Role of collagen heterogeneity in remodeling of acute and chronic heart scars

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Project Summary/Abstract The mammalian heart possesses a poor ability to regenerate after ischemic cardiac injury and heals via scar formation. Multiple clinical studies have demonstrated that the size of scar tissue is an independent predictor of cardiovascular outcomes and mortality after acute myocardial infarction. However, little is understood about factors that regulate the degree of fibrosis or size of scar tissue after acute ischemic cardiac injury. Collagens are the most differentially upregulated genes following ischemic cardiac injury and remain the most abundant form of extracellular matrix (ECM) proteins secreted in the infarcted heart. Type I and III collagens are the principal collagens found in the heart but we show that a large number of collagens that are minimally expressed in the uninjured heart are robustly induced following ischemic cardiac injury. In this proposal, we investigate the physiological necessity of collagen heterogeneity and demonstrate that type V collagen, a fibrillar collagen plays a critical role in regulating the size of scar tissue after ischemic cardiac injury. Using multiplexing of RNA-FISH (fluorescence in situ hybridization) or MERFISH, we create a collagen map of the heart and use genetic loss of function techniques to determine the functional significance of type V collagen in regulating the size of post infarct scar tissue and heart function. We determine how the chemical composition of ECM changes following type V collagen deletion, study the mechano-biological properties of altered matrix and examine how such changes affect cardiac function and distribution of myocardial wall stress. We dissect the molecular mechanisms mediating regulation of scar size by type V collagen. We demonstrate that type V collagen deletion is associated with profound activation of cardiac fibroblasts in the infarcted heart and show that augmented myofibroblast activation is secondary to an altered integrin expression profile on cardiac fibroblasts. We study the mechanisms of altered integrin expression, integrin mediated mechanisms driving myofibroblast activation and determine whether inhibition of specific integrins can rescue the phenotype of increased post infarct scarring observed in type V collagen deficient states. Taken together, our proposal will lead to a broader understanding of cardiac wound healing and illustrate a new paradigm of cardiac repair where the structural constituents of heart scars regulate the size of scar itself.