Aldose reductase mediates the mitogenic signals of cytokines

Kota V. Ramana, Deepak Chandra, Sanjay Srivastava, Aruni Bhatnagar, Satish K. Srivastava

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Chronic hyperglycemia is associated with the activation of aldose reductase (AR), an increase in cytokines such as TNF-α and IL-8 and oxidative stress. Alterations in this interdependent cascade of signals may be responsible for the diabetes-induced increase in the incidence and severity of cardiovascular diseases such as atherosclerosis and hypertension. We have previously shown that inhibition of AR prevents cultured vascular smooth muscle cell (VSMC) growth and restenosis of balloon-injured carotid arteries. To identify the mechanisms by which inhibition of AR prevents cell growth, we examined the effects of AR inhibition on mitogenic signaling by cytokines. Stimulation with TNF-α led to the activation of the transcription factor NF-κB and enhanced VSMC growth. Treatment with the AR inhibitors sorbinil or tolrestat, attenuated mitogen-induced activation of NF-κB and VSMC proliferation. In cultured VSMC, AR inhibitors prevented signaling events upstream of NF-κB activation, i.e. IκB-α phosphorylation and IκB-α degradation. Inhibition of AR also prevented protein kinase C (PKC) activation by TNF-α, but did not affect PKC activation by phorbol esters, indicating that inhibition of AR interrupts mitogenic signaling upstream of PKC. Together, these results indicate a pivotal role of AR or its reaction product(s) in the mitogenic signals initiated by cytokines that are elevated in diabetes and its cardiovascular complications such as atherosclerosis. These observations suggest a possible therapeutic use of AR inhibitors in these pathological conditions.

Original languageEnglish (US)
Pages (from-to)587-596
Number of pages10
JournalChemico-Biological Interactions
Volume143-144
DOIs
StatePublished - Feb 1 2003

Keywords

  • Aldose reductase
  • Cell growth
  • Smooth muscle cell
  • Sorbinil
  • TNF-α

ASJC Scopus subject areas

  • Toxicology

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