While cardiovascular disease is the leading cause of death in both men and women in the United States, it is only after menopause that the risk of developing congestive heart failure dramatically increases in women. The proposed study will investigate gender-specific differences in myocardial remodeling and the development of heart failure secondary to chronic volume overload. Specifically, the focus of this proposal will be estrogen's modulation of TNF-alpha production and release from cardiac mast cells. The overall hypothesis to be examined is that estrogen modulation of TNF-alpha is responsible for the gender differences in cardiovascular remodeling induced by chronic volume overload. To this end, the following specific aims will be addressed using a variety of physiological, biochemical, morphological and molecular techniques to delineate the mechanisms responsible for the gender-specific differences in cardiovascular function and the temporal progression of adverse ventricular remodeling induced secondary to either infrarenal aortocaval fistula or TNF-alpha infusion in rats.
Aim 1 : Does estrogen alter the dynamic remodeling process induced by chronic volume overload? Aim 2: What role does the estrogen modulation of TNF-alpha play in myocardial remodeling and development of heart failure? Aim 3: Is estrogen modulation of mast cell-derived TNF-alpha the mechanism responsible for cardioprotection observed in intact females? In summary, the proposed studies will provide a well integrated approach designed to fill a void in our understanding of the mechanisms responsible for the cardioprotection observed in premenopausal females. We have every expectation that the investigations will significantly increase our understanding of the important interactions between estrogen, cardiac mast cell-derived TNF-alpha, cardiac fibroblasts, myocytes, and the extracellular matrix during cardiovascular remodeling secondary to chronic volume overload and advance the development of novel therapeutic approaches for the prevention of heart failure. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL073990-02
Application #
6912610
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Massicot-Fisher, Judith
Project Start
2004-07-01
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$362,500
Indirect Cost
Name
University of South Carolina at Columbia
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
111310249
City
Columbia
State
SC
Country
United States
Zip Code
29208
Brower, Gregory L; Levick, Scott P; Janicki, Joseph S (2015) Differential Effects of Prevention and Reversal Treatment with Lisinopril on Left Ventricular Remodelling in a Rat Model of Heart Failure. Heart Lung Circ 24:919-24
Janicki, Joseph S; Brower, Gregory L; Levick, Scott P (2015) The emerging prominence of the cardiac mast cell as a potent mediator of adverse myocardial remodeling. Methods Mol Biol 1220:121-39
Li, Jianping; Jubair, Shaiban; Janicki, Joseph S (2015) Estrogen inhibits mast cell chymase release to prevent pressure overload-induced adverse cardiac remodeling. Hypertension 65:328-34
Stewart Jr, James A; Gardner, Jason D; Brower, Gregory L et al. (2014) Temporal changes in integrin-mediated cardiomyocyte adhesion secondary to chronic cardiac volume overload in rats. Am J Physiol Heart Circ Physiol 306:H101-8
Janicki, Joseph S; Spinale, Francis G; Levick, Scott P (2013) Gender differences in non-ischemic myocardial remodeling: are they due to estrogen modulation of cardiac mast cells and/or membrane type 1 matrix metalloproteinase. Pflugers Arch 465:687-97
Lu, Hong; Melendez, Giselle C; Levick, Scott P et al. (2012) Prevention of adverse cardiac remodeling to volume overload in female rats is the result of an estrogen-altered mast cell phenotype. Am J Physiol Heart Circ Physiol 302:H811-7
McLarty, Jennifer L; Meléndez, Giselle C; Levick, Scott P et al. (2012) Estrogenic modulation of inflammation-related genes in male rats following volume overload. Physiol Genomics 44:362-73
Melendez, Giselle C; Li, Jianping; Law, Brittany A et al. (2011) Substance P induces adverse myocardial remodelling via a mechanism involving cardiac mast cells. Cardiovasc Res 92:420-9
McLarty, Jennifer L; Melendez, Giselle C; Spencer, William J et al. (2011) Isolation of functional cardiac immune cells. J Vis Exp :
Levick, Scott P; Melendez, Giselle C; Plante, Eric et al. (2011) Cardiac mast cells: the centrepiece in adverse myocardial remodelling. Cardiovasc Res 89:12-9

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