Tat-SynGAP improves angiogenesis and post-stroke recovery by inhibiting MST1/JNK signaling

Hui Yang; Zhenqian Liu; Xiaomei Liu; Xiaowei Cao; Mo Chen; Shiying Lou; Liangqun Rong; Yun Xu; Qingxiu Zhang

doi:10.1016/j.brainresbull.2021.12.013

Tat-SynGAP improves angiogenesis and post-stroke recovery by inhibiting MST1/JNK signaling

Brain Res Bull. 2022 Mar:180:38-45. doi: 10.1016/j.brainresbull.2021.12.013. Epub 2022 Jan 3.

Authors

Hui Yang¹, Zhenqian Liu², Xiaomei Liu³, Xiaowei Cao⁴, Mo Chen², Shiying Lou⁵, Liangqun Rong², Yun Xu⁴, Qingxiu Zhang⁶

Affiliations

¹ 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.
² Department of Neurology, Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006 Jiangsu, China.
³ Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
⁴ 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.
⁵ Nanjing Drum Tower Clinical College of Xuzhou Medical University, Nanjing 210008, China.
⁶ 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. Electronic address: [email protected].

PMID: 34990733
DOI: 10.1016/j.brainresbull.2021.12.013

Abstract

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.

Keywords: Blood-brain barrier; Cerebral ischemia/reperfusion; JNK; MST1; Tat-SynGAP (670–685aa).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood-Brain Barrier / drug effects
Brain Edema / drug therapy*
Brain Ischemia / drug therapy*
Disease Models, Animal
GTPase-Activating Proteins / pharmacology*
Guanylate Kinases / drug effects
Hepatocyte Growth Factor
MAP Kinase Signaling System / drug effects*
Membrane Proteins / drug effects
Mice
Neovascularization, Physiologic / drug effects*
Neuroprotective Agents / pharmacology*
Proto-Oncogene Proteins / drug effects*
Reperfusion Injury / drug therapy*
Twin-Arginine-Translocation System*

Substances

GTPase-Activating Proteins
Membrane Proteins
Neuroprotective Agents
Proto-Oncogene Proteins
Twin-Arginine-Translocation System
macrophage stimulating protein
Hepatocyte Growth Factor
Dlg2 protein, mouse
Guanylate Kinases