Estrogen may contribute to ischemic tolerance through modulation of cellular stress-related proteins.
Ischemic tolerance describes a phenomenon whereby subcritical stimuli evoke cellular protective mechanisms resulting in increased tolerance to subsequent ischemia. In the present study we propose that the cytoprotective effects attributed to 17beta-estradiol and tunicamycin in an in vivo rodent model of ischemia are reflected by changes in neuronal tissue levels of m-calpain, HSP70, GRP94 and GRP78. Rats pretreated with 17beta-estradiol, tunicamycin or both demonstrated dose-dependent reductions in infarct area following 4 h of permanent middle cerebral artery occlusion (MCAO). Western blot analysis revealed that 4 h of MCAO was associated with decreased cortical expression of HSP70 and m-calpain and increased expression of GRP78. Pretreatment with 12.5 microg/kg 17beta-estradiol did not change this pattern of protein expression following MCAO. While GRP94 expression was elevated in sham-operated rats pretreated with 17beta-estradiol, the ensuing ischemic tolerance did not appear to be mediated by changes in cellular stress proteins. Pretreatment with 50 microg/kg tunicamycin significantly reduced HSP70 in cortical tissue samples taken from sham-operated rats and appeared to attenuate the threshold for activation of m-calpain in rats undergoing 4 h of MCAO. Lastly, a combined treatment in which rats undergoing MCAO were pretreated with both tunicamycin (24 h prior) and 17beta-estradiol (30 min prior) was associated with an attenuated stress response as indicated by reduced expression of GRP78 and GRP94 when compared to saline-treated controls. The results of this study suggest that the ischemic tolerance observed following MCAO in rats pretreated with either 17beta-estradiol or tunicamycin is likely mediated in part through differential effects on cellular stress proteins.
Saleh
Monique C
MC
Dept. of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada.
Connell
Barry J
BJ
Saleh
Tarek M
TM
D000818:Animals; D002154:Calpain / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014415:Tunicamycin / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP
D002154:Calpain; D004958:Estradiol; D004967:Estrogens; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D014415:Tunicamycin; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C018551:glucose-regulated proteins; C449000:m-calpain