| Activated CD47 promotes pulmonary arterial hypertension through targeting caveolin-1. | |
| | |
MedLine Citation:
|
PMID: 22215724 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
AIMS: Pulmonary arterial hypertension (PAH) is a progressive lung disease characterized by pulmonary vasoconstriction and vascular remodelling, leading to increased pulmonary vascular resistance and right heart failure. Loss of nitric oxide (NO) signalling and increased endothelial nitric oxide synthase (eNOS)-derived oxidative stress are central to the pathogenesis of PAH, yet the mechanisms involved remain incompletely determined. In this study, we investigated the role activated CD47 plays in promoting PAH. METHODS AND RESULTS: We report high-level expression of thrombospondin-1 (TSP1) and CD47 in the lungs of human subjects with PAH and increased expression of TSP1 and activated CD47 in experimental models of PAH, a finding matched in hypoxic human and murine pulmonary endothelial cells. In pulmonary endothelial cells CD47 constitutively associates with caveolin-1 (Cav-1). Conversely, in hypoxic animals and cell cultures activation of CD47 by TSP1 disrupts this constitutive interaction, promoting eNOS-dependent superoxide production, oxidative stress, and PAH. Hypoxic TSP1 null mice developed less right ventricular pressure and hypertrophy and markedly less arteriole muscularization compared with wild-type animals. Further, therapeutic blockade of CD47 activation in hypoxic pulmonary artery endothelial cells upregulated Cav-1, increased Cav-1CD47 co-association, decreased eNOS-derived superoxide, and protected animals from developing PAH. CONCLUSION: Activated CD47 is upregulated in experimental and human PAH and promotes disease by limiting Cav-1 inhibition of dysregulated eNOS. |
| | |
Authors:
|
Philip M Bauer; Eileen M Bauer; Natasha M Rogers; Mingyi Yao; Monica Feijoo-Cuaresma; Joseph M Pilewski; Hunter C Champion; Brian S Zuckerbraun; Maria J Calzada; Jeffrey S Isenberg |
Related Documents
:
|
21803504 - Does l-arginine supplementation play a role in cerebral small vessels disease? implicat... 16076334 - Effects of seprafilm on peritoneal fibrinolytic system. 9853284 - Leukocyte migration across human peritoneal mesothelial cells is dependent on directed ... 21860744 - Endothelial arginase ii and atherosclerosis. 14670114 - Engineered adipose tissue supplied by functional microvessels. 7930684 - Cationic lipid is not required for uptake and selective inhibitory activity of icam-1 p... |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-01-02 |
Journal Detail:
|
Title: Cardiovascular research Volume: 93 ISSN: 1755-3245 ISO Abbreviation: Cardiovasc. Res. Publication Date: 2012 Mar |
Date Detail:
|
Created Date: 2012-03-02 Completed Date: 2012-09-17 Revised Date: 2013-04-16 |
Medline Journal Info:
|
Nlm Unique ID: 0077427 Medline TA: Cardiovasc Res Country: England |
Other Details:
|
Languages: eng Pagination: 682-93 Citation Subset: IM |
Affiliation:
|
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Anoxia / metabolism, pathology Antigens, CD47 / metabolism* Case-Control Studies Caveolin 1 / metabolism* Cells, Cultured Disease Models, Animal Endothelium, Vascular / metabolism, pathology Humans Hypertension, Pulmonary / chemically induced, metabolism*, pathology Lung / metabolism*, pathology Male Mice Mice, Inbred C57BL Mice, Knockout Monocrotaline / adverse effects Nitric Oxide Synthase Type III / metabolism Oxidative Stress / physiology Rats Rats, Sprague-Dawley Reactive Oxygen Species / metabolism Signal Transduction / physiology* Thrombospondin 1 / deficiency, genetics, metabolism Up-Regulation / physiology* |
| Grant Support | |
ID/Acronym/Agency:
|
K22 CA128616/CA/NCI NIH HHS; P01HL103455/HL/NHLBI NIH HHS; R01 HL-085134/HL/NHLBI NIH HHS; R01 HL-108954/HL/NHLBI NIH HHS; UL1 RR024153/RR/NCRR NIH HHS; UL1 TR000005/TR/NCATS NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Antigens, CD47; 0/Caveolin 1; 0/Reactive Oxygen Species; 0/Thrombospondin 1; 315-22-0/Monocrotaline; EC 1.14.13.39/Nitric Oxide Synthase Type III |
| Comments/Corrections | |
Comment In:
|
Cardiovasc Res. 2012 Mar 15;93(4):540-2
[PMID:
22311719
]
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Mitochondrial complex II is essential for hypoxia-induced pulmonary vasoconstriction of intra- but n...
Next Document: Dermal tissue allograft for the repair of massive irreparable rotator cuff tears.