Extracellular signal-regulated kinase-5: Novel mediator of insulin and tumor necrosis factor α-stimulated vascular cell adhesion molecule-1 expression in vascular cells

J Diabetes. 2014 Nov;6(6):595-602. doi: 10.1111/1753-0407.12132. Epub 2014 Feb 26.


Background: Atherosclerosis may be stimulated by the increased presence of insulin and tumor necrosis-factor-α (TNFα) with subsequent expression of vascular cell adhesion molecule-1 (VCAM-1). We hypothesized that extracellular signal-regulated kinase-5 (ERK5) plays an important role in insulin and TNFα-stimulated total and cell surface VCAM-1 expression.

Methods: Rat aorta vascular endothelial cells were first transfected with either no inhibitory RNA, inactive (scrambled) inhibitory ERK5 RNA (scERK5) or active inhibitory ERK5 RNA (siERK5) and then treated with either (i) no analog; (ii) insulin (1 nM), or TNFα (1 ng/mL) alone, or (iii) insulin plus TNFα for 6 h. Thereafter either total VCAM-1 protein or surface VCAM-1 protein was determined.

Results: Genetic inhibition of ERK5 decreased TNFα-stimulated total VCAM-1 expression by 57% and surface expression by 27%. In contrast, genetic inhibition of ERK5 did not significantly decrease insulin-stimulated total or surface VCAM-1 expression. Interestingly, genetic inhibition of ERK5 did not significantly decrease insulin plus TNFα-stimulated total VCAM-1 expression, but significantly (P < 0.05) decreased insulin plus TNFα-stimulated surface VCAM-1 expression 41%.

Conclusions: We report here that ERK5 plays a minor role in insulin-stimulation of VCAM-1, but plays a significant role in TNFα-stimulation of both total and cell surface VCAM-1 protein expression. Taken together, these results demonstrate that not only does ERK5 have differential mediation of insulin and TNFα-stimulated VCAM-1 expression, but also has differential regulation of insulin plus TNFα-stimulated total and surface VCAM-1 expression, suggesting that other intermediates of the insulin and TNFα intracellular pathways are contributing to atherogenesis.

Keywords: extracellular signal-regulated kinase-5; hyperinsulinemia; tumor necrosis factor α; type-2 diabetes mellitus; vascular cell adhesion molecule-1; 关键词:细胞外信号调节激酶-5,高胰岛素血症,肿瘤坏死因子α,2型糖尿病,血管细胞粘附分子-1.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Aorta / cytology
  • Aorta / drug effects
  • Aorta / metabolism*
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Insulin / pharmacology*
  • Mitogen-Activated Protein Kinase 7 / genetics
  • Mitogen-Activated Protein Kinase 7 / metabolism*
  • Rats
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism*


  • Insulin
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Mitogen-Activated Protein Kinase 7