Abstract 16448: Matricellular Activation of CD47 Promotes Pulmonary Arterial Hypertension by Regulating Cellular Homolog of the V-Myconcogene
Introduction: Pulmonary arterial hypertension (PAH) remains progressive and incurable. There is currently a deficit in understanding the mechanisms that drive PAH. Recently, we reported that the matricellular protein thrombospondin-1 (TSP1) is induced in pre-clinical models of PAH and human disease. However, the role of its receptor, CD47, in PAH is unknown.
Methods: Age-matched male wild type (WT) and CD47-/- mice were challenged with chronic hypoxia (10% FiO2 for 3 weeks). Age-matched Sprague Dawley rats received monocrotaline for 2 weeks followed by CD47 blocking or isotype control antibody. At the end of treatment all animals underwent cardio-pulmonary and biomolecular analysis. Human, and murine WT and CD47-/- pulmonary endothelial and vascular cells were also studied.
Results: Mice lacking CD47 are resistant to hypoxia-mediated PAH with minimal evidence of pulmonary arterial overgrowth and no right ventricular hypertrophy compared to controls. Hypoxic CD47-/- mice demonstrated increased stroke volume and cardiac output compared to a significant deterioration in WT controls. Hypoxic WT animals displayed concurrent loss of cellular homolog of the v-myconcogene (cMyc) and upregulation of endothelin-1 (ET-1). In contrast, hypoxic CD47-/- animals demonstrated cMyc-mediated suppression of ET-1 signaling. The receptor for ET-1, ETA, was also substantially reduced. Disrupting TSP1-mediated activation of CD47 in monocrotaline treated rats upregulated cMyc, down regulated ET-1, and corrected established PAH. In cultured pulmonary endothelial cells, suppression of cMyc with an oligonucleotide upregulated ET-1; murine pulmonary endothelial cells demonstrated basal upregulation of cMyc and suppression of ET-1. Treating pulmonary arteries from patients with end-stage PAH with a CD47-blocking antibody in lungs normalized vasodilatation profiles to the endothelial activator acetylcholine and to the smooth muscle cell activator sodium nitroprusside.
Conclusions: These results suggest CD47 is an important and proximate promoter of PAH through cMyc-mediated inhibition of ET-1. Functional studies in diseased human PAH lung arteries also suggest that CD47 is a clinical target to restore pulmonary vascular function in end-stage PAH.
Author Disclosures: N. Rogers: None. M. Yao: None. M. Sharifi: None. C. St Croix: None. J. Isenberg: None.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.