Journal
CARDIOVASCULAR RESEARCH
Volume 113, Issue 1, Pages 15-29Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvw218
Keywords
Clinical pulmonary hypertension; Thrombospondin-1; CD47; cMyc; ET-1
Categories
Funding
- NIH [R01HL-108954, 1R01HL112914-01A1, 1R21EB017184-01A1, HL-112904, HL-128304, PI13/01866, P01 HL103455]
- American Heart Association (AHA) [11BGIA7210001]
- PIE from ISCIII [13/00041]
- Fondo Europeo de Desarrollo Regional (FEDER)
- AHA [13POST14520003]
- American Society of Transplantation Basic Science Fellowship
- Joseph A. Patrick Fellowship
- Instituto de Salud Carlos III [PI13/01866]
- Red Cardiovascular [RD12/0042/0065]
- Institute for Transfusion Medicine
- Hemophilia Center of Western Pennsylvania
- Vascular Medicine Institute of the University of Pittsburgh School of Medicine
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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-1stimulated 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.
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