Estradiol treatment initiated early after ovariectomy regulates myocardial gene expression and inhibits diastolic dysfunction in female cynomolgus monkeys: Potential roles for calcium homeostasis and extracellular matrix remodeling

© 2018 The Authors. Background—Left ventricular (LV) diastolic dysfunction often precedes heart failure with preserved ejection fraction, the dominant form of heart failure in postmenopausal women. The objective of this study was to determine the effect of oral estradiol treatment initiated early af...

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Main Authors: Kristofer T. Michalson, Leanne Groban, Timothy D. Howard, Carol A. Shively, Areepan Sophonsritsuk, Susan E. Appt, J. Mark Cline, Thomas B. Clarkson, J. Jeffrey Carr, Dalane W. Kitzman, Thomas C. Register
Other Authors: Wake Forest University School of Medicine
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Published: 2019
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Online Access:https://repository.li.mahidol.ac.th/handle/123456789/46210
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spelling th-mahidol.462102019-08-23T18:37:44Z Estradiol treatment initiated early after ovariectomy regulates myocardial gene expression and inhibits diastolic dysfunction in female cynomolgus monkeys: Potential roles for calcium homeostasis and extracellular matrix remodeling Kristofer T. Michalson Leanne Groban Timothy D. Howard Carol A. Shively Areepan Sophonsritsuk Susan E. Appt J. Mark Cline Thomas B. Clarkson J. Jeffrey Carr Dalane W. Kitzman Thomas C. Register Wake Forest University School of Medicine Faculty of Medicine, Ramathibodi Hospital, Mahidol University Vanderbilt University School of Medicine Medicine © 2018 The Authors. Background—Left ventricular (LV) diastolic dysfunction often precedes heart failure with preserved ejection fraction, the dominant form of heart failure in postmenopausal women. The objective of this study was to determine the effect of oral estradiol treatment initiated early after ovariectomy on LV function and myocardial gene expression in female cynomolgus macaques. Methods and Results—Monkeys were ovariectomized and randomized to receive placebo (control) or oral estradiol at a humanequivalent dose of 1 mg/day for 8 months. Monkeys then underwent conventional and tissue Doppler imaging to assess cardiac function, followed by transcriptomic and histomorphometric analyses of LV myocardium. Age, body weight, blood pressure, and heart rate were similar between groups. Echocardiographic mitral early and late inflow velocities, mitral annular velocities, and mitral E deceleration slope were higher in estradiol monkeys (all P<0.05), despite similar estimated LV filling pressure. MCP1 (monocyte chemoattractant protein 1) and LV collagen staining were lower in estradiol animals (P<0.05). Microarray analysis revealed differential myocardial expression of 40 genes (>1.2-fold change; false discovery rate, P<0.05) in estradiol animals relative to controls, which implicated pathways associated with better calcium ion homeostasis and muscle contraction and lower extracellular matrix deposition (P<0.05). Conclusions—Estradiol treatment initiated soon after ovariectomy resulted in enhanced LV diastolic function, and altered myocardial gene expression towards decreased extracellular matrix deposition, improved myocardial contraction, and calcium homeostasis, suggesting that estradiol directly or indirectly modulates the myocardial transcriptome to preserve cardiovascular function. 2019-08-23T11:37:44Z 2019-08-23T11:37:44Z 2018-11-01 Article Journal of the American Heart Association. Vol.7, No.21 (2018) 10.1161/JAHA.118.009769 20479980 2-s2.0-85056833456 https://repository.li.mahidol.ac.th/handle/123456789/46210 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85056833456&origin=inward
institution Mahidol University
building Mahidol University Library
continent Asia
country Thailand
Thailand
content_provider Mahidol University Library
collection Mahidol University Institutional Repository
topic Medicine
spellingShingle Medicine
Kristofer T. Michalson
Leanne Groban
Timothy D. Howard
Carol A. Shively
Areepan Sophonsritsuk
Susan E. Appt
J. Mark Cline
Thomas B. Clarkson
J. Jeffrey Carr
Dalane W. Kitzman
Thomas C. Register
Estradiol treatment initiated early after ovariectomy regulates myocardial gene expression and inhibits diastolic dysfunction in female cynomolgus monkeys: Potential roles for calcium homeostasis and extracellular matrix remodeling
description © 2018 The Authors. Background—Left ventricular (LV) diastolic dysfunction often precedes heart failure with preserved ejection fraction, the dominant form of heart failure in postmenopausal women. The objective of this study was to determine the effect of oral estradiol treatment initiated early after ovariectomy on LV function and myocardial gene expression in female cynomolgus macaques. Methods and Results—Monkeys were ovariectomized and randomized to receive placebo (control) or oral estradiol at a humanequivalent dose of 1 mg/day for 8 months. Monkeys then underwent conventional and tissue Doppler imaging to assess cardiac function, followed by transcriptomic and histomorphometric analyses of LV myocardium. Age, body weight, blood pressure, and heart rate were similar between groups. Echocardiographic mitral early and late inflow velocities, mitral annular velocities, and mitral E deceleration slope were higher in estradiol monkeys (all P<0.05), despite similar estimated LV filling pressure. MCP1 (monocyte chemoattractant protein 1) and LV collagen staining were lower in estradiol animals (P<0.05). Microarray analysis revealed differential myocardial expression of 40 genes (>1.2-fold change; false discovery rate, P<0.05) in estradiol animals relative to controls, which implicated pathways associated with better calcium ion homeostasis and muscle contraction and lower extracellular matrix deposition (P<0.05). Conclusions—Estradiol treatment initiated soon after ovariectomy resulted in enhanced LV diastolic function, and altered myocardial gene expression towards decreased extracellular matrix deposition, improved myocardial contraction, and calcium homeostasis, suggesting that estradiol directly or indirectly modulates the myocardial transcriptome to preserve cardiovascular function.
author2 Wake Forest University School of Medicine
author_facet Wake Forest University School of Medicine
Kristofer T. Michalson
Leanne Groban
Timothy D. Howard
Carol A. Shively
Areepan Sophonsritsuk
Susan E. Appt
J. Mark Cline
Thomas B. Clarkson
J. Jeffrey Carr
Dalane W. Kitzman
Thomas C. Register
format Article
author Kristofer T. Michalson
Leanne Groban
Timothy D. Howard
Carol A. Shively
Areepan Sophonsritsuk
Susan E. Appt
J. Mark Cline
Thomas B. Clarkson
J. Jeffrey Carr
Dalane W. Kitzman
Thomas C. Register
author_sort Kristofer T. Michalson
title Estradiol treatment initiated early after ovariectomy regulates myocardial gene expression and inhibits diastolic dysfunction in female cynomolgus monkeys: Potential roles for calcium homeostasis and extracellular matrix remodeling
title_short Estradiol treatment initiated early after ovariectomy regulates myocardial gene expression and inhibits diastolic dysfunction in female cynomolgus monkeys: Potential roles for calcium homeostasis and extracellular matrix remodeling
title_full Estradiol treatment initiated early after ovariectomy regulates myocardial gene expression and inhibits diastolic dysfunction in female cynomolgus monkeys: Potential roles for calcium homeostasis and extracellular matrix remodeling
title_fullStr Estradiol treatment initiated early after ovariectomy regulates myocardial gene expression and inhibits diastolic dysfunction in female cynomolgus monkeys: Potential roles for calcium homeostasis and extracellular matrix remodeling
title_full_unstemmed Estradiol treatment initiated early after ovariectomy regulates myocardial gene expression and inhibits diastolic dysfunction in female cynomolgus monkeys: Potential roles for calcium homeostasis and extracellular matrix remodeling
title_sort estradiol treatment initiated early after ovariectomy regulates myocardial gene expression and inhibits diastolic dysfunction in female cynomolgus monkeys: potential roles for calcium homeostasis and extracellular matrix remodeling
publishDate 2019
url https://repository.li.mahidol.ac.th/handle/123456789/46210
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