ERβ Selective Agonist Inhibits Angiotensin-Induced Cardiovascular Pathology in Female Mice

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. Ot...

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Veröffentlicht in:Endocrinology (Philadelphia) 2013-11, Vol.154 (11), p.4352-4364
Hauptverfasser: Pedram, Ali, Razandi, Mahnaz, Korach, Kenneth S, Narayanan, Ramesh, Dalton, James T, Levin, Ellis R
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container_issue 11
container_start_page 4352
container_title Endocrinology (Philadelphia)
container_volume 154
creator Pedram, Ali
Razandi, Mahnaz
Korach, Kenneth S
Narayanan, Ramesh
Dalton, James T
Levin, Ellis R
description 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.
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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. 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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. 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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.</abstract><cop>Chevy Chase, MD</cop><pub>Endocrine Society</pub><pmid>23970786</pmid><doi>10.1210/en.2013-1358</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record>
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subjects 17β-Estradiol
Agonists
AKT protein
Angiotensin
Angiotensin II
Angiotensins - toxicity
Animals
Biological and medical sciences
Cardiomegaly - chemically induced
Cardiomegaly - prevention & control
Cardiovascular diseases
Cardiovascular pathology
Coronary artery disease
Estradiol - pharmacology
Estrogen Receptor beta - agonists
Estrogen receptors
Estrogens
Female
Females
Fibrosis
Fundamental and applied biological sciences. Psychology
Gene expression
Glycogen
Glycogen synthase kinase 3
Glycogens
Heart - drug effects
Heart diseases
Hypertension
Hypertrophy
Isoquinolines - pharmacology
Kinases
Malignancy
Mice
Myocardium - pathology
Ovariectomy
Pathology
Receptors
Renal-Cardiac-Vascular
RNA, Messenger - genetics
RNA, Messenger - metabolism
Sex hormones
Signal Transduction - drug effects
Signal Transduction - physiology
Stimulators
Transcription activation
Uterus
Vertebrates: endocrinology
title ERβ Selective Agonist Inhibits Angiotensin-Induced Cardiovascular Pathology in Female Mice
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