Activated CD47 promotes pulmonary arterial hypertension through targeting caveolin-1.
OBJECTIVE
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.


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.


CONCLUSIONS
Activated CD47 is upregulated in experimental and human PAH and promotes disease by limiting Cav-1 inhibition of dysregulated eNOS.
Department of Surgery,  University of Pittsburgh School of Medicine, Pittsburgh, PA,  USA.
Philip M
PM
Bauer
Eileen M
EM
Bauer
Natasha M
NM
Rogers
Mingyi
M
Yao
Monica
M
Feijoo-Cuaresma
Joseph M
JM
Pilewski
Hunter C
HC
Champion
Brian S
BS
Zuckerbraun
Maria J
MJ
Calzada
Jeffrey S
JS
Isenberg
D000818:Animals; D051928:CD47 Antigen / Q000378:metabolism*; D016022:Case-Control Studies; D051242:Caveolin 1 / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016686:Monocrotaline / Q000009:adverse effects; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019700:Thrombospondin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*
D051928:CD47 Antigen; D051242:Caveolin 1; D017382:Reactive Oxygen Species; D019700:Thrombospondin 1; D016686:Monocrotaline; D052250:Nitric Oxide Synthase Type III