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

Spiekerkoetter E, Tian X, Cai J, Hopper RK, Sudheendra D, Li CG et al. The Journal of Clinical Investigation 2013 ; 123(8) :3600-3613.

Background: Despite advances in the treatment of pulmonary arterial hypertension (PAH), new therapies are needed; targeting cellular mechanisms to reverse vascular remodeling could be beneficial in patients with PAH. One potential strategy would be to improve function of the bone morphogenetic protein receptor-2 (BMPR2) signaling pathway, which is thought to inhibit proliferation of vascular smooth muscle. The goal of this current study was to use a high-throughput assay to find FDA-approved medications that increase signaling through the BMPR2 pathway, and then test these medications in human pulmonary artery endothelial cells and experimental models of PAH.

Methods and Results: A high throughput screen to identify activators of BMPR2 signaling was conducted on 3756 FDA-approved drugs.  By measuring inhibitor of differentiation 1 (ID1) activity, a read out for BMPR2 signaling in vascular cells, 3 major activators of BMPR2 signaling were identified: tacrolimus (FK506), ascomycin (FK520), and, to a lesser degree, rapamycin.  FK506 was investigated in human pulmonary artery endothelial cells (HPAECs) and murine models of PAH (monocrotaline and SUGEN/hypoxia). In HPAECs, FK506 increased ID1 mRNA, decreased apoptosis, and increased formation of endothelial cell tubular networks.  In a mouse model of PAH using hypoxia and BMPR2 knockout, low-dose FK506 prevented increased right ventricular systolic pressure (RVSP), RV hypertrophy (RVH), and vascular changes. Low-dose FK506 was also found to reverse PAH in mouse models.  After monocrotaline administration, 3 weeks of FK506 significantly reduced RVSP, RVH, and muscularization.  Low-dose FK506 also reversed neointimal changes caused by SUGEN/hypoxia.

Conclusions: By using a high throughput screening method, FK506 was found to be a major activator of BMPR2 signaling. In pulmonary artery endothelial cells from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling.  FK506 not only prevented PAH in a mouse model, but led to reversal of pulmonary vascular changes induced by both monocrotaline and SUGEN/hypoxia.  The proposed mechanism of FK506 is upregulation of apelin, which raises levels of miRNA that repress epithelial growth factor production, thereby suppressing smooth muscle cell proliferation.  FK506 may be a potential treatment option for humans with PAH. 

Commentary: Currently FDA-approved classes of medications have not provided a cure for PAH and many drug development studies may be hampered by slow discovery of small molecules to treat PAH and absent broad screening protocols. In this paper by Spiekerkoetter et al, the authors developed a high throughput screening technique to identify small molecules to enhance BMPR2-dependent signaling, identified FK506 as a potentially successful drug therapy and investigated the mechanisms that underlie the effect of FK506 and if this screening technique can identify potentially successful therapeutics by testing FK506 in two animal models of pulmonary hypertension.

This paper is important because it is the first to demonstrate proof of the concept that a luciferase reporter assay for ID1 expression can successfully identify compounds that increase expression of this indicator of SMAD-dependent BMPR2 signaling. Moreover, the assay proved successful in two animal models. The strengths of this paper lie in the novel techniques for small molecule screening, the use of multiple animal models and the mechanistic understanding of how FK506 enhances BMPR2-mediated signaling. BMPR2 has multiple signaling cascades, some of which are SMAD-dependent and some of which are not. It is not presently known in humans which signaling pathway or pathways drive development of pulmonary vascular disease, thus this small molecule screening paradigm that only assays SMAD-mediated signaling may not identify other potentially active small molecules. Nonetheless, the authors are to be commended for their creative approach and successful identification of a potential new class of therapeutics for PAH.

Article summary by: Matthew Lammi, MD; Assistant Professor of Medicine, Louisiana State University Health Sciences Center

Expert commentary by: Dr. Anna Hemnes, MD, Assistant Professor of Medicine and Assistant Director of the Pulmonary Vascular Disease Center at Vanderbilt University

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Last Reviewed: September 2016