Abstract 374: Cardiac Fibroblasts are Essential During Pathological Stress

Abstract

Cardiac fibroblasts reportedly play a role in normal heart function and are responsible for adverse remodeling after heart injury. Although fibroblast activities can be detrimental during disease, a basal level of cardiac fibroblast activity is required to maintain structural integrity and prevent rupture. We use transgenic mouse models to demonstrate that reduced fibroblasts numbers have serious consequences during pathological stress. At baseline, we observe a dramatic loss of the cardiac fibroblast lineage, which results in vasculature alterations, such as capillary dilation and decreased capillary density. Baseline changes in basement membrane (laminin) and cardiomyocyte structure have also been identified in fibroblast deficient hearts. These phenotypic changes become exacerbated after surgery indicating that fibroblasts are necessary for crosstalk between other cell types in the heart. In addition, we predict that the loss of fibroblasts will cause enhanced deterioration in cardiac function after injury due to reduced structural integrity of the heart. We will use transverse aortic constriction (TAC) as a pressure-overload model. After 5 weeks of TAC, we observe a ~50% (Baseline 71.99±6.06, TAC5wks 22.09±1.89) decrease in ejection fraction in fibroblast deficient hearts compared to a ~16% (Baseline 76.21±7.08, TAC5wks 59.59) decrease in control hearts. Our data suggest that a specific level of cardiac fibroblast activity is required to maintain normal heart function. Our goal is to identify both deleterious and beneficial roles of fibroblasts in the response of the heart to the types of pathological stress commonly encountered in patients.