P1: CD47 drives pulmonary hypertension through coordinate regulation of c-Myc and endothelin-1

Background Pulmonary hypertension (PH), regardless of etiology, remains progressive and incurable despite intensive research for over half a century. Existing therapies have only modestly enhanced survival with the only available “cure” being lung transplantation. The reasons for lack of progress in this area remain unknown but suggest a deficit in understanding the overarching mechanism (s) that drive PH. Recently we reported that the thrombospondin-1(TSP1)- CD47ligand receptor pathway is induced in multiple pre-clinical models of PH and human disease. Mice lacking secreted TSP1 are protected from PH. Methods Wild type and CD47null mice were challenged with hypoxia and cardiopulmonary assessment performed. Likewise, in cell culture experiments pulmonary arterial vascular smooth muscle cells were exposed to hypoxia and molecular signal transduction assessed. Results We know report that mice mutated to lack cell receptor CD47are highly resistant to hypoxia-mediated PH with minimal evidence of pulmonary arterial overgrowth and no right ventricular hypertrophycompared to controls. Hypoxic CD47null mice demonstrated increased stroke volume and cardiac output comparedto a significant deterioration of these functional parameters in wild type controls. Hypoxic wild type animals also displayed concurrent loss of cMyc and upregulation of endothelin-1. In contrast, hypoxic CD47null animals demonstrated cMyc-mediated suppression of endothelin-1 signaling. Impressively, under basal conditions endothelin-1 and the cognate receptors ETA and ETB where nearly undetectable in CD47null lungs. Disrupting TSP1-mediated activation of CD47in monocrotaline treated rats, and in hypoxic pulmonary arterial smooth muscle cell cultures, upregulated cMyc, inhibited endothelin-1 signaling and corrected established PH. Finally, antibody blocking CD47in lungs from patients with end-stage PH normalized the vasodilation profile of distal pulmonary arteries to acetylcholine and sodium nitroprusside. Conclusions The above preclinical results suggest CD47is an important and proximate promoter of PH through cMyc-mediated inhibition of endothelin-1, while results in diseased human PH lung arteriolessuggest that CD47is a clinical target to restore end-stage pulmonary arteriolefunction. Disclosure J.S.I. is Chair of the Scientific Advisory Boards and has equity interest in Vasculox, Inc. (St. Louis, MO) and Radiation Control Technologies, Inc. (Rockville, MD).