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Cardiovasc Res. 2017 Jan;113(1):15-29. doi: 10.1093/cvr/cvw218. Epub 2016 Oct 13.

TSP1-CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction.

Author information

1
Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
2
Division of Renal and Electrolytes, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
3
Starzl Transplant Institute, University of Pittsburgh, PA, USA.
4
Department of Pharmaceutical Science, College of Pharmacy-Glendale, Midwestern University, Glendale, AZ 85308, USA.
5
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
6
Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
7
Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
8
Dorothy P. & Richard P. Simmons Center for Interstitial Lung Disease, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
9
Hospital of the Princesa, Department of Medicine, Universidad Autónoma, Diego de León, 62 28006 Madrid, Spain.
10
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
11
Department of Ophthalmology, University of Pittsburgh School of Medicine, Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
12
Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA jsi5@pitt.edu.

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.

KEYWORDS:

CD47; Clinical pulmonary hypertension; ET-1; Thrombospondin-1; cMyc

PMID:
27742621
PMCID:
PMC5220673
[Available on 2018-01-01]
DOI:
10.1093/cvr/cvw218
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