Type VI collegen and integrins in cardiac remodeling

Northeastern Ohio Universities Coll Med, Rootstown OH

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Abstract

DESCRIPTION (provided by applicant): Hypertension, cardiac hypertrophy and heart failure are pathophysiological processes that cause significant alterations in the phenotype and physiology of cardiac fibroblasts, the major connective tissue cell in the heart. Cardiac fibroblasts respond to these stressors by becoming hypersecretory, hyperproliferative, and differentiating into myofibroblasts. Altered cell signaling due to the renin-angiotensin system has been implicated in this remodeling process. However, we plan to examine the role of another potential mediator this process: altered cell-extracellular matrix interactions. We will examine the role of integrin receptors and matrix, specifically type VI collagen, in cardiac fibroblast function. Type VI collagen causes physiological and phenotypic changes in cells, and lack of this collagen causes myopathies such as Bethlem's. We will address two specific aims. In Specific Aim 1, we will examine integrin profiles, matrix deposition, and myofibroblast differentiation in vivo in isoproteranol-induced cardiac fibrosis using immunocytochemical techniques. To address the role of type VI collagen in cardiac remodeling, a transgenic mouse model of Bethlem's myopathy will be utilized. All experiments will be performed using wild type, heterozygous and mutant col6a1 mice, to determine the role of integrins and type VI collagen in cardiac remodeling. In Specific Aim 2, we will evaluate the role of specific integrin subunits and type VI collagen in vitro. Fibroblasts will be isolated from col6a1 +/+, +/-, and -/- mouse hearts, and a variety of assays performed. Matrix deposition, adhesion, migration, proliferation, and myofibroblast differentiation in vitro will be analyzed using immunocytochemical techniques. To determine the role of specific integrins, function blocking antibodies be utilized. This will allow us to characterize integrin-substrate interactions, the role of cell-deposited type collagen, and isoproteranol-induced cellular injury. These studies will allow us to determine the role of integrins and type VI collagen in cardiac fibroblast physiology in vitro, and cardiac remodeling in vivo.