Low-Dose FK506 (Tacrolimus) in End-Stage Pulmonary Arterial Hypertension

Spiekerkoetter, Edda; Sung, Yon K.; Sudheendra, Deepti; Bill, Matthew A.; Aldred, Micheala A.; Veerdonk, Mariëlle C. van de; Vonk‐Noordegraaf, Anton; Long‐Boyle, Janel; Dash, Rajesh; Yang, Phillip C.; Lawrie, Allan; Swift, Andrew J.; Rabinovitch, Marlene; Zamanian, Roham T.

doi:10.1164/rccm.201411-2061le

Cited by 104 publications

(88 citation statements)

References 15 publications

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“…18 More recently, a pilot study with the same drug ameliorated the clinical condition of 3 patients with end-stage pulmonary hypertension. 53 Considering that, in our hands, tacrolimus upregulates hepcidin in Hjv KO hepatocytes and that in vivo Hjv is dispensable for hepcidin upregulation by iron, 54 tacrolimus-like drugs might be proposed for disorders of impaired hepcidin production, such as hemochromatosis and b-thalassemia. It remains to be defined whether the upregulation of hepcidin obtained by tacrolimus treatment may counteract severe iron overload.…”

mentioning

confidence: 81%

The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes

Colucci

Pagani

Pettinato

et al. 2017

Blood

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Key Points• FKBP12 suppresses hepcidin by interaction with the BMP receptor ALK2.• Disruption of FKBP12-ALK2 interaction increases hepcidin and renders the receptor responsive to the inflammatory ligand Activin A.The expression of the key regulator of iron homeostasis hepcidin is activated by the BMP-SMAD pathway in response to iron and inflammation and among drugs, by rapamycin, which inhibits mTOR in complex with the immunophilin FKBP12. FKBP12 interacts with BMP type I receptors to avoid uncontrolled signaling. By pharmacologic and genetic studies, we identify FKBP12 as a novel hepcidin regulator. Sequestration of FKBP12 by rapamycin or tacrolimus activates hepcidin both in vitro and in murine hepatocytes. Acute tacrolimus treatment transiently increases hepcidin in wild-type mice. FKBP12 preferentially targets the BMP receptor ALK2. ALK2 mutants defective in binding FKBP12 increase hepcidin expression in a ligand-independent manner, through BMP-SMAD signaling. ALK2 free of FKBP12 becomes responsive to the noncanonical inflammatory ligand Activin A. Our results identify a novel hepcidin regulator and a potential therapeutic target to increase defective BMP signaling in

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mentioning

confidence: 81%

The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes

Colucci

Pagani

Pettinato

et al. 2017

Blood

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“…A study screening 3,756 U.S. Food and Drug Administration-approved drugs identified FK506 (tacrolimus) as an effective upregulator of BMP signaling, and low-dose FK506 was an effective treatment for experimental PAH (62). Preliminary data also suggested that compassionate use of low-dose FK506 in three patients with endstage PAH might have been associated with clinical benefit (63). On the basis of these findings, a phase 2a RCT in PAH was initiated to evaluate the safety and tolerability of FK506 in stable patients with PAH (clinicaltrials.gov, NCT01647945).…”

Section: Confirmatory Investigationsmentioning

confidence: 99%

Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension

Bonnet

Provencher

Guignabert

et al. 2017

Am J Respir Crit Care Med

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“…FK506 dissociates FKBP12 from the BMPR2 coreceptor, permitting its phosphorylation and downstream signaling. FK506 reverses severe PH in rats (9), is in compassionate use for patients with PAH (20), and is in preparation for a pivotal clinical trial. Elafin is a neutrophil elastase inhibitor that reverses severe PH in rats and improves angiogenesis in IPAH/HPAH PAEC by enhancing BMPR2 signaling in a caveolin-1-dependent manner (3).…”

Section: Pah Paec and Ipsc-ec Respond Similarly To Elafin And Fk506mentioning

confidence: 99%

Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity

Chappell³

et al. 2017

Am J Respir Crit Care Med

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Rationale: Idiopathic or heritable pulmonary arterial hypertension is characterized by loss and obliteration of lung vasculature. Endothelial cell dysfunction is pivotal to the pathophysiology, but different causal mechanisms may reflect a need for patient-tailored therapies.Objectives: Endothelial cells differentiated from induced pluripotent stem cells were compared with pulmonary arterial endothelial cells from the same patients with idiopathic or heritable pulmonary arterial hypertension, to determine whether they shared functional abnormalities and altered gene expression patterns that differed from those in unused donor cells. We then investigated whether endothelial cells differentiated from pluripotent cells could serve as surrogates to test emerging therapies.Methods: Functional changes assessed included adhesion, migration, tube formation, and propensity to apoptosis. Expression of bone morphogenetic protein receptor type 2 (BMPR2) and its target, collagen IV, signaling of the phosphorylated form of the mothers against decapentaplegic proteins (pSMAD1/5), and transcriptomic profiles were also analyzed.Measurements and Main Results: Native pulmonary arterial and induced pluripotent stem cell-derived endothelial cells from patients with idiopathic and heritable pulmonary arterial hypertension compared with control subjects showed a similar reduction in adhesion, migration, survival, and tube formation, and decreased BMPR2 and downstream signaling and collagen IV expression. Transcriptomic profiling revealed high kisspeptin 1 (KISS1) related to reduced migration and low carboxylesterase 1 (CES1), to impaired survival in patient cells. A beneficial angiogenic response to potential therapies, FK506 and Elafin, was related to reduced slit guidance ligand 3 (SLIT3), an antimigratory factor.Conclusions: Despite the site of disease in the lung, our study indicates that induced pluripotent stem cell-derived endothelial cells are useful surrogates to uncover novel features related to disease mechanisms and to better match patients to therapies.

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Low-Dose FK506 (Tacrolimus) in End-Stage Pulmonary Arterial Hypertension

Cited by 104 publications

References 15 publications

The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes

The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes

Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension

Induced Pluripotent Stem Cell Model of Pulmonary Arterial Hypertension Reveals Novel Gene Expression and Patient Specificity

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