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Pflügers Archiv - European Journal of Physiology

, Volume 470, Issue 9, pp 1405–1417 | Cite as

Characterization of fibroblasts from hypertrophied right ventricle of pulmonary hypertensive rats

  • Keisuke Imoto
  • Muneyoshi OkadaEmail author
  • Hideyuki Yamawaki
Signaling and cell physiology
Part of the following topical collections:
  1. Topical Collection: Signaling and cell physiology

Abstract

Pulmonary arterial hypertension (PAH), which is characterized by an elevation of pulmonary arterial resistance, leads to a lethal right heart failure. It is an urgent issue to clarify the pathogenesis of PAH-induced right heart failure. The present study aimed to elucidate the characteristics of cardiac fibroblasts (CFs) isolated from hypertrophied right ventricles of monocrotaline (MCT)-induced PAH model rats. CFs were isolated from the right ventricles of MCT-injected rats (MCT-CFs) and saline-injected control rats (CONT-CFs). Expression of α-smooth muscle actin and collagen type I in MCT-CFs was lower than that in CONT-CFs. On the other hand, proliferation, migration, and matrix metalloproteinase (MMP)-9 production were significantly enhanced in MCT-CFs. In MCT-CFs, phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK), and Ca2+/calmodulin-dependent protein kinase (CaMK) II was significantly enhanced. In addition to mRNA expression of Orai1, a Ca2+ release-activated Ca2+ channel, and stromal interaction molecules (STIM) 1, an endoplasmic reticulum Ca2+ sensor, the associated store-operated Ca2+ entry (SOCE) was significantly higher in MCT-CFs than CONT-CFs. Pharmacological inhibition of ERK1/2 pathway prevented the enhanced proliferation of MCT-CFs. The enhanced migration of MCT-CFs was prevented by a pharmacological inhibition of ERK1/2, JNK, CaMKII, or SOCE pathway. The enhanced MMP-9 production in MCT-CFs was prevented by a pharmacological inhibition of ERK1/2, CaMKII, or SOCE pathway but not JNK. The present results suggested that MCT-CFs exhibit proliferative and migratory phenotypes perhaps through multiple signaling pathways. This study for the first time determined the characteristics of CFs isolated from hypertrophied right ventricles of MCT-induced PAH model rats.

Keywords

Cardiac fibroblasts Pulmonary arterial hypertension Right heart failure Proliferation Migration 

Notes

Funding information

This research was supported by JSPS KAKENHI Grant Number 18J11540 (Grant-in-Aid for JSPS Research Fellow).

Compliance with ethical standards

All animal care and treatments were conducted in accordance with the National Institutes of Health Guide for the Care of Laboratory Animals and the guidelines of the Kitasato University. All animal studies were approved by the President of Kitasato University through the judgment by Institutional Animal Care and Use Committee of Kitasato University (Approval no. 16-043 and 17-085).

Supplementary material

424_2018_2158_MOESM1_ESM.pdf (163 kb)
ESM 1 (PDF 163 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Laboratory of Veterinary Pharmacology, School of Veterinary MedicineKitasato UniversityTowada CityJapan

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