, China; Institute of Brain Sciences, Nanjing University, Nanjing 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210008, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing 210008, China; Nanjing Neurology Clinic Medical Center, Nanjing 210008, China; Department of Neurosurgery of Drum Tower Hospital, Nanjing University Medical School, Nanjing 210008, China.
Department of Neurology, Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006 Jiangsu, China.
出版信息
Brain Res Bull. 2022 Mar;180:38-45. doi: 10.1016/j.brainresbull.2021.12.013. Epub 2022 Jan 3.
Small G protein Ras induces the activation of apoptosis-related molecule mammalian Ste20-like kinase1 (MST1)/JNK signal pathway, which is involved in the regulation of tissue damage under pathological conditions such as ischemic stroke. Our previous study indicated that GTPase-activating protein for Ras (SynGAP), a negative regulator of Ras, could bind with postsynaptic density protein-93 (PSD-93) and Tat-SynGAP (670-685aa) small peptide to exhibit neuroprotective role. Here, we report that Tat-SynGAP (670-685aa) reduced cerebral edema at acute cerebral ischemia/reperfusion (I/R), improved integrity of blood-brain barrier, and decreased cortical and striatum neuronal injury. Mechanistically, Tat-SynGAP (670-685aa) not only inhibited the phosphorylation of MST1 and JNK and the cleavage of caspase-3, but also facilitated the expression of angiogenesis related molecules VEGF and Ang-1. In conclusion, Tat-SynGAP (670-685aa) reduces neuronal apoptosis and cerebral infarction volume and maintains vascular stability and blood-brain barrier integrity by inhibiting MST1/JNK signaling pathway.
小分子 G 蛋白 Ras 诱导凋亡相关分子哺乳动物 Ste20 样激酶 1（MST1）/JNK 信号通路的激活，该通路参与调节缺血性中风等病理条件下的组织损伤。我们之前的研究表明，Ras 的 GTP 酶激活蛋白（SynGAP）是 Ras 的负调节剂，可与突触后密度蛋白-93（PSD-93）和 Tat-SynGAP（670-685aa）小肽结合，发挥神经保护作用。在这里，我们报告 Tat-SynGAP（670-685aa）可减少急性脑缺血/再灌注（I/R）时的脑水肿，改善血脑屏障的完整性，并减少皮质和纹状体神经元损伤。在机制上，Tat-SynGAP（670-685aa）不仅抑制 MST1 和 JNK 的磷酸化以及 caspase-3 的切割，还促进血管生成相关分子 VEGF 和 Ang-1 的表达。总之，Tat-SynGAP（670-685aa）通过抑制 MST1/JNK 信号通路减少神经元凋亡和脑梗死体积，并维持血管稳定性和血脑屏障完整性。
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