Proteinase-activated receptor 1 antagonism ameliorates experimental pulmonary hypertension

Yukimitsu Kuwabara, Mariko Tanaka-Ishikawa, Kohtaro Abe, Mayumi Hirano, Yoshitaka Hirooka, Hiroyuki Tsutsui, Kenji Sunagawa, Katsuya Hirano

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Abstract

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.

Original languageEnglish
Pages (from-to)1357-1368
Number of pages12
JournalCardiovascular research
Volume115
Issue number8
DOIs
Publication statusPublished - Jul 1 2019

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PAR-1 Receptor
Pulmonary Hypertension
Monocrotaline
Pulmonary Artery
Right Ventricular Hypertrophy
Vascular Resistance
Hemodynamics
Gene Knockout Techniques
Thrombin
Real-Time Polymerase Chain Reaction
Up-Regulation
Arteries

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Proteinase-activated receptor 1 antagonism ameliorates experimental pulmonary hypertension. / Kuwabara, Yukimitsu; Tanaka-Ishikawa, Mariko; Abe, Kohtaro; Hirano, Mayumi; Hirooka, Yoshitaka; Tsutsui, Hiroyuki; Sunagawa, Kenji; Hirano, Katsuya.

In: Cardiovascular research, Vol. 115, No. 8, 01.07.2019, p. 1357-1368.

Research output: Contribution to journalArticle

Kuwabara, Yukimitsu ; Tanaka-Ishikawa, Mariko ; Abe, Kohtaro ; Hirano, Mayumi ; Hirooka, Yoshitaka ; Tsutsui, Hiroyuki ; Sunagawa, Kenji ; Hirano, Katsuya. / Proteinase-activated receptor 1 antagonism ameliorates experimental pulmonary hypertension. In: Cardiovascular research. 2019 ; Vol. 115, No. 8. pp. 1357-1368.
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