Low-dose FK506 (tacrolimus) in end-stage pulmonary arterial hypertension

E Spiekerkoetter, YK Sung, D Sudheendra… - American journal of …, 2015 - atsjournals.org
E Spiekerkoetter, YK Sung, D Sudheendra, M Bill, MA Aldred, MC van de Veerdonk…
American journal of respiratory and critical care medicine, 2015atsjournals.org
Despite recent advances in therapy, pulmonary arterial hypertension (PAH), characterized
by occlusive vasculopathy of the pulmonary arteries, remains a progressive disease without
a cure (1–3). Although currently approved PAH medications have not demonstrated
antiremodeling properties in humans, novel antiproliferative strategies have shown some
benefits and also raised safety concerns (4–6); for example, none target a genetic
predisposition of PAH: dysfunctional bone morphogenetic protein receptor 2 (BMPR2) …
Despite recent advances in therapy, pulmonary arterial hypertension (PAH), characterized by occlusive vasculopathy of the pulmonary arteries, remains a progressive disease without a cure (1–3). Although currently approved PAH medications have not demonstrated antiremodeling properties in humans, novel antiproliferative strategies have shown some benefits and also raised safety concerns (4–6); for example, none target a genetic predisposition of PAH: dysfunctional bone morphogenetic protein receptor 2 (BMPR2) signaling.
Loss-of-function mutations in BMPR2 in patients with familial and idiopathic PAH (7–9) are associated with increased pulmonary vasculopathy (10). Furthermore, reduced BMPR2 expression is observed even in patients without a mutation, reinforcing the importance of decreased BMPR2 in PAH (11). In a high-throughput screen of 3,600 drugs approved by the US Food and Drug Administration, we identified low-dose FK506 (tacrolimus) as a potent BMPR2 activator that reversed experimental PAH (12). We therefore hypothesized that low-dose FK506 would be beneficial in patients with PAH by increasing BMPR2 signaling.
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