Ischemic cardiovascular disease, specifically myocardial infarction (MI), is the leading cause of morbidity and mortality in Western society. There are clear gender-based differences in cardiac function and electrophysiology that influence the two major sequelae following MI: heart failure (NF), and susceptibility to arrhythmias. In women, MI is uncommon prior to menopause and postmenopausal estrogen replacement therapy decreases its incidence. These beneficial effects of estrogen have been attributed previously to indirect effects on classic risk factors. However, estrogen is now recognized to have direct effects on cardiovascular cells that are central to its beneficial effects on cardiovascular disease. Estrogen's effects are mediated by receptors that act as ligand-activated transcription factors. Two such receptors are currently known, ERALPHA, and the recently discovered ERbeta. We have developed and reported a series of novel murine models that provide unique tools for pursuing mechanistic questions related to the pathophysiology of cardiovascular diseases. These include a mouse model of MI and a mouse cardiac electrophysiology (EP) model. We now present preliminary data from murine models demonstrating: (a) gender- based differences in cardiac electrophysiology, susceptibility to ventricular arrhythmias, and post-MI cardiac remodeling; (b) alteration in cardiac performance and electrophysiology in ERalpha (ERalphaKO) and ERbeta (ERbetaKO) knockout mice; (c) expression of both ERalpha and ERbeta and (d) ER-dependent effects on gene expression in cardiomyocytes. Taken together, these data identify the heart as a novel target organ for the direct effects of estrogen and form the basis for this Project's central hypothesis: Estrogen receptors regulate left ventricular remodeling and susceptibility to arrhythmias following myocardial infarction. We propose to test this hypothesis by pursuing two specific aims:
Specific Aim 1 : Investigation of the role of estrogen receptors an the effect of estrogen receptor modulators, including the SERM raloxifene, on left ventricular remodeling following myocardial infarction, using wild-type, ERalphaKO and ERbetaKO mice, and Specific Aim 2: Investigation of the role of estrogen receptors and the effect of estrogen receptor modulators on arrhythmias following myocardial infarction, using wild-type, ERalphaKO and ERbetaKO mice. These in vivo studies explore the molecular pathways that mediate gender-based and hormonal influences on cardiac remodeling and arrhythmias following MI. In addition, they provide a conceptual bridge from the genetic and clinical studies (Projects 1 and 2) to the other basic science projects (Projects 4 and 4) of this SCOR in ischemic heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL063494-04
Application #
6719853
Study Section
Special Emphasis Panel (ZHL1)
Project Start
2003-02-01
Project End
2005-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
4
Fiscal Year
2003
Total Cost
$260,975
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111
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Demissie, Serkalem; Cupples, L Adrienne; Shearman, Amanda M et al. (2006) Estrogen receptor-alpha variants are associated with lipoprotein size distribution and particle levels in women: the Framingham Heart Study. Atherosclerosis 185:210-8
Yang, Qiong; Lai, Chao-Qiang; Parnell, Laurence et al. (2005) Genome-wide linkage analyses and candidate gene fine mapping for HDL3 cholesterol: the Framingham Study. J Lipid Res 46:1416-25
Peter, Inga; Shearman, Amanda M; Zucker, Deborah R et al. (2005) Variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in the Framingham Heart Study. J Hypertens 23:2193-200
Shearman, Amanda M; Demissie, Serkalem; Cupples, L Adrienne et al. (2005) Tobacco smoking, estrogen receptor alpha gene variation and small low density lipoprotein level. Hum Mol Genet 14:2405-13
Peter, Inga; Shearman, Amanda M; Vasan, Ramachandran S et al. (2005) Association of estrogen receptor beta gene polymorphisms with left ventricular mass and wall thickness in women. Am J Hypertens 18:1388-95
Jaffe, Iris Z; Mendelsohn, Michael E (2005) Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res 96:643-50
Mendelsohn, Michael E; Karas, Richard H (2005) Molecular and cellular basis of cardiovascular gender differences. Science 308:1583-7
Georgescu, Serban P; Li, Joyce H; Lu, Qing et al. (2005) Modulator recognition factor 1, an AT-rich interaction domain family member, is a novel corepressor for estrogen receptor alpha. Mol Endocrinol 19:2491-501
Shearman, Amanda M; Cooper, Jackie A; Kotwinski, Paul J et al. (2005) Estrogen receptor alpha gene variation and the risk of stroke. Stroke 36:2281-2

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