Dataset Information

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

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.

SUBMITTER: Rogers NM

PROVIDER: S-EPMC5220673 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Rogers Natasha M NM Sharifi-Sanjani Maryam M Yao Mingyi M Ghimire Kedar K Bienes-Martinez Raquel R Mutchler Stephanie M SM Knupp Heather E HE Baust Jeffrey J Novelli Enrico M EM Ross Mark M St Croix Claudette C Kutten Johannes C JC Czajka Caitlin A CA Sembrat John C JC Rojas Mauricio M Labrousse-Arias David D Bachman Timothy N TN Vanderpool Rebecca R RR Zuckerbraun Brian S BS Champion Hunter C HC Mora Ana L AL Straub Adam C AC Bilonick Richard A RA Calzada Maria J MJ Isenberg Jeffrey S JS

Cardiovascular research 20161013 1

<h4>Aims</h4>Thrombospondin-1 (TSP1) is a ligand for CD47 and TSP1<sup>-/-</sup> mice are protected from pulmonary hypertension (PH). We hypothesized the TSP1-CD47 axis is upregulated in human PH and promotes pulmonary arterial vasculopathy.<h4>Methods and results</h4>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 sh ...[more]

PMID: 27742621

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Project description:Aims:The pathogenic mechanisms of pulmonary arterial hypertension (PAH) remain unclear, but involve dysfunctional endothelial cells (ECs), dysregulated immunity and inflammation in the lung. We hypothesize that a developmental process called endothelial to haematopoietic transition (EHT) contributes to the pathogenesis of pulmonary hypertension (PH). We sought to determine the role of EHT in mouse models of PH, to characterize specific cell types involved in this process, and to identify potential therapeutic targets to prevent disease progression. Methods and results:When transgenic mice with fluorescence protein ZsGreen-labelled ECs were treated with Sugen/hypoxia (Su/Hx) combination to induce PH, the percentage of ZsGreen+ haematopoietic cells in the peripheral blood, primarily of myeloid lineage, significantly increased. This occurrence coincided with the depletion of bone marrow (BM) ZsGreen+ c-kit+ CD45- endothelial progenitor cells (EPCs), which could be detected accumulating in the lung upon PH-induction. Quantitative RT-PCR based gene array analysis showed that key transcription factors driving haematopoiesis were expressed in these EPCs. When transplanted into lethally irradiated recipient mice, the BM-derived EPCs exhibited long-term engraftment and haematopoietic differentiation capability, indicating these EPCs are haemogenic in nature. Specific inhibition of the critical haematopoietic transcription factor Runx1 blocked the EHT process in vivo, prevented egress of the BM EPCs and ultimately attenuated PH progression in Su/Hx- as well as in monocrotaline-induced PH in mice. Thus, myeloid-skewed EHT promotes the development of PH and inhibition of this process prevents disease progression in mouse models of PH. Furthermore, high levels of Runx1 expression were found in circulating CD34+ CD133+ EPCs isolated from peripheral blood of patients with PH, supporting the clinical relevance of our proposed mechanism of EHT. Conclusion:EHT contributes to the pathogenesis of PAH. The transcription factor Runx1 may be a novel therapeutic target for the treatment of PAH.

Project description:RationalePatients with idiopathic pulmonary arterial hypertension (iPAH) often have a low cardiac output. To compensate, neurohormonal systems such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system are up-regulated, but this may have long-term negative effects on the progression of iPAH.ObjectivesAssess systemic and pulmonary RAAS activity in patients with iPAH and determine the efficacy of chronic RAAS inhibition in experimental PAH.MethodsWe collected 79 blood samples from 58 patients with iPAH in the VU University Medical Center Amsterdam (between 2004 and 2010) to determine systemic RAAS activity.Measurements and main resultsWe observed increased levels of renin, angiotensin (Ang)I, and AngII, which were associated with disease progression (P < 0.05) and mortality (P < 0.05). To determine pulmonary RAAS activity, lung specimens were obtained from patients with iPAH (during lung transplantation, n = 13) and control subjects (during lobectomy or pneumonectomy for cancer, n = 14). Local RAAS activity in pulmonary arteries of patients with iPAH was increased, demonstrated by elevated angiotensin-converting enzyme activity in pulmonary endothelial cells and increased AngII type 1 (AT(1)) receptor expression and signaling. In addition, local RAAS up-regulation was associated with increased pulmonary artery smooth muscle cell proliferation via enhanced AT(1) receptor signaling in patients with iPAH compared with control subjects. Finally, to determine the therapeutic potential of RAAS activity, we assessed the chronic effects of an AT(1) receptor antagonist (losartan) in the monocrotaline PAH rat model (60 mg/kg). Losartan delayed disease progression, decreased right ventricular afterload and pulmonary vascular remodeling, and restored right ventricular-arterial coupling in rats with PAH.ConclusionsSystemic and pulmonary RAAS activities are increased in patients with iPAH and are associated with increased pulmonary vascular remodeling. Chronic inhibition of RAAS by losartan is beneficial in experimental PAH.

Dataset Information

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

Aims

Methods and results

Conclusions

Publications

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

Similar Datasets

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