Proteinase-activated Receptor 1 Antagonism Ameliorates Experimental Pulmonary Hypertension.

Aims: Pulmonary hypertension is characterized by progressive increases in pulmonary vascular resistance. Thrombotic lesions are common pathological findings. The pulmonary artery has a unique property regarding the vasoconstrictive response to thrombin, which is mediated by proteinase-activated receptor 1 (PAR1). We aim to elucidate the role of PAR1 in the development and progression of pulmonary hypertension.

Methods and Results: A rat model of monocrotaline-induced pulmonary hypertension and a mouse model of hypoxia-induced pulmonary hypertension were used to investigate the effects of atopaxar (a PAR1 antagonist) and PAR1 knockout on hemodynamic parameters, right ventricular hypertrophy, vascular remodeling and survival. In perfused lung preparations, the pressor response to PAR1 agonist was significantly augmented in monocrotaline-induced pulmonary hypertension. Both the preventive and therapeutic administration of atopaxar significantly inhibited the increase in pulmonary vascular resistance and the development of right ventricular hypertrophy and prolonged survival. A real-time PCR revealed that the level of PAR1 mRNA in the pulmonary artery was significantly higher than that in any of the systemic arteries examined in control rats, and the level was significantly upregulated in monocrotaline-induced pulmonary hypertension. PAR1 gene knockout significantly attenuated the hemodynamic and histological findings in the mouse model of hypoxia-induced pulmonary hypertension.

Conclusions: The specific expression of PAR1 in the pulmonary artery and its upregulation were suggested to play a critical role in the development and progression of experimental pulmonary hypertension in murine models. PAR1 is a potential therapeutic target for the treatment of pulmonary hypertension.