RGD Reference Report - FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. - Rat Genome Database

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FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension.

Authors: Spiekerkoetter, Edda  Tian, Xuefei  Cai, Jie  Hopper, Rachel K  Sudheendra, Deepti  Li, Caiyun G  El-Bizri, Nesrine  Sawada, Hirofumi  Haghighat, Roxanna  Chan, Roshelle  Haghighat, Leila  de Jesus Perez, Vinicio  Wang, Lingli  Reddy, Sushma  Zhao, Mingming  Bernstein, Daniel  Solow-Cordero, David E  Beachy, Philip A  Wandless, Thomas J  Ten Dijke, Peter  Rabinovitch, Marlene 
Citation: Spiekerkoetter E, etal., J Clin Invest. 2013 Aug;123(8):3600-13. doi: 10.1172/JCI65592. Epub 2013 Jul 15.
RGD ID: 329848996
Pubmed: PMID:23867624   (View Abstract at PubMed)
PMCID: PMC3726153   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI65592   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
semaxanib increases expression ISOIl2 (Rattus norvegicus)329848996; 329848996semaxanib (SUGEN) increases expression of IL2 mRNA in rat whole lungRGD 
semaxanib increases expression EXP 329848996semaxanib (SUGEN) increases expression of IL2 mRNA in rat whole lungRGD 
tacrolimus (anhydrous) increases expression ISOApln (Mus musculus)329848996; 329848996tacrolimus increases expression of mRNA in lung microvessel PAEC from BMPR2-/- miceRGD 
tacrolimus (anhydrous) increases expression EXP 329848996; 329848996tacrolimus increases expression of mRNA in lung microvessel PAEC from BMPR2-/- miceRGD 
tacrolimus (anhydrous) affects bindingEXP 329848996tacrolimus affects binding of Fkbp12 to type 1 receptors in 293T cellsRGD 
tacrolimus (anhydrous) affects bindingISOFKBP1A (Homo sapiens)329848996; 329848996tacrolimus affects binding of Fkbp12 to type 1 receptors in 293T cellsRGD 
tacrolimus (anhydrous) increases expression ISOId1 (Mus musculus)329848996; 329848996tacrolimus increases expression of Id1 mRNA and protein in mouse microvessel PAECRGD 
tacrolimus (anhydrous) multiple interactionsISOIl2 (Rattus norvegicus)329848996; 329848996tacrolimus inhibits the reaction [semaxanib (SUGEN) increases expression of IL2 mRNA] in rat whole lungRGD 
tacrolimus (anhydrous) increases expression EXP 329848996tacrolimus increases expression of Id1 mRNA and protein in mouse microvessel PAECRGD 
tacrolimus (anhydrous) multiple interactionsEXP 329848996tacrolimus inhibits the reaction [semaxanib (SUGEN) increases expression of IL2 mRNA] in rat whole lungRGD 
tacrolimus (anhydrous) increases expression ISONos3 (Mus musculus)329848996; 329848996tacrolimus increases expression of mRNA in lung microvessel PAEC from BMPR2-/- miceRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
response to tacrolimus  IEP 329848996; 329848996 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Apln  (apelin)
Bmpr2  (bone morphogenetic protein receptor type 2)
Fkbp1a  (FKBP prolyl isomerase 1A)
Id1  (inhibitor of DNA binding 1)
Ifng  (interferon gamma)
Il2  (interleukin 2)
Nos3  (nitric oxide synthase 3)

Genes (Mus musculus)
Apln  (apelin)
Bmpr2  (bone morphogenetic protein receptor type 2)
Fkbp1a  (FK506 binding protein 1a)
Id1  (inhibitor of DNA binding 1, HLH protein)
Ifng  (interferon gamma)
Il2  (interleukin 2)
Nos3  (nitric oxide synthase 3, endothelial cell)

Genes (Homo sapiens)
APLN  (apelin)
BMPR2  (bone morphogenetic protein receptor type 2)
FKBP1A  (FKBP prolyl isomerase 1A)
ID1  (inhibitor of DNA binding 1)
IFNG  (interferon gamma)
IL2  (interleukin 2)
NOS3  (nitric oxide synthase 3)


Additional Information