title: Estradiol abolishes reduction in cell death by the opioid agonist Met5-enkephalin after oxygen glucose deprivation in isolated cardiomyocytes from both sexes.
abstract: There is evidence for differences in the response to the treatment of cardiovascular disease in men and women. In addition, there are conflicting results regarding the effectiveness of pharmacologically induced protection or ischemic preconditioning in females. We investigated whether the ability of Met(5)-enkephalin (ME) to reduce cell death after oxygen-glucose deprivation (OGD) is influenced by the presence of 17beta-estradiol (E(2)) in a nitric oxide (NO)- and estrogen receptor-dependent manner. On postnatal day 7 to 8, murine cardiomyocytes from wild-type or inducible NO synthase (iNOS) knockout mice were separated by sex, isolated by collagenase digestion, cultured for 24 h, and subjected to 90 min OGD and 180 min reoxygenation at 37 degrees C (n = 4 to 5 replicates). Cell cultures were incubated in E(2) for 15 min or 24 h before OGD. ME was used to increase cell survival. Cell death was assessed by propidium iodide. More than 300 cells were examined for each treatment. Data are presented as means +/- SE. As a result, in both sexes, ME-induced cell survival was lost in the presence of E(2), and the ability of ME to improve cell survival was restored after treatment with the estrogen receptor antagonist ICI-182780. Furthermore, iNOS was necessary for ME to increase cell survival following OGD in vitro. We conclude that ME-induced reduction in cell death is abolished by E(2) in a sex-independent manner via activation of estrogen receptors, and this interaction is dependent on iNOS.
authors.affiliation: Dept. of Anesthesiology and Peri-Operative Medicine, Oregon Health and Science Univ., Portland, OR 97239-3098, USA. merkelm@ohsu.edu
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Merkel
authors.forename: Lijuan
authors.initials: L
authors.lastname: Liu
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Cao
authors.forename: William
authors.initials: W
authors.lastname: Packwood
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Hurn
authors.forename: Donna M
authors.initials: DM
authors.lastname: Van Winkle
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D019610:Cytoprotection; D004744:Enkephalin, Methionine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D005947:Glucose / Q000172:deficiency*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism*; D012737:Sex Factors
chemical_list: D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D017465:Receptors, Opioid, delta; D000077267:Fulvestrant; D004958:Estradiol; D004744:Enkephalin, Methionine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D005947:Glucose; D010100:Oxygen; D019331:NG-Nitroarginine Methyl Ester