Abstract 19273: Fibroblast-Derived TSP1, via CD47, Upregulates Connective Tissue Growth Factor to Promote Left Ventricular Fibrosis and Heart Failure

Abstract

Background: An estimated 5.5 million individuals in the United States have left ventricular heart failure (LV HF). Therapeutics, while relieving symptoms and extending life in some cases, cannot resolve this process. LV HF is characterized by excessive accumulation of the extracellular matrix. The causes of this process remain incompletely understood. Our team has recently described a widely expressed cell surface receptor CD47 that is activated by its high affinity ligand, thrombospondin-1 (TSP1) to promote LV HF. However, the role of TSP1-CD47 signaling in promoting fibrosis, in general, and in the setting of LV HF, in specific, is unknown. Methods: Wild type mice expressing CD47 and mutated mice lacking CD47 (CD47 null) were subjected to transverse aortic constriction (TAC) for 4 weeks followed by open chest pressure-volume loop analysis of cardiac hemodynamics. Signal transduction was confirmed in isolated left ventricles (LV) and normal human ventricular fibroblast cell culture systems. Results: In biopsy samples from failing human hearts and in pre-clinical model of TAC-driven LV HF, TSP1-CD47 signaling was altered. Post-TAC wild type (CD47+/+) mice developed cardiac fibrosis, associated cardiac stiffness and HF. In contrast, CD47 null mice subjected to TAC showed enhanced cardiac function and decreased fibrosis concordant with suppression of TSP1. In cardiac resident fibroblasts, but not myocytes, hypoxia rapidly induced TSP1 protein, while treating with 7N3, a TSP1-based peptide mimetic that selectively binds CD47, increased connective tissue growth factor (CTGF) protein. Further, treating cardiac fibroblast with 7N3 increased fibroblast collagen production. Finally, CD47 blocking antibody mitigated established TAC-driven LV fibrosis and HF. Conclusion: These data identify a proximate role for activated cardiac fibroblast CD47 in promoting LV fibrosis associated with HF and suggest possible therapeutic opportunity.