scholarly journals Erythropoietin-mediated expression of placenta growth factor is regulated via activation of hypoxia-inducible factor-1α and post-transcriptionally by miR-214 in sickle cell disease

2015 ◽  
Vol 468 (3) ◽  
pp. 409-423 ◽  
Author(s):  
Caryn S. Gonsalves ◽  
Chen Li ◽  
Marthe-Sandrine Eiymo Mwa Mpollo ◽  
Vinod Pullarkat ◽  
Punam Malik ◽  
...  
Keyword(s):  
Growth Factor ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Hypoxia Inducible Factor ◽  
Peroxisome Proliferator ◽  
Cell Disease ◽  
Placenta Growth Factor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hypoxia Inducible Factor 1Α ◽  
Novel Approach

We showed that erythropoietin (EPO)-mediated activation of hypoxia-inducible factor-1α (HIF-1α) increased the expression of placental growth factor (PlGF). Furthermore, miR-214 post-transcriptionally regulates PlGF expression. miR-214 itself is regulated by both peroxisome proliferator-activated receptor-α (PPARα) and HIF-1α, thus providing a novel approach for reduction in PlGF levels in sickle cell disease (SCD).

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 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

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 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.

Systemic Blood Pressure Is Associated with Anemia and Placenta Growth Factor In Sickle Cell Anemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2644-2644 ◽  
Author(s):  
Payal C. Desai ◽  
Julia Brittain ◽  
Allison Deal ◽  
Susan Jones ◽  
Alan Hinderliter ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Growth Factor ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
White Blood Count ◽  
Cell Disease ◽  
Placenta Growth Factor ◽  
Systemic Blood ◽  
History Of ◽  
Blood Pressures

Abstract Abstract 2644 Introduction: The seventh report of the Joint National Committee (JNC 7) defines hypertension as blood pressure (BP) ≥ 140/90 and pre-hypertension as BP ≥ 120/80. Data from the National Health and Nutrition Examination Survey (NHANES) shows that 42% of African American patients over the age of 20 are classified as hypertensive. Previous studies in patients with sickle cell disease (SCD) have reported that systemic blood pressures (BP) are lower than age- and race-matched controls. The purpose of this study was to evaluate the clinical and laboratory factors associated with systolic and diastolic blood pressures in SCD. Methods: The data for this study was obtained from an ongoing study to determine the natural history of pulmonary hypertension in SCD. The first available systemic BP measurement for each patient was recorded, along with clinical and laboratory parameters. We evaluated associations between systolic and diastolic BP and 25 clinical and laboratory covariates using Spearman's correlation coefficient, and Wilcoxon Rank Sum tests for categorical covariates. Patients were stratified based on age and SCD genotype (SS, Sb0, SD vs. SC, Sb+). Blood pressures from our SCD patients were compared to median values obtained from the Cooperative Study of Sickle Cell Disease (CSSCD) using Wilcoxon Signed Rank tests. Results: Blood pressures were evaluated in 153 separate patients (SS = 115, SC = 18, Sb0 = 10, Sb+ = 9, SD =1), with a median age of 37 years (range 18 – 71 years). Thirty two (21%) patients had a known history of hypertension and 38 (25%) patients were on at least one antihypertensive medication for either hypertension or proteinuria. The mean (STD) systolic and diastolic BP for the patients with SS, Sb0 thalassemia, and SD (N=126) were 122 mm Hg (±15) and 69 mm Hg (±10), respectively; and the median systolic and diastolic BP for patients with SC and Sb+ thalassemia (N=27) were 131 mm Hg (±12) and 75 mm Hg (±13), respectively. We observed significant correlations between systolic BP and age (r=0.36, p=<.0001) and body mass index (BMI) (r=0.42, p=<.0001). We also observed significant correlations between SBP and hemoglobin (r=0.20, p=0.01); reticulocyte count (r=-0.29, p=0.0003); lactate dehydrogenase (r= −0.18, p=0.02); total bilirubin (r=−0.28, p=0.0008); indirect bilirubin (r=−0.28, p=0.001); white blood count (WBC) (r=−0.24, p=0.0023); absolute neutrophil count (r=−0.24, p=0.005); and placenta growth factor (PIGF) (r=−0.36, p=0.02). When compared to patients from the CSSCD, systolic BP was significantly higher in females ages 25–34 and 35–44, and in males ages 25–34 and 35–44 (Table 1). Conclusion: The low systemic BP in SCD patients may be related to their lower BMI, combined with biologic factors such as anemia, hemolysis as well as increased levels of the vascular endothelial growth factor (VEGF) family member, placenta growth factor. The higher BP in our patient population compared to values in the CSSCD may be related to differences in BMI, degree of anemia, and levels of PlGF. With the increasing survival of SCD patients, studies are required to determine the appropriate BP levels to initiate anti-hypertensive therapy. Disclosures: No relevant conflicts of interest to declare.

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.

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.

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