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 |
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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. 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.</description><identifier>ISSN: 0013-7227</identifier><identifier>EISSN: 1945-7170</identifier><identifier>DOI: 10.1210/en.2013-1358</identifier><identifier>PMID: 23970786</identifier><identifier>CODEN: ENDOAO</identifier><language>eng</language><publisher>Chevy Chase, MD: Endocrine Society</publisher><subject>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</subject><ispartof>Endocrinology (Philadelphia), 2013-11, Vol.154 (11), p.4352-4364</ispartof><rights>Copyright © 2013 by The Endocrine Society</rights><rights>Copyright © 2013 by The Endocrine Society 2013</rights><rights>2014 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c518t-740e1ceaa69da1a13cbf2582f8a015129cd60de64e5b786ad867d5c1bdb755d63</citedby><cites>FETCH-LOGICAL-c518t-740e1ceaa69da1a13cbf2582f8a015129cd60de64e5b786ad867d5c1bdb755d63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27914713$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23970786$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pedram, Ali</creatorcontrib><creatorcontrib>Razandi, Mahnaz</creatorcontrib><creatorcontrib>Korach, Kenneth S</creatorcontrib><creatorcontrib>Narayanan, Ramesh</creatorcontrib><creatorcontrib>Dalton, James T</creatorcontrib><creatorcontrib>Levin, Ellis R</creatorcontrib><title>ERβ Selective Agonist Inhibits Angiotensin-Induced Cardiovascular Pathology in Female Mice</title><title>Endocrinology (Philadelphia)</title><addtitle>Endocrinology</addtitle><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.</description><subject>17β-Estradiol</subject><subject>Agonists</subject><subject>AKT protein</subject><subject>Angiotensin</subject><subject>Angiotensin II</subject><subject>Angiotensins - toxicity</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cardiomegaly - chemically induced</subject><subject>Cardiomegaly - prevention & control</subject><subject>Cardiovascular diseases</subject><subject>Cardiovascular pathology</subject><subject>Coronary artery disease</subject><subject>Estradiol - pharmacology</subject><subject>Estrogen Receptor beta - agonists</subject><subject>Estrogen receptors</subject><subject>Estrogens</subject><subject>Female</subject><subject>Females</subject><subject>Fibrosis</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene expression</subject><subject>Glycogen</subject><subject>Glycogen synthase kinase 3</subject><subject>Glycogens</subject><subject>Heart - drug effects</subject><subject>Heart diseases</subject><subject>Hypertension</subject><subject>Hypertrophy</subject><subject>Isoquinolines - pharmacology</subject><subject>Kinases</subject><subject>Malignancy</subject><subject>Mice</subject><subject>Myocardium - pathology</subject><subject>Ovariectomy</subject><subject>Pathology</subject><subject>Receptors</subject><subject>Renal-Cardiac-Vascular</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Sex hormones</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><subject>Stimulators</subject><subject>Transcription activation</subject><subject>Uterus</subject><subject>Vertebrates: endocrinology</subject><issn>0013-7227</issn><issn>1945-7170</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc2KFDEUhYMoTju6cy0FIm6sMTepVKo2QtPMaMOI4s_KRUglt7ozVCdtUtUwr-WDzDNNmm5nFHQRQpKPc07uIeQ50DNgQN-iP2MUeAlcNA_IDNpKlBIkfUhmdH8vGZMn5ElKV_lYVRV_TE4YbyWVTT0jP86_3PwqvuKAZnQ7LOar4F0ai6Vfu86NqZj7lQsj-uR8ufR2MmiLhY7WhZ1OZhp0LD7rcR2GsLounC8ucKMHLD46g0_Jo14PCZ8d91Py_eL82-JDefnp_XIxvyyNgGYsZUURDGpdt1aDBm66nomG9Y2mIIC1xtbUYl2h6HJmbZtaWmGgs50Uwtb8lLw76G6nboPWoB-jHtQ2uo2O1ypop_5-8W6tVmGnBG8b0bIs8PIoEMPPCdOorsIUfc6sOHBasyavTL05UCaGlCL2dw5A1b4KhV7tq1D7KjL-4s9Ud_Dv2Wfg1RHIg9RDH7U3Lt1zsoVKAs_c6wMXpu3_LMujJT-Q6G0w0XncRkzp_jf_DHoLagywUQ</recordid><startdate>20131101</startdate><enddate>20131101</enddate><creator>Pedram, Ali</creator><creator>Razandi, Mahnaz</creator><creator>Korach, Kenneth S</creator><creator>Narayanan, Ramesh</creator><creator>Dalton, James T</creator><creator>Levin, Ellis R</creator><general>Endocrine Society</general><general>Oxford University Press</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20131101</creationdate><title>ERβ Selective Agonist Inhibits Angiotensin-Induced Cardiovascular Pathology in Female Mice</title><author>Pedram, Ali ; Razandi, Mahnaz ; Korach, Kenneth S ; Narayanan, Ramesh ; Dalton, James T ; Levin, Ellis R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c518t-740e1ceaa69da1a13cbf2582f8a015129cd60de64e5b786ad867d5c1bdb755d63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>17β-Estradiol</topic><topic>Agonists</topic><topic>AKT protein</topic><topic>Angiotensin</topic><topic>Angiotensin II</topic><topic>Angiotensins - toxicity</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cardiomegaly - chemically induced</topic><topic>Cardiomegaly - prevention & control</topic><topic>Cardiovascular diseases</topic><topic>Cardiovascular pathology</topic><topic>Coronary artery disease</topic><topic>Estradiol - pharmacology</topic><topic>Estrogen Receptor beta - agonists</topic><topic>Estrogen receptors</topic><topic>Estrogens</topic><topic>Female</topic><topic>Females</topic><topic>Fibrosis</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene expression</topic><topic>Glycogen</topic><topic>Glycogen synthase kinase 3</topic><topic>Glycogens</topic><topic>Heart - drug effects</topic><topic>Heart diseases</topic><topic>Hypertension</topic><topic>Hypertrophy</topic><topic>Isoquinolines - pharmacology</topic><topic>Kinases</topic><topic>Malignancy</topic><topic>Mice</topic><topic>Myocardium - pathology</topic><topic>Ovariectomy</topic><topic>Pathology</topic><topic>Receptors</topic><topic>Renal-Cardiac-Vascular</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Sex hormones</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - physiology</topic><topic>Stimulators</topic><topic>Transcription activation</topic><topic>Uterus</topic><topic>Vertebrates: endocrinology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pedram, Ali</creatorcontrib><creatorcontrib>Razandi, Mahnaz</creatorcontrib><creatorcontrib>Korach, Kenneth S</creatorcontrib><creatorcontrib>Narayanan, Ramesh</creatorcontrib><creatorcontrib>Dalton, James T</creatorcontrib><creatorcontrib>Levin, Ellis R</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Endocrinology (Philadelphia)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pedram, Ali</au><au>Razandi, Mahnaz</au><au>Korach, Kenneth S</au><au>Narayanan, Ramesh</au><au>Dalton, James T</au><au>Levin, Ellis R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ERβ Selective Agonist Inhibits Angiotensin-Induced Cardiovascular Pathology in Female Mice</atitle><jtitle>Endocrinology (Philadelphia)</jtitle><addtitle>Endocrinology</addtitle><date>2013-11-01</date><risdate>2013</risdate><volume>154</volume><issue>11</issue><spage>4352</spage><epage>4364</epage><pages>4352-4364</pages><issn>0013-7227</issn><eissn>1945-7170</eissn><coden>ENDOAO</coden><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.</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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source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection; Journals@Ovid Complete |
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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