Chronic ventricular volume overload leads to structural remodeling of the muscular, vascular and extracellular matrix components of the myocardium. However, the compensatory hypertrophy and ventricular dilatation induced by this condition ultimately has a detrimental affect on ventricular function, resulting in heart failure. A suitable explanation for this pathologic remodeling has not been established, although myocardial collagen fiber degradation represents a common pathway that could produce these adverse structural and architectural alterations. Fibrillar collagen provides the framework which interconnects the cardiomyocytes and blood vessels in the myocardium, thereby maintaining ventricular shape and size and contributing to tissue stiffness. These myocardial collagen fibers must be disrupted for ventricular dilatation, sphericalization and wall thinning to occur. Activation of myocardial metalloproteinases (i.e., collagenase) has been implicated in this adverse ventricular remodeling, however, virtually no studies have been performed to elucidate how this activation occurs in the heart. Recent evidence from our laboratory indicates that mast cell degranulation is responsible for collagenase activation in chronic volume overload. The proposed studies are designed to test the hypothesis that cardiac mast cells contribute to the pathologic ventricular remodeling which precedes the development of heart failure. Accordingly, this proposal will use infrarenal aortocaval fistula and myocardial infarction models of chronic volume overload in rats to examine the role of cardiac mast cells at the organ, tissue, and cellular levels.
The specific aims of the proposal are 1) to determine: if cardiac mast cells are involved in the myocardial remodeling process; whether mast cell phenotype and/or protein expression change during this process; and mast cell sensitivity to cytokines, ANP, and other neuroendocrine hormones; 2) to assess the ability of mast cell secretory products to regulate cardiac mast cell density and the synthesis and degradation of the cardiac ECM as well as their effect on the interaction of cardiac myocytes and fibroblasts with the ECM; and 3) to determine whether pharmacological inhibition of the mast cell- induced MMP activation cascade will prevent the development of heart failure. These studies will utilize a variety of physiologic, morphologic, biochemical, and molecular techniques to characterize the role of cardiac mast cells in the ventricular remodeling at critical pathological stages in the development of heart failure.
|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|
|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|
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