Congestive heart failure (CHF) is the eventual endpoint of the adverse myocardial remodeling induced by chronic elevations in ventricular stress. Although the mechanisms involved in the transition from compensated myocardial remodeling to overt CHF have yet to be elucidated, recent findings in our laboratory have resulted in several novel observations implicating cardiac mast cells in the regulation of myocardial remodeling. These include: 1) cardiac mast cells are pivotal in initiating activation of matrix metalloproteinases, resulting in marked extracellular matrix (ECM) degradation and subsequent ventricular dilatation; 2) inhibition of mast cell degranulation prevents the adverse myocardial remodeling and significantly attenuates mortality due to CHF; 3) significant increases in TNF-alpha (TNF-a) and IL-6 occur prior to the development of CHF; and 4) antagonism of TNF-a significantly attenuated the myocardial remodeling. Other observations complementing these findings include the significant ventricular dilatation and structural alterations in the myocardium produced by chronic infusion of TNF-a and the observation that alterations in cellular function and protein expression mediated by cardiac mast cells was mirrored by treatment of fibroblast cultures with TNF-a. Also, constitutive expression of TNF-a is localized predominantly in mast cells in the heart. Thus, the overall hypothesis is that cardiac mast cell mediated elevations in TNF-a contribute to the pathologic ventricular remodeling ultimately resulting in the development of CHF. This proposal will utilize cytokine infusions, aortocaval fistula and mast cell deficient rat models to determine: 1) mast celt phenotype during the temporal course of myocardial remodeling and the ability of mast cell secretory products to regulate a) cardiac mast cell maturation and density, and b) cardiac myocyte and fibroblast interaction with the ECM in the progression to CHF; 2) the causal relationships between mast cell activation, induction of TNF-a and the initial myocardial remodeling associated with chronic volume overload; 3) the mechanisms by which chronic pathophysiologic elevations in TNF-a mediate the adverse myocardial remodeling responsible for the development of CHF; and 4) the efficacy of pharmacological inhibition of endothelin, mast cell degranulation and proinfiammatory cytokines in preventing the adverse myocardial remodeling and subsequent development of CHF. It is expected that these investigations will increase our understanding of the contributions of cardiac mast cells and TNF-a to ventricular remodeling and may potentially identify novel therapeutic approaches for the prevention of CHF. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062228-07
Application #
7125176
Study Section
Special Emphasis Panel (ZRG1-PTHA (02))
Program Officer
Massicot-Fisher, Judith
Project Start
1999-07-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
7
Fiscal Year
2006
Total Cost
$358,314
Indirect Cost
Name
University of South Carolina at Columbia
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
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
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
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
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
McLarty, Jennifer L; Meléndez, Giselle C; Brower, Gregory L et al. (2011) Tryptase/Protease-activated receptor 2 interactions induce selective mitogen-activated protein kinase signaling and collagen synthesis by cardiac fibroblasts. Hypertension 58:264-70

Showing the most recent 10 out of 43 publications