title: FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension.
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.
authors.affiliation: The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, California 94305-5162, USA.
authors.forename: Edda
authors.initials: E
authors.lastname: Spiekerkoetter
authors.forename: Xuefei
authors.initials: X
authors.lastname: Tian
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Hopper
authors.forename: Deepti
authors.initials: D
authors.lastname: Sudheendra
authors.forename: Caiyun G
authors.initials: CG
authors.lastname: Li
authors.forename: Nesrine
authors.initials: N
authors.lastname: El-Bizri
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sawada
authors.forename: Roxanna
authors.initials: R
authors.lastname: Haghighat
authors.forename: Roshelle
authors.initials: R
authors.lastname: Chan
authors.forename: Leila
authors.initials: L
authors.lastname: Haghighat
authors.forename: Vinicio
authors.initials: V
authors.lastname: de Jesus Perez
authors.forename: Lingli
authors.initials: L
authors.lastname: Wang
authors.forename: Sushma
authors.initials: S
authors.lastname: Reddy
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.forename: David E
authors.initials: DE
authors.lastname: Solow-Cordero
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beachy
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wandless
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Dijke
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
mesh_terms: D000818:Animals; D017209:Apoptosis; D055415:Bone Morphogenetic Protein 4 / Q000502:physiology; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D057166:High-Throughput Screening Assays; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055806:Microvessels / Q000473:pathology; D058426:Neointima / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011651:Pulmonary Artery / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D051785:Smad Proteins; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II; D022061:Tacrolimus Binding Protein 1A; D016559:Tacrolimus