Placenta growth factor activates monocytes and correlates with sickle cell disease severity

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1506-1514 ◽  
Author(s):  
Natalya Perelman ◽  
Suresh K. Selvaraj ◽  
Sandeep Batra ◽  
Lori R. Luck ◽  
Anat Erdreich-Epstein ◽  
...  
Keyword(s):  
Steady State ◽  
Growth Factor ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Mononuclear Cells ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Erythroid Cells ◽  
Cell Disease ◽  
Placenta Growth Factor

Abstract Sickle cell disease (SCD) results in chronic hypoxia and secondarily increased erythropoietin concentrations. Leukocytosis and activated monocytes are also observed in SCD in absence of infection or vaso-occlusion (steady state), the reasons for which are unknown. We found that erythroid cells produced placenta growth factor (PlGF), an angiogenic growth factor belonging to the vascular endothelial growth factor (VEGF) family, and its expression was induced in bone marrow CD34+ progenitor cells in the presence of erythropoietin. Furthermore, the steady state circulating PlGF levels in subjects with severe SCD (at least 3 vaso-occlusive crises [VOCs] per year) were 18.5 ± 1.2 pg/mL (n = 9) compared with 15.5 ± 1.2 pg/mL (n = 13) in those with mild SCD (fewer than 3 VOCs per year) and 11.3 ± 0.7 pg/mL (n = 9) in healthy controls (P < .05), suggesting a correlation between PlGF levels and SCD severity. In addition, PlGF significantly increased mRNA levels of the proinflammatory cytochemokines interleukin-1β, interleukin-8, monocyte chemoattractant protein-1, and VEGF in peripheral blood mononuclear cells (MNCs) of healthy subjects (n = 4; P < .05). Expression of these same cytochemokines was significantly increased in MNCs from subjects with SCD at steady state (n = 14), compared with healthy controls. Of the leukocyte subfractions, PlGF stimulated monocyte chemotaxis (P < .05, n = 3). Taken together, these data show for the first time that erythroid cells intrinsically release a factor that can directly activate monocytes to increase inflammation. The baseline inflammation seen in SCD has always been attributed to sequelae secondary to the sickling phenomenon. We show that PlGF contributes to the inflammation observed in SCD and increases the incidence of vaso-occlusive events.

Placenta Growth Factor Induces 5-Lipoxygenase-Activating Protein Via Hypoxia-Inducible Factor-1α and Contributes to Increased Leukotrienes in Sickle Cell Disease.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1447-1447
Author(s):  
Vijay K Kalra ◽  
Nitin Patel ◽  
Caryn Gonsalves ◽  
Minyang Yang ◽  
Punam Malik
Keyword(s):  
Steady State ◽  
Growth Factor ◽  
Sickle Cell Disease ◽  
Lung Disease ◽  
Sickle Cell ◽  
Mononuclear Cells ◽  
Cell Disease ◽  
Placenta Growth Factor ◽  
Hypoxia Response

Abstract Subjects with sickle cell disease (SCD) have a chronic baseline inflammation and higher incidence of lung disease – airway hyper-reactivity predominates in children and restrictive lung disease in adults. The degree of inflammation, reflected in leukocytosis and leukocyte activation, correlates with higher mortality (Platt, NEJM, 1994). Stuart and colleagues have shown high plasma and urinary leukotriene (LT)-B4 at steady state, and even higher levels during acute sickle events and acute chest syndrome (J Lab Clin Med 2002). DeBaun and colleagues have shown high levels of urinary LT-E4 in this patient population (Am J Hematol, 2008). LT-B4 is one of the most potent activator of neutrophils, while cysteinyl leukotrienes (cys-LT), LT-C4, LT-D4 and LT-E4, promote bronchial smooth muscle constriction and asthma. LT are produced from arachidonic acid through a series of metabolic steps, with two critical steps catalyzed by five-lipoxygenase (5LO) and 5-lipoxygenase activating protein (FLAP). We have previously shown that that placenta growth factor (PLGF) is produced at high levels from the hyperplastic erythroid compartment in SCD and thalassemia and induces a strong proinflammatory cytochemokine response from monocytes (Perelman et al, Blood 2003; Selvaraj et al, Blood 2003). PLGF levels were high in subjects with SCD, and associated with activated mononuclear cells with augmented expression of pro-inflammatory cytochemokines (Perelman et al, Blood 2003). We now show PLGF induces FLAP expression. FLAP mRNA was significantly higher in peripheral blood mononuclear cells (PBM) of subjects with SCD at steady state, compared to healthy controls. PLGF activated PBM to increase FLAP expression and LT-B4 formation. It also increased Cys-LT production from PBM and the THP-1 monocytic cell line. PLGF-mediated increased FLAP expression was attenuated by PI-3 kinase inhibitor and PTEN; and by NADPH-oxidase inhibitor and p47phox siRNA in THP-1 cells. An in silico analysis of the FLAP promoter showed presence of hypoxia response elements, CEBP and NFκB sites. We found that FLAP induction by PLGF was mediated via HIF-1α. PLGF induced HIF-1α mRNA expression. Silencing with HIF-1α siRNA attenuated PLGF mediated FLAP expression, while over expression of HIF-1α had the converse effect. PLGF augmented FLAP-promoter luciferase activity by several folds, and this effect was abrogated upon mutation of hypoxia-response element (HRE), but not the NF-κB binding site in the FLAP proximal promoter. These studies indicate the role of HIF-1α motif in inducing FLAP expression, which was confirmed by electrophoretic mobility shift assays. Chromatin immunoprecipitation (ChIP) analysis further confirmed the role of HIF-1a in regulating PLGF-mediated FLAP expression. Our studies identify, for the first time, HIF-1α as a hypoxia-independent target of PLGF, which then upregulates FLAP and increases LT formation. Our studies define a mechanism of increased LT in SCD. The intrinsic elevated levels of PLGF seen in SCD could explain the increased leukotriene levels observed in patients with SCD, thereby contributing to the baseline inflammation and pulmonary pathology present in this disease. LT inhibitors are FDA approved in asthma, and could be used as a new modality to ameliorate inflammation and lung complications in SCD.

scholarly journals Placenta growth factor induces 5-lipoxygenase–activating protein to increase leukotriene formation in sickle cell disease

Blood ◽  
2009 ◽  
Vol 113 (5) ◽  
pp. 1129-1138 ◽  
Author(s):  
Nitin Patel ◽  
Caryn S. Gonsalves ◽  
Minyang Yang ◽  
Punam Malik ◽  
Vijay K. Kalra
Keyword(s):  
Growth Factor ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Mononuclear Cells ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nuclear Factor Κb ◽  
Airway Hyperreactivity ◽  
Cell Disease ◽  
Placenta Growth Factor ◽  
Peripheral Blood Mononuclear

Abstract Individuals with sickle cell disease (SCD) have increased inflammation, a high incidence of airway hyperreactivity (AH), and increased circulating leukotrienes (LT). We show that expression of 5-lipoxygenase and 5-lipoxygenase activating protein (FLAP), key catalytic molecules in the LT pathway, were significantly increased in peripheral blood mononuclear cells (MNCs) in patients with SCD, compared with healthy controls. Placenta growth factor (PlGF), elaborated from erythroid cells, activated MNC and THP-1 monocytic cells to induce LT production. PlGF-mediated increased FLAP mRNA expression occurred via activation of phosphoinositide-3 (PI-3) kinase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and hypoxia inducible factor-1α (HIF-1α). HIF-1α small interfering RNA (siRNA) reduced PlGF-induced FLAP expression. FLAP promoter-driven luciferase constructs demonstrated that PlGF-mediated luciferase induction was abrogated upon mutation of HIF-1α response element (HRE), but not the nuclear factor-κB (NF-κB) site in the FLAP promoter; a finding confirmed by chromatin immunoprecipitation (ChIP) analysis. PlGF also increased HIF-1α binding to the HRE in the FLAP promoter. Therefore, it is likely that the intrinsically elevated levels of PlGF in SCD subjects contribute to increased LT, which in turn, mediate both inflammation and AH. Herein, we identify a mechanism of increased LT in SCD and show HIF-1α as a hypoxia-independent target of PlGF. These studies provide new avenues to ameliorate these complications.

Placenta Growth Factor Is Regulated By Heme-Bound Iron Via Erythroid Krüppel-Like Factor In Erythroid Cells and Is Linked To Iron Status In Vivo In Sickle Cell Disease and Hereditary Hemochromatosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 432-432
Author(s):  
Xunde Wang ◽  
Laurel G. Mendelsohn ◽  
Heather Marie Rogers ◽  
Susan F. Leitman ◽  
Andrew Perkins ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Growth Factor ◽  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Hereditary Hemochromatosis ◽  
Angiogenic Factor ◽  
Erythroid Cells ◽  
Cell Disease ◽  
Placenta Growth Factor

Abstract Iron is a critical element for erythroid development and the function of many proteins, but is toxic in excessive amounts, most often by inducing oxidative stress that may play a role in vasculopathy. We have shown that markers of high iron burden such as serum ferritin have been associated with excessive production of the angiogenic factor placenta growth factor (PlGF), high estimated pulmonary artery pressure and death in adults with sickle cell disease. Enforced PlGF expression in mice promotes high circulating levels of the potent vasoconstrictor endothelin-1 and pulmonary hypertension. We find that heme-bound iron stimulates PlGF gene transcription by Erythroid Krüppel‐like Factor (EKLF). Heme-bound iron (hemin) induces PlGF mRNA in erythroid cells more than 200-fold in a dose-dependent and time-dependent fashion. PlGF mRNA is induced by other complexes of iron, but not iron-free heme or zinc protoporphyrin, suggesting that PlGF induction specifically requires iron. In murine and human cell lines, expression of EKLF developmentally precedes PlGF, and enforced expression of EKLF in human erythroid progenitor cells induces PlGF mRNA. Now we further report that hemin-induced expression of PlGF is abolished in EKLF-deficient mouse erythroid cells but rescued by conditional expression of EKLF. By chromosome immunoprecipitation we find that EKLF binds directly to the PlGF promoter region that contains an EKLF consensus sequence. We find that SCD patients have higher level expression than healthy controls of both EKLF and PlGF mRNA in peripheral blood cells, and expression of the two are correlated with each other (r=0.822, p<0.001). Demonstrating the generalizability of this link of iron overload to PlGF expression, we find that patients with hereditary hemochromatosis have a high plasma level of PlGF, which falls after correction of iron overload by periodic phlebotomy therapy (p=0.018). Reductant N-acetyl cysteine completely blocks hemin induction of PlGF, supporting the participation of oxidant stress response pathways already known to mediate signaling by iron on other promoters such as heme oxygenase-1. Our results for the first time demonstrate a specific mechanistic pathway induced by excess iron that is linked in humans with SCD and in mice to vasculopathy and pulmonary hypertension, suggesting that aggressive use of clinically approved iron chelation drugs should be investigated as adjunctive therapy to reduce the risk of pulmonary hypertension in SCD patients with associated iron overload. Linkage of iron overload in patients without hemolysis or anemia to abnormally high level expression of an angiogenic factor shown to induce pulmonary hypertension suggests a general pathobiological pathway connecting iron and vasculopathy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Placenta growth factor in sickle cell disease: association with hemolysis and inflammation

Blood ◽  
2010 ◽  
Vol 115 (10) ◽  
pp. 2014-2020 ◽  
Author(s):  
Julia E. Brittain ◽  
Ben Hulkower ◽  
Susan K. Jones ◽  
Dell Strayhorn ◽  
Laura De Castro ◽  
...  
Keyword(s):  
Growth Factor ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Predictive Accuracy ◽  
Cross Sectional Study ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Placenta Growth Factor ◽  
Cross Sectional

Abstract Placenta growth factor (PlGF) is released by immature erythrocytes and is elevated in sickle cell disease (SCD). Previous data generated in vitro suggest that PlGF may play a role in the pathophysiology of SCD-associated pulmonary hypertension (PHT) by inducing the release of the vasoconstrictor, endothelin-1. In this cross-sectional study of 74 patients with SCD, we confirm that PlGF is significantly elevated in SCD compared with healthy control subjects. We found significantly higher levels of PlGF in SCD patients with PHT but observed no association of PlGF with the frequency of acute pain episodes or history of acute chest syndrome. The observed correlation between PlGF and various measures of red cell destruction suggests that hemolysis, and the resultant erythropoietic response, results in the up-regulation of PlGF. Although relatively specific, PlGF, as well as N-terminal pro-brain natriuretic peptide and soluble vascular cell adhesion molecule, has low predictive accuracy for the presence of PHT. Prospective studies are required to conclusively define the contribution of PlGF to the pathogenesis of PHT and other hemolytic complications in SCD.

scholarly journals High levels of placenta growth factor in sickle cell disease promote pulmonary hypertension

Blood ◽  
2010 ◽  
Vol 116 (1) ◽  
pp. 109-112 ◽  
Author(s):  
Nambirajan Sundaram ◽  
Anitaben Tailor ◽  
Laurel Mendelsohn ◽  
Janaka Wansapura ◽  
Xunde Wang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Growth Factor ◽  
Sickle Cell Disease ◽  
Right Ventricle ◽  
Sickle Cell ◽  
Angiogenic Factor ◽  
Cell Disease ◽  
Placenta Growth Factor ◽  
Endothelin 1 ◽  
Erythroid Hyperplasia

Abstract Pulmonary hypertension is associated with reduced nitric oxide bioavailability and early mortality in sickle cell disease (SCD). We previously demonstrated that placenta growth factor (PlGF), an angiogenic factor produced by erythroid cells, induces hypoxia-independent expression of the pulmonary vasoconstrictor endothelin-1 in pulmonary endothelial cells. Using a lentivirus vector, we simulated erythroid expression of PlGF in normal mice up to the levels seen in sickle mice. Consequently, endothelin-1 production increased, right ventricle pressures increased, and right ventricle hypertrophy and pulmonary changes occurred in the mice within 8 weeks. These findings were corroborated in 123 patients with SCD, in whom plasma PlGF levels were significantly associated with anemia, endothelin-1, and tricuspid regurgitant velocity; the latter is reflective of peak pulmonary artery pressure. These results illuminate a novel mechanistic pathway linking hemolysis and erythroid hyperplasia to increased PlGF, endothelin-1, and pulmonary hypertension in SCD, and suggest that strategies that block PlGF signaling may be therapeutically beneficial. This trial was registered at http://clinicaltrials.gov as #NCT00011648.

scholarly journals Heme-bound iron activates placenta growth factor in erythroid cells via erythroid Krüppel-like factor

Blood ◽  
2014 ◽  
Vol 124 (6) ◽  
pp. 946-954 ◽  
Author(s):  
Xunde Wang ◽  
Laurel Mendelsohn ◽  
Heather Rogers ◽  
Susan Leitman ◽  
Nalini Raghavachari ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Growth Factor ◽  
Sickle Cell Disease ◽  
Erythroid Cells ◽  
Cell Disease ◽  
Placenta Growth Factor ◽  
Key Points ◽  
Factor Expression ◽  
Growth Factor Expression ◽  
In Erythroid Cells

Key Points Heme-bound iron activates placenta growth factor expression in erythroid cells via EKLF, a crucial erythroid-specific transcription factor. Markers of iron burden predict mortality in adults with sickle cell disease.

scholarly journals Circulating Cell-Free DNA in Sickle Cell Disease: Is It a Potentially Useful Biomarker?

2014 ◽  
Vol 138 (5) ◽  
pp. 678-683 ◽  
Author(s):  
Salah Al-Humood ◽  
Rajaa Zueriq ◽  
Lama Al-Faris ◽  
Rajaa Marouf ◽  
Fahd Al-Mulla
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Plasma Cell ◽  
Sickle Cell Trait ◽  
Healthy Controls ◽  
Cell Disease ◽  
Cell Free Dna ◽  
Free Dna ◽  
Polymerase Chain

Context.—Vascular occlusion in sickle cell disease causes increased levels of plasma cell-free DNA as a result of cell death and tissue damage. Objectives.—This study investigates plasma cell-free DNA concentrations in sickle cell disease patients, and aims at exploring the significance of plasma cell-free DNA as a potential biomarker in predicting its complications. Design.—Plasma cell-free DNA levels were measured using real-time quantitative polymerase chain reaction to quantitatively measure β-globin gene in blood samples from 57 sickle cell disease patients with acute vaso-occlusive crisis, 42 patients in steady state, 16 individuals with sickle cell trait, and 40 healthy controls. Results.—Plasma cell-free DNA level was significantly elevated in samples from patients with acute vaso-occlusive crisis when compared with those in steady state (P = .002), and was significantly higher both in crisis and in steady state when compared with individuals with sickle cell trait and healthy controls (P &lt; .001). There was no difference in cell-free DNA levels between individuals with sickle cell trait and healthy controls. There was no association between plasma cell-free DNA levels and various clinical complications of sickle cell disease and comorbidity. Conclusions.—Plasma cell-free DNA, as quantified by polymerase chain reaction amplification of the β-globin and human telomerase reverse transcriptase genes, is increased in sickle cell disease patients in vaso-occlusive crisis and in steady state compared with individuals with sickle cell trait and healthy controls, and may be used as a tool to diagnose and monitor the sickle cell crisis and differentiate post–packed red cell transfusion sickle cell disease patients from individuals with sickle cell trait.

scholarly journals Placenta growth factor mediated gene regulation in sickle cell disease

Blood Reviews ◽  
2018 ◽  
Vol 32 (1) ◽  
pp. 61-70 ◽  
Author(s):  
Vijay K. Kalra ◽  
Shuxiao Zhang ◽  
Punam Malik ◽  
Stanley M. Tahara
Keyword(s):  
Gene Regulation ◽  
Growth Factor ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease ◽  
Placenta Growth Factor
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