Pulmonary arterial hypertension in rats due to age-related arginase activation in intermittent hypoxia

Akina Nara, Hisashi Nagai, Kaori Shintani-Ishida, Sayoko Ogura, Tatsuo Shimosawa, Ichiro Kuwahira, Mikiyasu Shirai, Ken Ichi Yoshida

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Pulmonary arterial hypertension (PAH) is prevalent in patients with obstructive sleep apnea syndrome (OSAS). Aging induces arginase activation and reduces nitric oxide (NO) production in the arteries. Intermittent hypoxia (IH), conferred by cycles of brief hypoxia and normoxia, contributes to OSAS pathogenesis. Here, we studied the role of arginase and aging in the pathogenesis of PAH in adult (9-mo-old) and young (2-mo-old) male Sprague-Dawley rats subjected to IH or normoxia for 4 weeks and analyzed them with a pressure-volume catheter inserted into the right ventricle (RV) and by pulsed Doppler echocardiography. Western blot analysis was conducted on arginase, NO synthase isoforms, and nitrotyrosine. IH induced PAH, as shown by increased RV systolic pressure and RV hypertrophy, in adult rats but not in young rats. IH increased expression levels of arginase I and II proteins in the adult rats. IH also increased arginase I expression in the pulmonary artery endothelium and arginase II in the pulmonary artery adventitia. Furthermore, IH reduced pulmonary levels of nitrate and nitrite but increased nitrotyrosine levels in adult rats. An arginase inhibitor (Nv-hydroxynor-1-arginine) prevented IH-induced PAH and normalized nitrite and nitrate levels in adult rats. IH induced arginase up-regulation and PAH in adult rats, but not in young rats, through reduced NO production. Our findings suggest that arginase inhibition prevents or reverses PAH.

Original languageEnglish
Pages (from-to)184-192
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume53
Issue number2
DOIs
Publication statusPublished - 2015 Aug 1

Keywords

  • Age
  • Arginase
  • Intermittent hypoxia
  • Pulmonary arterial hypertension
  • Sleep apnea syndrome

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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    Nara, A., Nagai, H., Shintani-Ishida, K., Ogura, S., Shimosawa, T., Kuwahira, I., Shirai, M., & Yoshida, K. I. (2015). Pulmonary arterial hypertension in rats due to age-related arginase activation in intermittent hypoxia. American journal of respiratory cell and molecular biology, 53(2), 184-192. https://doi.org/10.1165/rcmb.2014-0163OC