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FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension
Edda Spiekerkoetter, … , Peter ten Dijke, Marlene Rabinovitch
Edda Spiekerkoetter, … , Peter ten Dijke, Marlene Rabinovitch
Published July 15, 2013
Citation Information: J Clin Invest. 2013;123(8):3600-3613. https://doi.org/10.1172/JCI65592.
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Research Article Vascular biology Article has an altmetric score of 20

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

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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

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 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

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Figure 3

Low-dose FK506 rescues IPAH mvPAEC dysfunction.

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Low-dose FK506 rescues IPAH mvPAEC dysfunction.
(A) Representative immun...
(A) Representative immunoblot and densitometry showing BMPR2 and ID1/β-actin in human PAECs stimulated with BMP4 (10 ng/ml) or FK506 (15 ng/ml) following knockdown of BMPR2 with BMPR2si compared with NTsi as control (n = 3; *P < 0.05 vs. CON, 2-way ANOVA). (B) Representative immunoblot and densitometry of mvPAECs from 3 patients with IPAH showing ID1/β-actin at baseline (CON) or at various time points after stimulation with BMP4 (10 ng/ml) or FK506 (15 ng/ml) (n = 3; *P < 0.05 vs. CON, 2-way ANOVA). (C) ID1/18S mRNA 4 hours after and apelin/18S mRNA 8 hours after stimulation with BMP4 (10 ng/ml) and low-dose FK506 (0.2 ng/ml) in the same IPAH mvPAECs as in B (n = 3; *P < 0.05; **P < 0.01, vs. CON, 1-way ANOVA, Dunnett’s post test). (D) Representative images and quantitative analysis of tube number and length of tubes formed in Matrigel with mvPAECs from a patient with IPAH 4 hours after unstimulated CON, VEGF (10 ng/ml), BMP4 (10 ng/ml), and FK506 (0.2 ng/ml) (n = 6; ***P < 0.001; **P < 0.01 vs. CON, 1-way ANOVA, Dunnett’s post test; scale bar: 100 μm). (E) Proposed model of activation of BMPR2 in the presence of a subactivating dose of BMPs and an activating dose of BMPs and mutated or dysfunctional BMPR2 receptor with an activating dose of BMPs or with a subactivating dose of BMPs and FK506. Mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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