title: Aging reduces the efficacy of estrogen substitution to attenuate cardiac hypertrophy in female spontaneously hypertensive rats.
abstract: Clinical trials failed to show a beneficial effect of postmenopausal hormone replacement therapy, whereas experimental studies in young animals reported a protective function of estrogen replacement in cardiovascular disease. Because these diverging results could in part be explained by aging effects, we compared the efficacy of estrogen substitution to modulate cardiac hypertrophy and cardiac gene expression among young (age 3 months) and senescent (age 24 months) spontaneously hypertensive rats (SHRs), which were sham operated or ovariectomized and injected with placebo or identical doses of 17beta-estradiol (E2; 2 microg/kg body weight per day) for 6 weeks (n=10/group). Blood pressure was comparable among sham-operated senescent and young SHRs and not altered by ovariectomy or E2 treatment among young or among senescent rats. Estrogen substitution inhibited uterus atrophy and gain of body weight in young and senescent ovariectomized SHRs, but cardiac hypertrophy was attenuated only in young rats. Cardiac estrogen receptor-alpha expression was lower in intact and in ovariectomized senescent compared with young SHRs and increased with estradiol substitution in aged rats. Plasma estradiol and estrone levels were lower not only in sham-operated but surprisingly also in E2-substituted senescent SHRs and associated with a reduction of hepatic 17beta-hydroxysteroid dehydrogenase type 1 enzyme activity, which converts weak (ie, estrone) into potent estrogens, such as E2. Aging attenuates the antihypertrophic effect of estradiol in female SHRs and is associated with profound alterations in cardiac estrogen receptor-alpha expression and estradiol metabolism. These observations contribute to explain the lower efficiency of estrogen substitution in senescent SHRs.
authors.affiliation: Department of Medicine, University of Würzburg, Würzburg, Germany.
authors.forename: Virginija
authors.initials: V
authors.lastname: Jazbutyte
authors.forename: Kai
authors.initials: K
authors.lastname: Hu
authors.forename: Patricia
authors.initials: P
authors.lastname: Kruchten
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bey
authors.forename: Sebastian K G
authors.initials: SK
authors.lastname: Maier
authors.forename: Karl-Heinrich
authors.initials: KH
authors.lastname: Fritzemeier
authors.forename: Katja
authors.initials: K
authors.lastname: Prelle
authors.forename: Christa
authors.initials: C
authors.lastname: Hegele-Hartung
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: Ludwig
authors.initials: L
authors.lastname: Neyses
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
authors.forename: Theo
authors.initials: T
authors.lastname: Pelzer
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000375:Aging; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000209:etiology* / Q000473:pathology*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D012739:Gonadal Steroid Hormones / Q000097:blood; D006439:Hemodynamics; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D007527:Isoenzymes / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D013686:Telemetry
chemical_list: D012739:Gonadal Steroid Hormones; D007527:Isoenzymes; D009124:Muscle Proteins; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; D018995:Myosin Heavy Chains