Proteinase-activated receptor 1 antagonism ameliorates experimental pulmonary hypertension

Autor: Katsuya Hirano, Yoshitaka Hirooka, Yukimitsu Kuwabara, Kenji Sunagawa, Mayumi Hirano, Mariko Tanaka-Ishikawa, Hiroyuki Tsutsui, Kohtaro Abe
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
Agonist
Pyridines
Physiology
medicine.drug_class
Hypertension
Pulmonary
Pulmonary Artery
Vascular Remodeling
030204 cardiovascular system & hematology
Pharmacology
Ventricular Function
Left
Vascular remodelling in the embryo
Rats
Sprague-Dawley
03 medical and health sciences
0302 clinical medicine
Right ventricular hypertrophy
Physiology (medical)
medicine.artery
Animals
Medicine
Arterial Pressure
Receptor
PAR-1
Antihypertensive Agents
Mice
Knockout
Monocrotaline
Lung
Hypertrophy
Right Ventricular
Ventricular Remodeling
business.industry
Thrombin
Hypoxia (medical)
medicine.disease
Pulmonary hypertension
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Pulmonary artery
cardiovascular system
Vascular resistance
Imines
medicine.symptom
Cardiology and Cardiovascular Medicine
business
Zdroj: Cardiovascular Research. 115:1357-1368
ISSN: 1755-3245
0008-6363
DOI: 10.1093/cvr/cvy284
Popis: Aims Pulmonary hypertension (PH) is characterized by progressive increases in pulmonary vascular resistance (PVR). 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 PH. Methods and results A rat model of monocrotaline-induced PH and a mouse model of hypoxia (Hx)-induced PH were used to investigate the effects of atopaxar (a PAR1 antagonist) and PAR1 knockout on haemodynamic parameters, right ventricular hypertrophy (RVH), vascular remodelling and survival. In perfused lung preparations, the pressor response to PAR1 agonist was significantly augmented in monocrotaline-induced PH. Both the preventive and therapeutic administration of atopaxar significantly inhibited the increase in PVR and the development of RVH 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 up-regulated in monocrotaline-induced PH. PAR1 gene knockout significantly attenuated the haemodynamic and histological findings in the mouse model of Hx-induced PH. Conclusion The specific expression of PAR1 in the pulmonary artery and its up-regulation were suggested to play a critical role in the development and progression of experimental PH in murine models. PAR1 is a potential therapeutic target for the treatment of PH.
Databáze: OpenAIRE
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