title: Forebrain specific heparin-binding epidermal growth factor-like growth factor knockout mice show exacerbated ischemia and reperfusion injury.
abstract: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a hypoxia-inducible neuroprotective protein that also stimulates proliferation of neuronal precursor cells. In this study, we investigated the possible role of HB-EGF in ischemia and reperfusion injury by measuring the changes in its mRNA expression following focal cerebral ischemia. We also examined neural damage after a middle cerebral artery occlusion (MCAO) and reperfusion in ventral forebrain specific HB-EGF knockout (KO) mice. The levels of HB-EGF mRNA in the cerebral cortex of wild-type (WT) mice were significantly increased 3-24 h after MCAO and reperfusion. Cerebral infraction in HB-EGF KO mice was aggravated at 1 day and 6 days after MCAO and reperfusion compared with WT mice. The number of terminal deoxynucleotidyl transferase (TdT)-mediated dNTP nick end labeling (TUNEL) and an oxidative stress marker, 8-hydroxy-2'-deoxyguanosine (8-OHdG) positive cells, were higher in HB-EGF KO mice than in WT mice. On the other hand, fewer bromodeoxyuridine (BrdU) positive cells were found in the subventricular zone in HB-EGF KO mice compared with WT mice. These results indicate that HB-EGF may play a pivotal role in ischemia and reperfusion injury and that endogenously synthesized HB-EGF is necessary for both the neuroprotective effect and for regulation of cell proliferation in the subventricular zone.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Oyagi
authors.forename: N
authors.initials: N
authors.lastname: Morimoto
authors.forename: J
authors.initials: J
authors.lastname: Hamanaka
authors.forename: M
authors.initials: M
authors.lastname: Ishiguro
authors.forename: K
authors.initials: K
authors.lastname: Tsuruma
authors.forename: M
authors.initials: M
authors.lastname: Shimazawa
authors.forename: H
authors.initials: H
authors.lastname: Hara
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D053687:Adult Stem Cells / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002552:Cerebral Ventricles / Q000502:physiology; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D066257:Heparin-binding EGF-like Growth Factor; D020287:In Situ Nick-End Labeling / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016548:Prosencephalon / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications / Q000473:pathology*; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D000080242:8-Hydroxy-2'-Deoxyguanosine; D001973:Bromodeoxyuridine; D003849:Deoxyguanosine