Increasing extracellular Ca2 + sensitizes TNF-alpha-induced vascular cell adhesion molecule-1 (VCAM-1) via a TRPC1/ERK1/2/NFκB-dependent pathway in human vascular endothelial cells

Songtao Li, Hua Ning, Yaxin Ye, Wei Wei, Rui Guo, Qing Song, Lei Liu, Yunyun Liu, Lixin Na, Yuchun Niu, Xia Chu, Rennan Feng, Naima Moustaid-Moussa, Ying Li, Changhao Sun

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Increasing circulating Ca2 + levels within the normal range has been reported to positively correlate with the incidence of fatal cardiovascular diseases (CVDs). However, limited studies have been able to delineate the potential mechanism(s) linking circulating Ca2 + to CVD. In this study, we exposed primary human umbilical vein endothelial cells (HUVECs) and human umbilical vein cell line (EA.hy926) to different extracellular Ca2 + to mimic the physiological state. Our data revealed that increasing extracellular Ca2 + significantly enhanced susceptibility to tumor necrosis factor (TNF)-alpha-stimulated vascular cell adhesion molecule (VCAM)-1 expression and monocytes adhesion. Knocking-down VCAM-1 by siRNA abolished calcium-induced monocytes adhesion on HUVECs. Follow up mechanistic investigations identified that extracellular Ca2 +-increased calcium influx contributed to the activation of VCAM-1. This was mediated via upregulation of transient receptor potential channel (TRPC)1 in a nuclear factor (NF)κB-dependent manner. Most importantly, we found that a novel TRPC1-regulated extracellular signal-regulated kinase 1/2 (ERK1/2) pathway exclusively contributed to calcium-induced NFκB activation. This study provided direct evidence that increasing extracellular Ca2 + enhanced TNF-alpha-induced VCAM-1 activation and monocytes adhesion. Moreover, we identified a novel TRPC1/ERK1/2/NFκB signaling pathway mediating VCAM-1 activation and monocyte adhesion in this pathological process. Our studies indicate that blood calcium levels should be strictly monitored to help prevent CVD, and that TRPC1 might act as a potential target for the treatment and prevention against increased circulating calcium-enhanced CVDs.

Original languageEnglish
Pages (from-to)1566-1577
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1864
Issue number10
DOIs
StatePublished - Oct 2017

Keywords

  • Calcium influx
  • Extracellular Ca
  • TRPC1
  • Vascular cell adhesion molecule-1
  • Vascular endothelial cell

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