title: Ischemia/reperfusion-induced upregulation of TIGAR in brain is mediated by SP1 and modulated by ROS and hormones involved in glucose metabolism.
abstract: We previously found that TIGAR (TP53-induced glycolysis and apoptosis regulator) was upregulated in response to ischemia/reperfusion insult in a TP53-independent manner. The present study sought to investigate the regulatory mechanisms of TIGAR upregulation in animal and cellular models of stroke. The animal and cellular models of ischemia/reperfusion were produced by transient middle cerebral artery occlusion and reperfusion (tMCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R), respectively. The expression of TIGAR protein in cortical tissues and hippocampal neuronal cell line HT22 cells or primary neurons was determined. Glucose, hormones and hydrogen peroxide (H2O2) were administered to mice via injection into the tail vein or lateral ventricle or directly added into cell culture medium. In mice subjected to tMCAO/R, the blood glucose level rapidly increased, peaking at 0.5 h and then declined. TIGAR protein was also significantly increased and then declined with a delayed time-course. The increase in TIGAR protein was blunted when blood glucose levels were controlled with insulin. However, administering glucose solution to mice or adding glucose to cell culture medium had no effect on TIGAR protein levels. In contrast adrenaline, hydrocortisone, glucagon and H2O2 significantly increased TIGAR protein expression, whereas insulin inhibited TIGAR expression. The transcription factor SP1 was induced by ischemia/reperfusion ahead of TIGAR upregulation. Inhibiting SP1 with mithramycin A or silencing SP1 with siRNA blocked the ischemia-induced TIGAR upregulation. These results suggest that ROS and hormones regulating blood glucose metabolism play a role in ischemia/reperfusion-induced TIGAR upregulation.
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science, Suzhou 215123, China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science, Suzhou 215123, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science, Suzhou 215123, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Zhejiang University, Hangzhou 310058, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Han
authors.affiliation: Department of Pathophysiology, Nantong University School of Medical Science, Nantong 226001, China.
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Gu
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science, Suzhou 215123, China.
authors.forename: Jiaming
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science, Suzhou 215123, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Han
authors.affiliation: Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science, Suzhou 215123, China. Electronic address: qinzhenhong@suda.edu.cn.
authors.forename: Zheng-Hong
authors.initials: ZH
authors.lastname: Qin
authors.affiliation: Department of Radiology, Affiliated Hospital of Guilin Medical College, Guilin 541001, China. Electronic address: qinzhenhong@suda.edu.cn.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006854:Hydrocortisone / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010744:Phosphoric Monoester Hydrolases; D011506:Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D011506:Proteins; D017382:Reactive Oxygen Species; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D005934:Glucagon; D010744:Phosphoric Monoester Hydrolases; C554952:TIGAR protein, mouse; D005947:Glucose; D006854:Hydrocortisone
keywords: Glucagon; Glucose; Hydrogen peroxide; Insulin; SP1; TIGAR