Abstract 16487: Crucial Role of Proteinase-Activated Receptor 1 in the Development of Monocrotaline Induced Pulmonary Arterial Hypertension in Rats
Introduction: Pulmonary arterial hypertension (PAH) is a disease with poor prognosis, as characterized by a progressive elevation of pulmonary artery resistance and pressure. PAH is frequently associated with in situ thrombus. Thrombin exerts various vascular effects, such as endothelium-dependent relaxation, vasoconstriction and vascular remodeling, by acting on proteinase-activated receptor 1 (PAR1). We revealed a unique property of pulmonary artery that contracts in response to thrombin, which is in clear contrast to the systemic artery, where an endothelium-dependent relaxation was most frequently observed.
Hypothesis: PAR1 plays a key role in the pathogenesis and pathophysiology in PAH, and it could be a novel therapeutic target for the treatment of PAH. We therefore investigated the therapeutic effect of a PAR1 antagonist on monocrotaline (MCT)-induced pulmonary hypertension in rats.
Methods and Results: Rats received a single subcutaneous injection of MCT (60 mg/kg) on day 0, and they were thereafter treated with either atopaxar (atopaxar group; 30 mg/kg/day, once a day by gavage) or vehicle (MCT group). On day 21, we evaluated hemodynamics and histology. MCT markedly increased right ventricular (RV) systolic pressure (MCT: 74±4 mmHg in 10 rats vs. Control: 23±3 mmHg in 6 rats, p<0.05 ) and hypertrophied RV as evaluated by the weight ratio of RV/(LV+septum) (MCT: 0.43±0.02 in 11 rats, vs. normal: 0.26±0.01 in 6 rats, p<0.05 ). MCT significantly increased medial thickness (0.56±0.01 in 54 vessels of 3 rats) in comparison to the normal rats (0.26±0.01 in 55 vessels of 3 rats), as evaluated by a ratio of medial area/arterial area. Treatment with atopaxar significantly attenuated the increase in RV systolic pressure (47±3 mmHg in 15 rats, p<0.05), RV hypertrophy (0.31±0.02, in 15 rats, p<0.05) and medial thickening (0.45±0.02 in 53 vessels of 3 rats). Atopaxar did not affect arterial pressure or heart rate.
Conclusion: This study provides the first evidence that PAR1 plays a critical role in the pathogenesis of PAH. The results suggest a potential of PAR1 as a novel therapeutic target for the treatment of PAH.
- © 2013 by American Heart Association, Inc.