Angiotensin II upregulates fibroblast-myofibroblast transition through Cx43-dependent CaMKII and TGF-β1 signaling in neonatal rat cardiac fibroblasts

Li Cao, Yunlin Chen, Li Lu, Yihao Liu, Yaowen Wang, Jinqi Fan, Yuehui Yin

Research output: Contribution to journalArticlepeer-review

Abstract

In cardiac fibroblasts, angiotensin II (Ang II) can increase connexin 43 (Cx43) expression and promote calmodulin-dependent protein kinase II (CaMKII) activation. Cx43 overexpression is crucial for the fibroblast-myofibroblast transition. The main purpose of the present study was to investigate the role of CaMKII in regulating Cx43 expression and to determine whether the CaMKII/Cx43 pathway is essential for controlling fibroblast activation and differentiation. In vivo, 4 weeks of Ang II infusion enhanced CaMKII activation but reduced Cx43 expression in hearts undergoing fibrosis remodeling, while in cultured neonatal rat fibroblasts, CaMKII activation upregulated Cx43 expression via transforming growth factor-beta1 (TGF-β1). CaMKII inhibition by Ang-(1-7) or autocamtide 2-related inhibitory peptide reversed the Ang II-induced changes in Cx43 expression and attenuated Ang II-induced upregulation of alpha smooth muscle actin and TGF-β1 in both Ang II-infused rats and cultured fibroblasts. Based on the in vivo and in vitro experimental results, CaMKII plays a pivotal role in the Ang II-mediated fibroblast-myofibroblast transition by modulating the expressions of TGF-β1 and Cx43. We conclude that Ang II mediates the fibroblastmyofibroblast transition partially via the Ang II/CaMKII/TGF-β1/Cx43 signaling pathway.

Original languageEnglish (US)
Pages (from-to)843-852
Number of pages10
JournalActa Biochimica et Biophysica Sinica
Volume50
Issue number9
DOIs
StatePublished - Sep 1 2018
Externally publishedYes

Keywords

  • Angiotensin II
  • CaMKII
  • Cardiac fibroblast
  • Connexin 43
  • TGF-β

ASJC Scopus subject areas

  • Molecular Biology
  • Biophysics
  • Biochemistry

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