Fibroblast-Cardiomyocyte Interactions in the Pressure-Overloaded Myocardium
Abstract
In addition to cariomyocytes (the cardiac cells responsible for heart contraction), the heart contains abundant fibroblasts, a cell type that, when activated following injury, deposits matrix proteins to repair the heart. In heart failure, cardiac fibroblasts become activated and may secrete extracellular matrix, increasing the stiffness of the heart. A stiff heart fails to relax properly; as a result, pressures in the cardiac chambers increase and patients develop shortness of breath. Moreover, deposition of matrix in the heart may precipitate deadly heart rhythm irregularities. Considering all the detrimental actions that fibroblasts may exert, the basis for their abundant numbers in the heart is a mystery. Our preliminary studies suggest that fibroblasts may also have protective actions, preventing death of cardiomyocytes under conditions of stress. We found that disruption of a specific pathway that activates fibroblasts, the Smad3 pathway, causes death of cardiomyocytes under conditions of stress and leads to accelerated heart failure. These findings suggest that intact fibroblasts may protect cardiomyocytes from death. Our proposal will identify proteins that, when secreted by activated fibroblasts, reduce susceptibility of cardiomyocytes to noxious stimuli. Our ultimate goal is to use these proteins for treatment in heart failure. These concepts will be studied in three specific aims: Specific Aim 1: To investigate the role the Smad proteins (important regulators of fibroblast function) in the failing and remodeling heart. Specific Aim 2: To investigate whether fibroblasts protect cardiomyocytes by altering composition of the matrix that surrounds the cardiomyocytes. Thus, fibroblasts may be protective because they "coat" the matrix with protective substances, called "matricellular proteins" that reduce susceptibility of cardiomyocytes to death. Specific Aim 3: To use new methodologies, including proteomics and bioinformatics computational analysis, in order to identify novel substances that protect cardiomyocytes from death. Our proposal combines expertise in fibrosis of the heart, heart failure, cell death, proteomics, and bioinformatics. Our combined expertise will allow us to identify new molecules that may protect cardiomyocytes from death, under conditions of stress.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610564
Entities
People
- Richard N Kitsis
Organizations
- Albert Einstein College of Medicine
- United States Army