Pharmacology, University of South Alabama
University of Texas, Southwestern
Department of Pharmacology
Ischemic heart disease is the leading cause of mortality in men and postmenopausal women. Premenopausal women are protected from this injury, suggesting that estrogen protects the heart. A protective effect of estrogen in the heart has been reported in human observational studies, and our preliminary data in male rats along with many other animal studies have also shown that estrogen protects the heart from ischemia/reperfusion injury. By contrast, clinical trials do not show a significant cardiovascular benefit of hormone replacement therapy (HRT). A difference in the time of HRT initiation may explain the discrepant results. Further analysis of clinical trials showed that HRT reduces cardiovascular events in young postmenopausal women, but has no effect in older women. The underlying mechanism by which the time of HRT is critical for cardioprotection is not known. Given the fact that mortality is a more likely result of cardiovascular events in postmenopausal women than in men, elucidation of the underlying mechanism by which HRT fails to protect older postmenopausal women is essential. Estrogen is thought to exert its cardioprotective effects via estrogen receptors (ERs) which are located in the cytosol, nucleus, mitochondria, and membrane caveolae. The expression of ERs is regulated by estrogen with the type of regulation dependent upon the tissue. The signaling pathways implicated in estrogen action in the heart include p38 MAPK, ERKs, JNKs, PI-3 kinase, and nitric oxide.
However, the exact signaling mechanism by which estrogen exerts its cardioprotective effect is not clear. Delineation of the signaling mechanism mediating the cardioprotective actions of estrogen may ultimately lead to novel pharmacological interventions that reduce the number and severity of myocardial ischemia/reperfusion events in postmenopausal women. Our long term goal is to develop a strategy to lower cardiovascular event-related mortality in post-menopausal women. The objective for this project is to determine the role of compartmentalized ER? signaling in estrogen cardioprotection. Based on our preliminary studies, we propose the central hypothesis that estrogen protects the heart from ischemia/reperfusion injury through compartmentalized ER?-mediated p38 MAPK signaling. We and others have shown that the cardioprotective actions of estrogen occur via the estrogen receptor ? (ER?) subtype. We have further shown that expression of this receptor is significantly reduced in specific subcellular compartments in ovariectomized (OVX) female rats, an effect that is reversed in some but not all compartments by 72 hours estrogen replacement. Acute administration of estrogen or an ER? agonist fails to protect the OVX rats from ischemia/reperfusion injury.
These preliminary results suggest that diminished ER? expression may lead to estrogen insensitivity in the OVX rats and may explain the lack of cardiovascular benefit of HRT in older postmenopausal women. We have also shown that estrogen decreases p38 MAPK activation in membrane and mitochondrial fractions and increases the levels of the phosphatase MKP-1. Since overexpression of MKP-1 has been shown to protect the heart from ischemic injury, the cardioprotective effects of estrogen may be mediated by increased MKP-1 expression and a reduction in p38 MAPK activity. Completion of this study will provide the basis for the development of therapeutic strategies to overcome ER? down-regulation and may limit gender-related cardiovascular deaths.