Placenta growth factor (PlGF), a novel inducer of plasminogen activator inhibitor-1 (PAI-1) in sickle cell disease (SCD).
Sickle cell disease (SCD) is characterized by a prothrombotic state. Plasminogen activator inhibitor-1 (PAI-1) is known to modulate fibrinolysis, lung injury/fibrosis, and angiogenesis. However, its role in SCD is less understood, and the molecular mechanisms underlying increased PAI-1 are unknown. Herein, we show a novel link between PAI-1 and sickle erythropoiesis. Plasma PAI-1 levels were high in SCD patients at steady state and in two humanized sickle mouse models, with increased PAI-1 immunolabeling in sickle mouse lung, bronchial epithelial cells, alveolar macrophages, and pulmonary microvascular endothelial cells. Placenta growth factor (PlGF), released at high levels by sickle erythroblasts, induced PAI-1 expression in primary human pulmonary microvascular endothelial cells and monocytes through activation of c-Jun N-terminal kinase (JNK), NADPH oxidase, and hypoxia-inducible factor-1alpha (HIF-1alpha). Analysis of the human PAI-1 promoter revealed this induction was mediated by hypoxia-response element (HRE)-1, HRE-2, and distal activator protein (AP-1) sites. We also identify the involvement of c-Jun, c-Jun/c-Fos, and JunD, but not JunB, in binding with AP-1 sites of the PAI-1 promoter upon PlGF induction. Consistent with these findings, levels of PAI-1 were low in PlGF knock-out mice and sickle-PlGF knock-out mice; overexpression of PlGF in normal mice increased circulating PAI-1. In conclusion, we identify a novel mechanism of PAI-1 elevation in SCD.
Patel
Nitin
N
Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.
Sundaram
Nambirajan
N
Yang
Mingyan
M
Madigan
Catherine
C
Kalra
Vijay K
VK
Malik
Punam
P
D000755:Anemia, Sickle Cell / Q000378:metabolism*; D000818:Animals; D004730:Endothelium, Vascular / Q000166:cytology; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008168:Lung / Q000166:cytology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008833:Microcirculation; D008954:Models, Biological; D000072483:Placenta Growth Factor; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011257:Pregnancy Proteins / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D017395:Plasminogen Activator Inhibitor 1; D011257:Pregnancy Proteins; D018808:Transcription Factor AP-1; D000072483:Placenta Growth Factor