1. TSP1-CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction.
- Author
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Rogers, Natasha M., Sharifi-Sanjani, Maryam, Mingyi Yao, Ghimire, Kedar, Bienes-Martinez, Raquel, Mutchler, Stephanie M., Knupp, Heather E., Baust, Jeffrey, Novelli, Enrico M., Ross, Mark, Croix, Claudette St., Kutten, Johannes C., Czajka, Caitlin A., Sembrat, John C., Rojas, Mauricio, Labrousse-Arias, David, Bachman, Timothy N., Vanderpool, Rebecca R., Zuckerbraun, Brian S., and Champion, Hunter C.
- Subjects
THROMBOSPONDIN-1 ,CD47 antigen ,PULMONARY hypertension ,MOLECULAR biology ,MESSENGER RNA - 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. [ABSTRACT FROM AUTHOR]- Published
- 2017
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