EXPERIMENTAL STUDY
Low concentrations of 17ß-estradiol protect single cardiac cells against metabolic stress-induced Ca2+ loading
Sofija Jovanovi , DVM, PhD*  ,
Aleksandar Jovanovi, MD, PhD* ,
Win K. Shen, MD, FACC* and
Andre Terzic, MD, PhD*
* Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Mayo Foundation, Rochester, Minnesota, USA
Tayside Institute of Child Health, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom
Manuscript received October 8, 1999;
revised manuscript received March 15, 2000,
accepted April 26, 2000.
Reprint requests and correspondence: Dr. Aleksandar Jovanovi, Tayside Institute of Child Health, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, United Kingdom
OBJECTIVES
The main objective of the present study was to determine whether low physiological levels of estrogen directly protect cardiac cells against metabolic stress.
BACKGROUND
The beneficial effect of estrogens on the cardiovascular system has been traditionally ascribed to decrease in peripheral vascular resistance and to an antiatherogenic action. Whether physiological concentrations of 17ß-estradiol (E2) are also able to protect cardiomyocytes against metabolic insult directly is unknown.
METHODS
Isolated ventricular cardiomyocytes were loaded with the Ca2+-sensitive fluorescent dye Fluo-3 and imaged by a digital epifluorescence imaging system. In cardiac cells preincubated with hormones and/or drugs for 8 h, metabolic stress was induced by addition and removal of 2,4-dinitrophenol (DNP).
RESULTS
In cardiomyocytes, a 3-min-long exposure to chemical hypoxia, followed by reoxygenation, produced intracellular Ca2+ loading independently of gender (female: 729 ± 88 nmol/liter; male: 778 ± 97 nmol/liter). Pretreatment with E2 (10 nmol/liter) significantly reduced the magnitude of hypoxia/reoxygenation-induced Ca2+ loading in female (E2-treated: 298 ± 39 nmol/liter; untreated: 729 ± 88 nmol/liter), but not in male (E2-treated: 1029 ± 177 nmol/liter; untreated: 778 ± 97 nmol/liter) cardiac cells. The protective action of E2 was not mimicked by the inactive estrogen stereoisomer, 10 nmol/liter 17 estradiol (17 estradiol-treated: 886 ± 122 nmol/liter; untreated: 729 ± 88 nmol/liter), and was abolished by tamoxifen (1 µmol/liter), which acts as an antagonist of E2 on estrogen receptors (E2 plus tamoxifen-treated: 702 ± 98 nmol/liter; untreated: 729 ± 88 nmol/liter).
CONCLUSIONS
In a gender-dependent manner, E2 directly protects cardiac cells against hypoxia-reoxygenation injury through an estrogen receptor–mediated mechanism. Such property of E2 may contribute to cardioprotection in the female gender.
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Abbreviations and Acronyms
| | DNP | = 2,4-dinitrophenol | | E2 | = 17ß-estradiol | | Fluo-3AM | = Fluo-3 acethoxymethyl ester |
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