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
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 L...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2018-11-01
|
| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.118.009769 |
| _version_ | 1818312251203911680 |
|---|---|
| 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_facet | 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 |
| collection | DOAJ |
| description | 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 human‐equivalent 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. |
| first_indexed | 2024-12-13T08:14:53Z |
| format | Article |
| id | doaj.art-4a1ba9d5740344c885ebb677183efc56 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-13T08:14:53Z |
| publishDate | 2018-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-4a1ba9d5740344c885ebb677183efc562022-12-21T23:54:08ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802018-11-0172110.1161/JAHA.118.009769Estradiol 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 RemodelingKristofer T. Michalson0Leanne Groban1Timothy D. Howard2Carol A. Shively3Areepan Sophonsritsuk4Susan E. Appt5J. Mark Cline6Thomas B. Clarkson7J. Jeffrey Carr8Dalane W. Kitzman9Thomas C. Register10Section on Comparative Medicine Department of Pathology Wake Forest University School of Medicine Winston‐Salem NCDepartment of Anesthesiology Wake Forest University School of Medicine Winston‐Salem NCDepartment of Biochemistry Wake Forest University School of Medicine Winston‐Salem NCSection on Comparative Medicine Department of Pathology Wake Forest University School of Medicine Winston‐Salem NCSection on Comparative Medicine Department of Pathology Wake Forest University School of Medicine Winston‐Salem NCSection on Comparative Medicine Department of Pathology Wake Forest University School of Medicine Winston‐Salem NCSection on Comparative Medicine Department of Pathology Wake Forest University School of Medicine Winston‐Salem NCSection on Comparative Medicine Department of Pathology Wake Forest University School of Medicine Winston‐Salem NCDepartment of Radiology Vanderbilt University School of Medicine Nashville TNSection on Cardiology Department of Internal Medicine Wake Forest University School of Medicine Winston‐Salem NCSection on Comparative Medicine Department of Pathology Wake Forest University School of Medicine Winston‐Salem NCBackground 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 human‐equivalent 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.https://www.ahajournals.org/doi/10.1161/JAHA.118.009769diastolic dysfunctionestrogenfibrosismenopausetranscriptome |
| spellingShingle | 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 Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease diastolic dysfunction estrogen fibrosis menopause transcriptome |
| 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_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_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_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 |
| topic | diastolic dysfunction estrogen fibrosis menopause transcriptome |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.118.009769 |
| work_keys_str_mv | AT kristofertmichalson estradioltreatmentinitiatedearlyafterovariectomyregulatesmyocardialgeneexpressionandinhibitsdiastolicdysfunctioninfemalecynomolgusmonkeyspotentialrolesforcalciumhomeostasisandextracellularmatrixremodeling AT leannegroban estradioltreatmentinitiatedearlyafterovariectomyregulatesmyocardialgeneexpressionandinhibitsdiastolicdysfunctioninfemalecynomolgusmonkeyspotentialrolesforcalciumhomeostasisandextracellularmatrixremodeling AT timothydhoward estradioltreatmentinitiatedearlyafterovariectomyregulatesmyocardialgeneexpressionandinhibitsdiastolicdysfunctioninfemalecynomolgusmonkeyspotentialrolesforcalciumhomeostasisandextracellularmatrixremodeling AT carolashively estradioltreatmentinitiatedearlyafterovariectomyregulatesmyocardialgeneexpressionandinhibitsdiastolicdysfunctioninfemalecynomolgusmonkeyspotentialrolesforcalciumhomeostasisandextracellularmatrixremodeling AT areepansophonsritsuk estradioltreatmentinitiatedearlyafterovariectomyregulatesmyocardialgeneexpressionandinhibitsdiastolicdysfunctioninfemalecynomolgusmonkeyspotentialrolesforcalciumhomeostasisandextracellularmatrixremodeling AT susaneappt estradioltreatmentinitiatedearlyafterovariectomyregulatesmyocardialgeneexpressionandinhibitsdiastolicdysfunctioninfemalecynomolgusmonkeyspotentialrolesforcalciumhomeostasisandextracellularmatrixremodeling AT jmarkcline estradioltreatmentinitiatedearlyafterovariectomyregulatesmyocardialgeneexpressionandinhibitsdiastolicdysfunctioninfemalecynomolgusmonkeyspotentialrolesforcalciumhomeostasisandextracellularmatrixremodeling AT thomasbclarkson estradioltreatmentinitiatedearlyafterovariectomyregulatesmyocardialgeneexpressionandinhibitsdiastolicdysfunctioninfemalecynomolgusmonkeyspotentialrolesforcalciumhomeostasisandextracellularmatrixremodeling AT jjeffreycarr estradioltreatmentinitiatedearlyafterovariectomyregulatesmyocardialgeneexpressionandinhibitsdiastolicdysfunctioninfemalecynomolgusmonkeyspotentialrolesforcalciumhomeostasisandextracellularmatrixremodeling AT dalanewkitzman estradioltreatmentinitiatedearlyafterovariectomyregulatesmyocardialgeneexpressionandinhibitsdiastolicdysfunctioninfemalecynomolgusmonkeyspotentialrolesforcalciumhomeostasisandextracellularmatrixremodeling AT thomascregister estradioltreatmentinitiatedearlyafterovariectomyregulatesmyocardialgeneexpressionandinhibitsdiastolicdysfunctioninfemalecynomolgusmonkeyspotentialrolesforcalciumhomeostasisandextracellularmatrixremodeling |