title: ERβ selective agonist inhibits angiotensin-induced cardiovascular pathology in female mice.
abstract: Cardiac hypertrophy in humans can progress to cardiac failure if the underlying impetus is poorly controlled. An important direct stimulator of hypertrophy and its progression is the angiotensin II (AngII) peptide. AngII also causes hypertension that indirectly contributes to cardiac hypertrophy. Others and we have shown that estrogens acting through the estrogen receptor (ER)-β can inhibit AngII-induced or other forms of cardiac hypertrophy in mice. However, the proliferative effects of estrogen in breast and uterus that promote the development of malignancy preclude using the steroid to prevent cardiac disease progression. We therefore tested whether an ERβ selective agonist, β-LGND2, can prevent hypertension and cardiac pathology in female mice. AngII infusion over 3 weeks significantly stimulated systolic and diastolic hypertension, cardiac hypertrophy, and cardiac fibrosis, all significantly prevented by β-LGND2 in wild-type but not in ERβ genetically deleted mice. AngII stimulated the Akt kinase to phosphorylate and inhibit the glycogen synthase kinase-3β kinase, leading to GATA4 transcription factor activation and hypertrophic mRNA expression. As a novel mechanism, all these actions were opposed by estradiol and β-LGND2. Our findings provide additional understanding of the antihypertrophic effects of ERβ and serve as an impetus to test specific receptor agonists in humans to prevent the worsening of cardiovascular disease.
authors: MD, Medical Service (111-I), Long Beach Veterans Affairs Medical Center, 5901 East Seventh Street, Long Beach, California 90822. ellis.levin@va.gov.
authors: Ali
authors: A
authors: Pedram
authors: Mahnaz
authors: M
authors: Razandi
authors: Kenneth S
authors: KS
authors: Korach
authors: Ramesh
authors: R
authors: Narayanan
authors: James T
authors: JT
authors: Dalton
authors: Ellis R
authors: ER
authors: Levin
mesh_terms: D000809:Angiotensins / Q000633:toxicity*; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced* / Q000517:prevention & control; D004958:Estradiol / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000819:agonists*; D005260:Female; D006321:Heart / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D009206:Myocardium / Q000473:pathology; D010052:Ovariectomy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000809:Angiotensins; D047629:Estrogen Receptor beta; D007546:Isoquinolines; D012333:RNA, Messenger; C585485:beta-LGND2; D004958:Estradiol
references: J Hypertens. 2001 Feb;19(2):269-78
references: 11212970
references: Nat Rev Cardiol. 2012 Mar 20;9(5):276-85
references: 22430830
references: Nucl Recept Signal. 2006;4:e013
references: 16862219
references: J Biol Chem. 2001 Jul 27;276(30):28586-97
references: 11382772
references: Circulation. 2007 Jun 26;115(25):3197-204
references: 17562954
references: J Appl Physiol (1985). 2012 Jul;113(1):149-58
references: 22628376
references: Nature. 1979 Nov 1;282(5734):105-7
references: 91973
references: Am J Physiol Heart Circ Physiol. 2002 Jan;282(1):H58-65
references: 11748047
references: Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4586-91
references: 11904392
references: J Am Soc Nephrol. 2002 Dec;13(12):2860-8
references: 12444204
references: J Biol Chem. 2005 May 20;280(20):19704-10
references: 15764600
references: Cell. 1998 Apr 17;93(2):215-28
references: 9568714
references: N Engl J Med. 1998 Jul 30;339(5):321-8
references: 9682046
references: Circ Res. 2003 May 30;92(10):1079-88
references: 12775656
references: Hypertens Res. 2002 Mar;25(2):153-9
references: 12047028
references: Mol Cell Biol. 1999 Jun;19(6):4355-65
references: 10330176
references: J Biol Chem. 2010 Oct 8;285(41):31292-303
references: 20657011
references: Int J Vasc Med. 2012;2012:246058
references: 22848833
references: Am J Hypertens. 1999 Apr;12(4 Pt 1):418-22
references: 10232503
references: Endocrinology. 2008 Jul;149(7):3361-9
references: 18372323
references: Circ Res. 2002 Dec 13;91(12):1103-13
references: 12480810
references: Hypertension. 2003 Dec;42(6):1177-82
references: 14581297
references: Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3328-33
references: 11248078
references: Circulation. 2012 Aug 28;126(9):1016-9
references: 22859685
references: J Biol Chem. 2003 Sep 26;278(39):36981-4
references: 12881512
references: Nat Med. 2007 Mar;13(3):324-31
references: 17322895
references: Nature. 2002 Mar 21;416(6878):334-8
references: 11907581
references: Circ Res. 2002 Nov 1;91(9):821-9
references: 12411397
references: Am J Cardiol. 1999 Apr 1;83(7):1132-4, A9
references: 10190535
references: Cardiovasc Res. 2008 Mar 1;77(4):774-81
references: 18056768
references: Anal Chem. 1970 Jun;42(7):702-6
references: 5431521
references: Mol Endocrinol. 2008 Nov;22(11):2448-65
references: 18801930
references: J Biol Chem. 2002 Aug 16;277(33):30401-7
references: 12063245
references: J Am Coll Cardiol. 2003 Oct 1;42(7):1238-45
references: 14522488
references: Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):907-12
references: 11782539
references: Crit Rev Oncol Hematol. 2004 Apr;50(1):3-22
references: 15094156
references: Science. 2002 Jan 18;295(5554):505-8
references: 11799247
references: J Am Coll Cardiol. 2000 Aug;36(2):529-33
references: 10933368
references: J Investig Med. 2007 Nov;55(7):341-59
references: 18062896
references: Am J Physiol Heart Circ Physiol. 2003 May;284(5):H1560-9
references: 12560213
references: Circ Res. 2006 Apr 28;98(8):988-9
references: 16645147
references: Arterioscler Thromb Vasc Biol. 2000 Feb;20(2):428-34
references: 10669640
references: Mol Endocrinol. 2010 Nov;24(11):2152-65
references: 20810711
references: Nat Rev Cancer. 2006 May;6(5):360-8
references: 16633364
references: Circulation. 2001 Nov 6;104(19):2300-4
references: 11696469
references: J Biol Chem. 2001 Jun 22;276(25):22011-5
references: 11274189
references: Int J Biochem Cell Biol. 1999 Mar-Apr;31(3-4):395-403
references: 10224666
references: Med Clin North Am. 2004 Jan;88(1):83-97
references: 14871052
references: J Clin Invest. 2007 Mar;117(3):568-75
references: 17332884
references: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15677-82
references: 9861029
references: Clin Exp Pharmacol Physiol. 2004 Nov;31(11):791-4
references: 15566395
references: J Biol Chem. 2005 Jul 15;280(28):26339-48
references: 15899894
references: Mol Cell Biol. 2002 Nov;22(21):7603-13
references: 12370307