Monday, March 24, 2025
3/24/2025
Extracellular matrix turnover in pathological cardiac remodeling Heart failure remains a leading cause of mortality and morbidity. Matrix remodeling accompanies systolic and diastolic dysfunction in the failing heart, and is associated with an alteration of the structure and function of the cardiac extracellular matrix. Understanding the complex dynamical processes of extracellular matrix re-model- ing holds the promise for identifying targets and developing therapeutics that may arrest or reverse disease progression. In failing hearts, changes in extracellular matrix compositions are driven largely by matrix turnover, which occurs through the continual deposition and degradation of matrix components. Matrix deposition is, in turn, rate limited by underlying protein synthesis and secretion kinetics. Knowledge into the synthesis and deg- radation flux of the matrix proteome is therefore essential to understanding the plasticity of matrix adaptation. In prior work, our team investigated the extracellular matrix proteomes of remodeling mouse hearts to uncover evidence of hidden fibrotic remodeling in a heart disease model. We have also refined experimental protocols to measure protein turnover in animal models, and discovered new disease pathways in cardiac hypertrophy that are not apparent from steady-state protein levels. Spurred by these developments, here we aim to elucidate the dynamics and plasticity of matrix remodeling, using spatial and temporal proteomics screens that we hy- pothesize will allow novel targets for anti-fibrotic remodeling strategies to be elucidated. Specifically, we pro- pose to: (1) measure the individual synthesis and deposition kinetics of matrix proteins in animal models of heart failure, and examine their changes in relation to matrix composition and function during hypertrophy, systolic and diastolic dysfunction, and recovery; and (2) dissect regulatory principles of matrix degradation and examine the respective contributions of cardiomyocytes and fibroblasts in normal and fibrotic remodeling con- texts. Success will reveal insights into the sequence of molecular events that underpin matrix remodeling in cardiac remodeling and failure. This information may be broadly useful for uncovering new intervention targets and guiding the development of therapeutic strategies.
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