title: Knockout of ho-1 protects the striatum from ferrous iron-induced injury in a male-specific manner in mice.
abstract: Men have worse survival than premenopausal women after intracerebral hemorrhage (ICH). After ICH, overproduction of iron associated with induction of heme oxygenase-1 (HO-1) in brain was observed. Rodent ICH model using ferrous citrate (FC)-infusion into the striatum to simulate iron overload, showed a higher degree of injury severity in males than in females. However, the participation of HO-1 in sex-differences of iron-induced brain injury remains unknown. The present results showed a higher level of HO-1 expression associated with more severe injury in males compared with females after FC-infusion. Estradiol (E2) contributed to lower levels of FC-induced HO-1 expression in females compared with males. Heterozygote ho-1 KO decreased the levels of FC-induced injury severity, histological lesions, behavioral deficits, autophagy and autophagic cell death in the striatum of males but not in females. Moreover, ho-1 deficiency enhanced the neuroprotection by E2 only in males. These results suggested that over induction of HO-1 plays a harmful role in FC-induced brain injury in a male-specific manner. Suppression of HO-1 combined with E2 exhibits a synergistic effect on neuroprotection against FC-induced striatal injury in males. These findings open up the prospect for male-specific neuroprotection targeting HO-1 suppression for patients suffering from striatal iron overload.
authors.affiliation: Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, Kaohsiung, Taiwan.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Wang
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, Kaohsiung, Taiwan.
authors.forename: Kazunari K
authors.initials: KK
authors.lastname: Yokoyama
authors.affiliation: Department of Neurosurgery, Faculty of Medicine, College of Medicine; Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, Kaohsiung, Taiwan.
authors.forename: Chih-Lung
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Department of Physiology, Faculty of Medicine, College of Medicine; Kaohsiung Medical University, Kaohsiung, No. 100, Shih-Chuan 1st Road, Kaohsiung, Taiwan.
authors.forename: Tzu-Yin
authors.initials: TY
authors.lastname: Chen
authors.affiliation: Department of Physiology, Faculty of Medicine, College of Medicine; Kaohsiung Medical University, Kaohsiung, No. 100, Shih-Chuan 1st Road, Kaohsiung, Taiwan.
authors.forename: Hsiu-Wen
authors.initials: HW
authors.lastname: Hsiao
authors.affiliation: Department of Physiology, Faculty of Medicine, College of Medicine; Kaohsiung Medical University, Kaohsiung, No. 100, Shih-Chuan 1st Road, Kaohsiung, Taiwan.
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Chiang
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, Kaohsiung, Taiwan.|Department of Physiology, Faculty of Medicine, College of Medicine; Kaohsiung Medical University, Kaohsiung, No. 100, Shih-Chuan 1st Road, Kaohsiung, Taiwan.
authors.forename: Chin
authors.initials: C
authors.lastname: Hsu
mesh_terms: D000818:Animals; D017209:Apoptosis; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D019343:Citric Acid; D003342:Corpus Striatum / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005296:Ferrous Compounds / Q000008:administration & dosage / Q000633:toxicity*; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012720:Severity of Illness Index; D012727:Sex Characteristics; D015854:Up-Regulation
chemical_list: D005296:Ferrous Compounds; D008565:Membrane Proteins; D019343:Citric Acid; C016600:ferrous citrate; D004958:Estradiol; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse