Role of endothelial nitric oxide synthase and collagen metabolism in right ventricular remodeling due to pulmonary hypertension

Suvd Nergui, Yoshihiro Fukumoto, Zhulanqiqige Do.e, Sota Nakajima, Toru Shimizu, Shohei Ikeda, Md Elias-Al-Mamun, Hiroaki Shimokawa

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: Pulmonary hypertension (PH) causes elevated right ventricular (RV) systolic pressure, RV remodeling and finally RV failure to death. However, the mechanisms of RV remodeling in PH remain to be fully elucidated. Methods and Results: RV autopsy samples from 6 PH patients with RV failure against 3 age- and sex-matched controls were first examined. Next, RV remodeling in 2 mouse models of chronic hypoxia-induced PH with endothelial nitric oxide synthase-deficient (eNOS-/-) and collagenase-resistant knock-in (ColR/R) mice were examined. In humans, RV failure was associated with RV hypertrophy, interstitial and perivascular fibrosis, decreased RV capillary density and increased macrophage recruitment. Furthermore, immunostaining showed that perivascular matrix metalloproteinase- 2 was increased in PH patients with RV failure. In animals, both hypoxic eNOS-/- and ColR/R mice developed a greater extent of RV hypertrophy, perivascular remodeling and macrophage infiltration compared with wild-type mice. Capillary rarefaction was developed in hypoxic eNOS-/- mice, while ColR/R mice were able to increase their capillary density in the RV in response to chronic hypoxia. Both mouse models showed increased autophagy even under normoxic condition. Conclusions: These results indicate that RV remodeling occurs early during PH development through fibrosis, perivascular remodeling, capillary rarefaction and autophagy, in which the eNOS pathway and collagen metabolism might be involved.

Original languageEnglish
Pages (from-to)1465-1474
Number of pages10
JournalCirculation Journal
Volume78
Issue number6
DOIs
Publication statusPublished - 2014

Keywords

  • Endothelial nitric oxide synthase
  • Inflammatory cell
  • Pulmonary hypertension
  • Rho-kinase
  • Right ventricular fibrosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Nergui, S., Fukumoto, Y., Do.e, Z., Nakajima, S., Shimizu, T., Ikeda, S., Elias-Al-Mamun, M., & Shimokawa, H. (2014). Role of endothelial nitric oxide synthase and collagen metabolism in right ventricular remodeling due to pulmonary hypertension. Circulation Journal, 78(6), 1465-1474. https://doi.org/10.1253/circj.CJ-13-1586