Conference: 2012 International PHA Conference and Scientific Sessions
Release Date: 06.22.2012
Presentation Type: Abstracts
BACKGROUND: Dysfunctional bone morphogenetic protein receptor (BMPR)2 signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We hypothesized that increasing BMPR2 signaling might rescue endothelial dysfunction and reverse PAH.
METHODS: 3600 FDA approved drugs were screened for their propensity to activate BMP signaling, using C2C12 cells expressing a BMP response element (BRE) from the Id1 promoter fused to the luciferase-gene (BRE-luc). We tested in cell culture whether the best “hit” would rescue BMPR2 signaling as well as endothelial cell function in control and IPAH Pulmonary Artery (PA)ECs. We then assessed whether the BMPR2 activator could also reverse established PAH in an experimental rat model of severe pulmonary hypertension that mimics clinical disease (SU5416/hypoxia/normoxia).
RESULTS: FK-506 (tacrolimus) was the main activator of BMPR2 signaling in our screen and low dose FK-506 (0.2 ng/ml) rescued BMPR2 signaling and tube formation in patient PAECs where BMP4 (10ng/ml) was ineffective (n=3). In rats with established PAH after injury with the VEGF receptor blocker SUGEN5416 and hypoxia, a 3-week treatment with low dose FK-506 via osmotic pump (0.05mg/kg/d) prevented progression and induced regression of PAH (RVSP 66.5±4.1mmHg vs 39.5±0.6 mmHg, RVH 0.49±0.07 vs 0.34±0.02, n=8, p<0.05). Neointima formation in small pulmonary arteries per total vessel number decreased from 61.2±6.1% to 16.2±5.8% (n=4, p<0.01).
CONCLUSION: As FK-506 is an FDA approved drug it would be an ideal drug to test in PAH patients where BMPR2 signaling is dysfunctional.