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

Autor: Thomas C. Register, J. Mark Cline, Areepan Sophonsritsuk, Leanne Groban, Susan E. Appt, Kristofer T. Michalson, J. Jeffrey Carr, Carol A. Shively, Thomas B. Clarkson, Dalane W. Kitzman, Timothy D. Howard
Rok vydání: 2018
Předmět:
0301 basic medicine
Cardiac function curve
medicine.medical_specialty
Time Factors
medicine.drug_class
Ovariectomy
Diastole
menopause
Gene Expression
030204 cardiovascular system & hematology
Random Allocation
03 medical and health sciences
0302 clinical medicine
Internal medicine
estrogen
Animals
Homeostasis
Medicine
Postoperative Period
Original Research
Heart Failure
Calcium metabolism
Gene Expression & Regulation
Estradiol
business.industry
Myocardium
fibrosis
Heart
medicine.disease
Extracellular Matrix
Macaca fascicularis
030104 developmental biology
Endocrinology
Blood pressure
Animal Models of Human Disease
Echocardiography
Estrogen
Heart failure
Calcium ion homeostasis
diastolic dysfunction
Calcium
Female
Cardiology and Cardiovascular Medicine
Heart failure with preserved ejection fraction
business
transcriptome
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
DOI: 10.1161/jaha.118.009769
Popis: 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 LV filling pressure. MCP1 (monocyte chemoattractant protein 1) and LV collagen staining were lower in estradiol animals ( P 1.2‐fold change; false discovery rate, P P 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.
Databáze: OpenAIRE
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