TSP1–CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction. Issue 1 (13th October 2016)

• Record Type: Journal Article
• Authors: Rogers, Natasha M.; Sharifi-Sanjani, Maryam; Yao, Mingyi; Ghimire, Kedar; Bienes-Martinez, Raquel; Mutchler, Stephanie M.; Knupp, Heather E.; Baust, Jeffrey; Novelli, Enrico M.; Ross, Mark; St. Croix, Claudette; Kutten, Johannes C.; Czajka, Caitlin A.; Sembrat, John C.; Rojas, Mauricio; Labrousse-Arias, David; Bachman, Timothy N.; Vanderpool, Rebecca R.; Zuckerbraun, Brian S.; Champion, Hunter C.; Mora, Ana L.; Straub, Adam C.; Bilonick, Richard A.; Calzada, Maria J.; Isenberg, Jeffrey S.
• Is Part Of: Cardiovascular research. Volume 113: Issue 1(2017)
• Page Start: 15
• Page End: 29
• Publication Date: 2016-10-13
• Subjects: Clinical pulmonary hypertension -- Thrombospondin-1 -- CD47 -- cMyc -- ET-1; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvw218
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract : Aims: Thrombospondin-1 (TSP1) is a ligand for CD47 and TSP1 −/− mice are protected from pulmonary hypertension (PH). We hypothesized the TSP1–CD47 axis is upregulated in human PH and promotes pulmonary arterial vasculopathy. Methods and results: We analyzed the molecular signature and functional response of lung tissue and distal pulmonary arteries (PAs) from individuals with ( n = 23) and without ( n = 16) PH. Compared with controls, lungs and distal PAs from PH patients showed induction of TSP1–CD47 and endothelin-1/endothelin A receptor (ET-1/ETA) protein and mRNA. In control PAs, treatment with exogenous TSP1 inhibited vasodilation and potentiated vasoconstriction to ET-1. Treatment of diseased PAs from PH patients with a CD47 blocking antibody improved sensitivity to vasodilators. Hypoxic wild type (WT) mice developed PH and displayed upregulation of pulmonary TSP1, CD47, and ET-1/ETA concurrent with down regulation of the transcription factor cell homolog of the v-myc oncogene (cMyc). In contrast, PH was attenuated in hypoxic CD47 −/− mice while pulmonary TSP1 and ET-1/ETA were unchanged and cMyc was overexpressed. In CD47 −/− pulmonary endothelial cells cMyc was increased and ET-1 decreased. In CD47 +/+ cells, forced induction of cMyc suppressed ET-1 transcript, whereas suppression of cMyc increased ET-1 signaling. Furthermore, disrupting TSP1–CD47 signaling in pulmonary smooth muscle cells abrogated ET-1-stimulated hypertrophy. Finally, a CD47 antibody given 2 weeks after monocrotaline challenge in rats upregulated pulmonary cMyc and improved aberrations in PH-associated cardiopulmonary parameters. Conclusions: In pre-clinical models of PH CD47 targets cMyc to increase ET-1 signaling. In clinical PH TSP1–CD47 is upregulated, and in both, contributes to pulmonary arterial vasculopathy and dysfunction.