Mechanobiology of Cardiac Disease and Fibrosis: a Novel Role for Cadherin-11
Schroer, Alison Koelle
Heart disease is a leading cause of death worldwide, and many cardiac conditions that contribute to high morbidity and mortality are characterized by tissue fibrosis and maladaptive remodeling. Build-up of extracellular matrix (ECM) proteins in the myocardium, primarily produced by activated myofibroblasts, increase tissue stiffness and decrease function throughout the progression of disease. Resident cells sense changes in their mechanical environment and transmit intracellular forces to the ECM and neighboring cells through integrins and cadherins, respectively. Cadherin-11 has been recently identified as a key mediator of inflammatory signaling and myofibroblast-driven remodeling in other organ systems, but has never before been studied in the myocardium. This dissertation studies fibroblast activation and function in response to chemical and mechanical cues relevant to cardiac disease. Cadherin-11 was found to be expressed and play a contributory role in the dynamic inflammatory and fibrotic remodeling that occurs after myocardial infarction (MI). Furthermore, targeting cadherin-11 with a functional blocking antibody treatment reduced excess inflammation and improved functional outcomes in mice after MI relative to mice treated with a control antibody. Specifically, this treatment alters the cellular interactions between macrophages and myofibroblasts that promote expression of IL-6, TGF-beta1 and MMP1. Finally, new tools were developed to quantify alterations in cardiomyocyte mechanics which in turn can affect fibroblast activation, fibrosis, and cardiac function during disease. Overall, this work presents new techniques to understand the role of mechanical forces in the progression of heart disease and identifies cadherin-11 as a promising therapeutic target for improving outcomes after MI.