Extracellular Matrix Dynamics During Remodeling

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Project Summary Investigations of ventricular remodeling have focused almost exclusively on changes in collagen deposition and matrix metalloproteinase activity. While such investigations have provided numerous insights into fibrillar changes in the extracellular matrix (ECM), little attention has been paid to the non-fibrillar components of the ECM. Indeed, the ECM is composed of numerous soluble and bound factors. The roles of these various ECM components are diverse, but largely unknown. Moreover, how these factors interact with existing parenchymal cells, the changing and expanding populations of mesenchymal cells, and the transitory leukocytes, such as macrophages, remains to be examined carefully. Despite the complexity of the ECM, our understanding of it remains primitive. In fact, one of the most abundant components of the ECM, hyaluronan (HA), functions through largely cryptic or presumed mechanisms. Ultimately derived from glucose, HA is synthesized by a family of enzymes, known as hyaluronan synthases (HAS). The role of HA may differ dynamically throughout remodeling. Our preliminary data indicate that HA accumulates in the heart early after a myocardial infarction (MI) and its accumulation persists for weeks after MI. We also show that acutely activated fibroblasts contribute to HA production. Given that HA accumulates quickly following MI and activated fibroblasts can increase HA production, this suggests a potential role for a fibroblast-HA axis in acute scar formation. Yet, the persistent accumulation of HA may provoke macrophage-dependent inflammation and contribute to adverse remodeling after the scar has matured. Our preliminary data show that HA directly impairs macrophage function, which may underlie non-resolving inflammation in the remodeling heart. We posit that the changing roles of HA in the acute post-MI setting versus chronic heart failure comprise major, unappreciated events in ventricular remodeling. This insinuates that HA is neither purely pathologic nor purely adaptive. Rather, the role of HA is context dependent. For these reasons, we must understand the regulation of HA production in the failing heart. We posit that acutely after MI, fibroblasts leverage metabolic changes to produce more HA and contribute to scar formation; however, the inexorable accumulation of HA may transition into a contributor to pathology in the chronic phases. Over the course of this project, we will use a battery of gain- and loss-of-function approaches to test the central hypothesis that changes in fibroblast glucose metabolism drive hyaluronan production, which acutely aids in scar formation but chronically prolongs inflammation and promotes adverse remodeling. Regardless of specific outcomes, completion of this project will create fundamental, mechanistic insights into the causes and consequences of changes in the extracellular matrix during ventricular remodeling.