Trial reportBlood2014
Heme-bound iron activates placenta growth factor in erythroid cells via erythroid Krüppel-like factor.
Trial report in Blood, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 4 registered trials, which are not on this map. Cited by 32 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Studies of Phlebotomy Therapy in Hereditary Hemochromatosis
Inhaled Nitric Oxide and Transfusion Therapy for Patients With Sickle Cell Anemia and Secondary Pulmonary Hypertension
Studies of the Natural History of Sickle Cell Disease
Cardiopulmonary Function Assessment and NO Based Therapies for Patients With Hemolysis-Associated Pulmonary Hypertension
Who cites it
32 citing papers in PubMed, 1 synthesis or guideline pooled it, 44 citations in OpenAlex.
- Role of innate immunity-triggered pathways in the pathogenesis of Sickle Cell Disease: a meta-analysis of gene expression studies.Scientific reports · 2015Pooled it
- Iron as a Modifiable Factor for Adverse Pregnancy Outcomes: Refining and Understanding Causal Estimates Using Mendelian Randomization.Biological trace element research · 2025Article
- Heme oxygenase/carbon monoxide system affects the placenta and preeclampsia.Medical gas research · 2025Review
- Gene-environmental influence of space and microgravity on red blood cells with sickle cell disease.NPJ genomic medicine · 2024Review
- Pyroptotic T cell-derived active IL-16 has a driving function in ovarian endometriosis development.Cell reports. Medicine · 2024Article
- The inflammatory profiles of pulmonary alveolar macrophages and alveolar type 2 cells in SCD.Experimental biology and medicine (Maywood, N.J.) · 2023Article
- The Role of Inflammation in The Cellular and Molecular Mechanisms of Cardiopulmonary Complications of Sickle Cell Disease.Biomolecules · 2023Review
- Endothelin A receptor antagonist attenuated renal iron accumulation in iron overload heme oxygenase-1 knockout mice.Canadian journal of physiology and pharmacology · 2022Article
- Anti-inflammatory cytokines in sickle cell disease.Molecular biology reports · 2022Review
- Hyperglycaemia up-regulates placental growth factor (PlGF) expression and secretion in endothelial cells via suppression of PI3 kinase-Akt signalling and activation of FOXO1.Scientific reports · 2021Article
- Fluid shear stress regulates placental growth factor expression via heme oxygenase 1 and iron.Scientific reports · 2021Article
- Cardiac pathophysiology in sickle cell disease.Journal of thrombosis and thrombolysis · 2021Review
- Pathologic angiogenesis in the bone marrow of humanized sickle cell mice is reversed by blood transfusion.Blood · 2020Article
- The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease.Frontiers in immunology · 2020Review
- Cardiac expression of HMOX1 and PGF in sickle cell mice and haem-treated wild type mice dominates organ expression profiles via Nrf2 (Nfe2l2).British journal of haematology · 2019Article
- Free heme regulates placenta growth factor through NRF2-antioxidant response signaling.Free radical biology & medicine · 2019Article
- Ischemia-Reperfusion Injury in Sickle Cell Disease: From Basics to Therapeutics.The American journal of pathology · 2019Review
- Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains.The Journal of clinical investigation · 2018Review
- Placenta growth factor mediated gene regulation in sickle cell disease.Blood reviews · 2018Review
- Metabolic dysfunction in pulmonary hypertension: from basic science to clinical practice.European respiratory review : an official journal of the European Respiratory Society · 2017Review
Corrections and comments
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Authors and funding
12 authors at 6 institutions in 2 countries.
Funding
Abstract
In adults with sickle cell disease (SCD), markers of iron burden are associated with excessive production of the angiogenic protein placenta growth factor (PlGF) and high estimated pulmonary artery pressure. Enforced PlGF expression in mice stimulates production of the potent vasoconstrictor endothelin-1, producing pulmonary hypertension. We now demonstrate heme-bound iron (hemin) induces PlGF mRNA >200-fold in a dose- and time-dependent fashion. In murine and human erythroid cells, expression of erythroid Krüppel-like factor (EKLF) precedes PlGF, and its enforced expression in human erythroid progenitor cells induces PlGF mRNA. Hemin-induced expression of PlGF is abolished in EKLF-deficient murine erythroid cells but rescued by conditional expression of EKLF. Chromatin immunoprecipitation reveals that EKLF binds to the PlGF promoter region. SCD patients show higher level expression of both EKLF and PlGF mRNA in circulating blood cells, and markers of iron overload are associated with high PlGF and early mortality. Finally, PlGF association with iron burden generalizes to other human diseases of iron overload. Our results demonstrate a specific mechanistic pathway induced by excess iron that is linked in humans with SCD and in mice to markers of vasculopathy and pulmonary hypertension. These trials were registered at www.clinicaltrials.gov as #NCT00007150, #NCT00023296, #NCT00081523, and #NCT00352430.
Indexed as
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.