4.5 Article

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

Journal

JOURNAL OF DIABETES
Volume 6, Issue 6, Pages 595-602

Publisher

WILEY
DOI: 10.1111/1753-0407.12132

Keywords

extracellular signal-regulated kinase-5; hyperinsulinemia; tumor necrosis factor alpha; type-2 diabetes mellitus; vascular cell adhesion molecule-1

Funding

  1. Research Service of the Department of Veterans Affairs
  2. VA Career Development Award

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Background: Atherosclerosis may be stimulated by the increased presence of insulin and tumor necrosis-factor-alpha (TNF alpha) 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 TNF alpha-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 TNF alpha (1 ng/mL) alone, or (iii) insulin plus TNFa for 6 h. Thereafter either total VCAM-1 protein or surface VCAM-1 protein was determined. Results: Genetic inhibition of ERK5 decreased TNF alpha-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 TNFa-stimulated total VCAM-1 expression, but significantly (P < 0.05) decreased insulin plus TNFa-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 TNF alpha-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 TNF alpha-stimulated VCAM-1 expression, but also has differential regulation of insulin plus TNF alpha-stimulated total and surface VCAM-1 expression, suggesting that other intermediates of the insulin and TNF alpha intracellular pathways are contributing to atherogenesis.

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