ArticleThe Journal of clinical investigation2013
FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension.
Article in The Journal of clinical investigation, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 254 papers, 2 of them syntheses that pooled it.
What it found
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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.
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Who cites it
254 citing papers in PubMed, 2 syntheses or guidelines pooled it, 439 citations in OpenAlex.
- Searching for Old and New Small-Molecule Protein Kinase Inhibitors as Effective Treatments in Pulmonary Hypertension-A Systematic Review.International journal of molecular sciences · 2024Pooled it
- A Systematic Review of Novel Therapies of Pulmonary Arterial Hypertension.American journal of cardiovascular drugs : drugs, devices, and other interventions · 2024Pooled it
- Nedd4L-mediated stabilization of morphogenetic protein receptor 2 in lung fibroblasts confers protection against pulmonary fibrosis.Signal transduction and targeted therapy · 2026Article
- Apelin analog treatment reverses severe pulmonary arterial hypertension and right ventricular heart failure.JCI insight · 2026Article
- Identification of oxidative stress-related hub genes and immune infiltration characterization in chronic spontaneous urticaria.Molecular genetics and genomics : MGG · 2026Article
- Nitazoxanide activates BMP9-ALK1-SMAD signaling cascade and improves HHT vascular pathology.bioRxiv : the preprint server for biology · 2026Article
- International Union of Basic and Clinical Pharmacology. CXXI. Apelin receptor pharmacology in the human cardiovascular system and emerging clinical applications.Pharmacological reviews · 2026Review
- Sex-Specific Pathophysiological Signatures in Allometric Dosing-Controlled Bleomycin Acute Lung Injury Model.bioRxiv : the preprint server for biology · 2026Article
- A circulating MicroRNA signature for the diagnosis of pulmonary arterial hypertension and functional characterization of candidate miR-3168.Scientific reports · 2026Article
- Review
- Advances in Novel Therapeutic Strategies for Pulmonary Arterial Hypertension.Canadian respiratory journal · 2026Review
- The role of Id genes on pulmonary hypertension development in left heart failure.American heart journal plus : cardiology research and practice · 2026Article
- Activin A-Activated ALK4 Induces Pathogenic Th17-Involved Endothelial-Mesenchymal Transition in Systemic Lupus Erythematosus-Associated Pulmonary Arterial Hypertension.Arthritis & rheumatology (Hoboken, N.J.) · 2025Article
- Pathophysiology of Pulmonary Arterial Hypertension: Focus on Vascular Endothelium as a Potential Therapeutic Target.International journal of molecular sciences · 2025Review
- Signaling pathways and targeted therapy for pulmonary hypertension.Signal transduction and targeted therapy · 2025Review
- Therapeutic targets for pulmonary arterial hypertension: insights into the emerging landscape.Expert opinion on therapeutic targets · 2025Review
- Loss of Type 2 Bone Morphogenetic Protein Receptor Activates NOD-Like Receptor Family Protein 3/Gasdermin E-Mediated Pyroptosis in Pulmonary Arterial Hypertension.Journal of the American Heart Association · 2025Article
- From bench to bedside: murine models of inherited and sporadic brain arteriovenous malformations.Angiogenesis · 2025Review
- In vitro and in vivo characterization of wild type BMP9 and a non-osteogenic variant in models of pulmonary arterial hypertension.PloS one · 2025Article
- Increased Bone Morphogenetic Protein-Responsive Transcription Factors in Distinct Endothelial and Mesenchymal Cells in Pulmonary Artery Hypertension.American journal of respiratory and critical care medicine · 2025Article
194 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
21 authors at 6 institutions in 4 countries.
Funding
Abstract
Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH.
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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.