title: Role of androgens in sex differences in cardiac damage during myocardial infarction.
abstract: Age-specific incidence of ischemic heart disease in men is higher than in women, although women die more frequently without previous symptoms; the molecular mechanism(s) are poorly understood. Most studies focus on protection by estrogen, with less attention on androgen receptor-mediated androgen actions. Our aim was to determine the role of androgens in the sex differences in cardiac damage during myocardial infarction. Mature age-matched male and female Sprague Dawley rats, intact or surgically gonadectomized (Gx), received testosterone (T) or 17β-estradiol (E2) via subdermal SILASTIC (Dow Corning Corp.) implants; a subset of male rats received dihydrotestosterone. After 21 days, animals were anesthetized, and hearts were excised and subjected to ex vivo regional ischemia-reperfusion (I-R). Hearts from intact males had larger infarcts than those from females following I-R; Gx produced the opposite effect, confirming a role for sex steroids. In Gx males, androgens (dihydrotestosterone, T) and E2 aggravated I-R-induced cardiac damage, whereas in Gx females, T had no effect and E2 reduced infarct area. Increased circulating T levels up-regulated androgen receptor and receptor for advanced glycation end products, which resulted in enhanced apoptosis aggravating cardiac damage in both males and females. In conclusion, our study demonstrates, for the first time, that sex steroids regulate autophagy during myocardial infarction and shows that a novel mechanism of action for androgens during I-R is down-regulation of antiapoptotic protein Bcl-xL (B cell lymphoma-extra large), a key controller for cross talk between autophagy and apoptosis, shifting the balance toward apoptosis and leading to aggravated cardiac damage.
authors.affiliation: Kolling Institute of Medical Research (T.Y.L.L., A.W.A., M.M., A.S.M.), Royal North Shore Hospital and The University of Sydney; Department of Cardiology (T.Y.L.L., M.M., A.S.M.), Royal North Shore Hospital; Division of Perinatal Research (A.W.A.), Royal North Shore Hospital; Department of Cardiology (M.M.), Westmead Hospital, Sydney, New South Wales, Australia; Prince Henry's Institute (P.G.S., J.W.F.), Clayton, Victoria, Australia; and Anzac Research Institute (D.J.H.), University of Sydney, Sydney, Australia.
authors.forename: Thi Y L
authors.initials: TY
authors.lastname: Le
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Ashton
authors.forename: Mahidi
authors.initials: M
authors.lastname: Mardini
authors.forename: Peter G
authors.initials: PG
authors.lastname: Stanton
authors.forename: John W
authors.initials: JW
authors.lastname: Funder
authors.forename: David J
authors.initials: DJ
authors.lastname: Handelsman
authors.forename: Anastasia S
authors.initials: AS
authors.lastname: Mihailidou
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D013196:Dihydrotestosterone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D012727:Sex Characteristics; D013739:Testosterone / Q000494:pharmacology
chemical_list: D000728:Androgens; D004967:Estrogens; D013196:Dihydrotestosterone; D013739:Testosterone; D004958:Estradiol