FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension
Edda Spiekerkoetter,Xuefei Tian,Jie Cai,Rachel K. Hopper,Deepti Sudheendra,Caiyun G. Li,Nesrine El-Bizri,Hirofumi Sawada,Roxanna Haghighat,Roshelle Chan,Leila Haghighat,Vinicio A. de Jesus Perez,Lingli Wang,Sushma Reddy,Mingming Zhao,Daniel Bernstein,David E. Solow-Cordero,Philip A. Beachy,Thomas J. Wandless,Peter ten Dijke,Marlene Rabinovitch +20 more
TLDR
Low-dose FK506 reversed dysfunctional BMPR2 signaling in pulmonary artery endothelial cells from patients with idiopathic PAH and prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin.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.read more
Citations
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Journal ArticleDOI
Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension.
TL;DR: It is shown how genetic and metabolic abnormalities are inextricably linked to dysregulated immunity and adverse remodeling in the pulmonary arteries.
Journal ArticleDOI
Pulmonary arterial hypertension: pathogenesis and clinical management.
TL;DR: Patients with PAH have dyspnea, reduced exercise capacity, exertional syncope, and premature death from right ventricular failure, and targeted therapies, used alone or in combination, improve functional capacity and hemodynamics and reduce hospital admissions.
Journal ArticleDOI
TGF-β Signaling from Receptors to Smads.
Akiko Hata,Ye-Guang Chen +1 more
TL;DR: This review introduces some basic components of the TGF-β signaling pathways and their actions, and discusses posttranslational modifications and modulatory partners that modify the outcome of the signaling and contribute to its context-dependence, including small noncoding RNAs.
Journal ArticleDOI
Signaling Receptors for TGF-β Family Members
TL;DR: Transforming growth factor β (TGF-β) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors that are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation.
Journal ArticleDOI
Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension.
Lu Long,Mark L. Ormiston,Xudong Yang,Mark Southwood,Stefan Gräf,Rajiv D. Machado,Matthias Mueller,Bernd Kinzel,Lai Ming Yung,Janine Mary Wilkinson,Stephen D Moore,Kylie M Drake,Micheala A. Aldred,Paul B. Yu,Paul D. Upton,Nicholas W. Morrell +15 more
TL;DR: Administration of BMP9 reversed established PAH in mice bearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, and demonstrated the promise of direct enhancement of endothelial BMP signaling as a new therapeutic strategy for PAH.
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Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension
Laimute Taraseviciene-Stewart,Yasunori Kasahara,Lori Alger,Peter Hirth,Gerald Mc Mahon,Johannes Waltenberger,Norbert F. Voelkel,Rubin M. Tuder +7 more
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