Abstract 8785: CYT387, a Novel Jak1/Jak2 Inhibitor, Prevents Progression of Pulmonary Arterial Hypertension in the Rat Monocrotaline Model
Introduction: The JAK/STAT pathway has been implicated in the pathophysiology of pulmonary arterial hypertension (PAH).
Hypothesis: This study tested the hypothesis that CYT387 (N-(cyanomethyl)-(4-(2-4-morpholinophenylamino) pyrimidin-4-yl)benzamide) a highly potent combined JAK1/JAK2 inhibitor, could ameliorate PAH.
Methods: The effect of CYT387 on PAH was examined in the rat monocrotaline model. Three weeks after administration of monocrotaline, study animals were dosed with either vehicle or CYT387 via osmotic mini-pumps for a period of 1 week. In a subset of animals, pulmonary arterial pressure was monitored with DSI telemetry devices. At the end of the study, the heart and lungs were harvested for Western blot and histologic analysis. The effect of CYT387 on pre-constricted rat pulmonary artery rings and on IL-6 induced STAT3 phosphorylation in human pulmonary microvascular endothelial cells was examined. Statistical analysis was performed with SPSS 14.0.
Results: Prior to starting treatment (day 21 post monocrotaline),the mean PA pressure (±SEM) was 31.6 ± 2.7 mm Hg (CYT387 n=5) and 35.4 ± 3.7 mm (vehicle n=4; p=NS). On day seven of treatment the mean PA pressure (±SEM) in the drug treated group was 23.0 ± 2.8 mm Hg vs. 63.7 ± 9.5 mm Hg in the vehicle group, a 60% reduction (p=0.001). CYT387 decreased phosphorylated STAT1, 3, and 5 in the lungs of treated animals compared to vehicle. Pulmonary arteriole hypertrophy/hyperplasia was lower in the CYT387 treated group (media area to lumen area ratio: 0.99± 0.07 (CYT387 group) vs. 3.1± 0.48 (vehicle), p<0.01). There was a significant decrease in the RV free wall weight (0.278± 0.03 g vs. 0.407± 0.03 g), and the RV/LV free wall weight ratio (0.52 ±0.05 vs. 0.79 ±0.06); CYT387 (n=8) vs. vehicle group (n=11), p<0.01). CYT387 had a significant vasorelaxant effect on rat pulmonary artery rings pre-constricted with phenylephrine or serotonin. The IC50 for CYT387 on IL6 induced STAT3 phosphorylation in pulmonary microvascular endothelial cells was determined by Western blotting to be ∼0.5 μM.
Conclusion: CYT387, a novel and highly potent JAK1/JAK2 inhibitor prevented the progression of PAH in the rat monocrotaline model of this disease.
- © 2010 by American Heart Association, Inc.