Abstract 13392: CD47 Drives Left Ventricular Heart Failure by Activating HDAC3 and Targeting Autophagy
Background: An estimated 5.5 million individuals in the United States have heart failure (HF). Therapeutics, while relieving symptoms and extending life in some cases, cannot resolve this process and transplant remains the option of last resort for many. Our team has recently described a widely expressed cell surface receptor CD47 that is activated by its high affinity ligand, thrombospondin-1 (TSP1), secreted in acute and chronic disease. However, the role of TSP1-CD47 signaling in heart disease, in general, and heart failure (HF), in specific, is unknown.
Methods: Wild type mice expressing CD47 (control and morpholino treated) 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 LV and cardiac myocyte 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 induced, concurrent with profound up-regulation of cardiac HDAC3. Wild type CD47 expressing mice developed LV hypertrophy and HF due to TAC. In contrast, CD47-null mice subjected to TAC showed enhanced cardiac function, decreased cellular hypertrophy and fibrosis concordant with suppression of TSP1 and HDAC3. Attenuated HDAC3 activation and its cellular translocation resulted in altered cardiac autophagy. In cell culture, activation of cardiac myocyte CD47, with a TSP1-based peptide mimetic that selectively binds CD47, increased HDAC3 and autophagy signaling and stimulated cardiac myocyte hypertrophy which was abolished with CD47 or HDAC3 morpholino treatment. HDAC3 gene silencing in wild type CD47 positive mice abrogated established TAC-driven LV HF and hypertrophy. Likewise, in wild type animals a CD47 blocking antibody corrected established LV HF.
Conclusion: These data identify a proximate role for activated cardiac CD47 in promoting LV HF via up-regulation of HDAC3 and dysregulated autophagy and suggest multiple possible therapeutic opportunities.
- © 2013 by American Heart Association, Inc.