title: Susceptibility to intracerebral hemorrhage-induced brain injury segregates with low aerobic capacity in rats.
abstract: Although low exercise capacity is a risk factor for stroke, the exact mechanisms that underlie this connection are not known. As a model system for exploring the association between aerobic capacity and disease risks we applied two-way artificial selection over numerous generations in rats to produce low capacity runners (LCR) and high capacity runners (HCR). Here we compared intracerebral hemorrhage (ICH)-induced brain injury in both genders of these rat lines. HCR and LCR rats had 100μl blood injected into the right caudate and were killed at days 1, 3, 7 and 28 for brain water content determination, immunohistochemistry, histology, Western blot, and behavioral tests. Compared to male HCRs, male LCRs had more severe ICH-induced brain injury including worse brain edema, necroptosis, brain atrophy, and neurological deficits, but not increased numbers of Fluoro-Jade C positive cells or elevated cleaved caspase-3 levels. This was associated with greater microglial activation, and heme oxygenase-1 and protease activated receptor (PAR)-1 upregulation. In females, edema was also greater in LCRs than in HCRs, although it was less severe in females than in males for both LCRs and HCRs. Thus, ICH-induced brain injury was more severe in LCRs, a model of low exercise capacity, than in HCRs. Increased activation of microglia and PAR-1 may participate mechanistically in increased ICH-susceptibility. Females were protected against ICH-induced brain edema formation in both HCRs and LCRs.
authors.affiliation: Deparment of Neurosurgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Yangdong
authors.initials: Y
authors.lastname: He
authors.affiliation: Deparment of Neurosurgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Wenquan
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Koch
authors.affiliation: Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Britton
authors.affiliation: Deparment of Neurosurgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Keep
authors.affiliation: Deparment of Neurosurgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Guohua
authors.initials: G
authors.lastname: Xi
authors.affiliation: Deparment of Neurosurgery, University of Michigan, Ann Arbor, MI, USA. Electronic address: yahua@umich.edu.
authors.forename: Ya
authors.initials: Y
authors.lastname: Hua
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D001921:Brain / Q000473:pathology* / Q000503:physiopathology*; D001929:Brain Edema / Q000473:pathology / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D005552:Forelimb / Q000503:physiopathology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D044463:Receptor, PAR-1 / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D012420:Running / Q000502:physiology*; D012720:Severity of Illness Index; D012727:Sex Characteristics; D013045:Species Specificity
chemical_list: D000199:Actins; D044463:Receptor, PAR-1; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D017346:Protein Serine-Threonine Kinases; C586536:RIPK1 protein, rat; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3