Estrogen inhibits cardiac hypertrophy: role of estrogen receptor-beta to inhibit calcineurin.
Estrogen has been reported to prevent development of cardiac hypertrophy in female rodent models and in humans. However, the mechanisms of sex steroid action are incompletely understood. We determined the cellular effects by which 17beta-estradiol (E2) inhibits angiotensin II (AngII)-induced cardiac hypertrophy in vivo. Two weeks of angiotensin infusion in female mice resulted in marked hypertrophy of the left ventricle, exacerbated by the loss of ovarian steroid hormones from oophorectomy. Hypertrophy was 51% reversed by the administration of E2 (insertion of 0.1 mg/21-d-release tablets). The effects of E2 were mainly mediated by the estrogen receptor (ER) beta-isoform, because E2 had little effect in ERbeta-null mice but comparably inhibited AngII-induced hypertrophy in wild-type or ERalpha-null mice. AngII induced a switch of myosin heavy chain production from alpha to beta, but this was inhibited by E2 via ERbeta. AngII-induced ERK activation was also inhibited by E2 through the beta-receptor. E2 stimulated brain natriuretic peptide protein expression and substantially prevented ventricular interstitial cardiac fibrosis (collagen deposition) as induced by AngII. Importantly, E2 inhibited calcineurin activity that was stimulated by AngII, related to E2 stimulating the modulatory calcineurin-interacting protein (MCIP) 1 gene and protein expression. E2 acting mainly through ERbeta mitigates the important signaling by AngII that produces cardiac hypertrophy and fibrosis in female mice.
Pedram
Ali
A
Department of Medicine, Veterans Affairs Medical Center, Long Beach, CA 90822, USA.
Razandi
Mahnaz
M
Lubahn
Dennis
D
Liu
Jinghua
J
Vannan
Mani
M
Levin
Ellis R
ER
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D006332:Cardiomegaly / Q000139:chemically induced / Q000188:drug therapy*; D003094:Collagen / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005355:Fibrosis; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D010052:Ovariectomy
D002135:Calcium-Binding Proteins; C511512:DSCR1 protein, mouse; D047629:Estrogen Receptor beta; D004967:Estrogens; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D000804:Angiotensin II; D004958:Estradiol; D003094:Collagen; D019703:Calcineurin; D018995:Myosin Heavy Chains