Aldose reductase mediates mitogenic signaling in vascular smooth muscle cells

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

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

Abnormal vascular smooth muscle cell (VSMC) proliferation is a key feature of atherosclerosis and restenosis; however, the mechanisms regulating growth remain unclear. Herein we show that inhibition of the aldehyde-metabolizing enzyme aldose reductase (AR) inhibits NF-κB activation during restenosis of balloon-injured rat carotid arteries as well as VSMC proliferation due to tumor necrosis factor a (TNF-α) stimulation. Inhibition of VSMC growth by AR inhibitors was not accompanied by increase in cell death or apoptosis. Inhibition of AR led to a decrease in the activity of the transcription factor NF-κB in culture and in the neointima of rat carotid arteries after balloon injury. Inhibition of AR in VSMC also prevented the activation of NF-κB by basic fibroblast growth factor (bFGF), angiotensin-II (Ang-II), and platelet-derived growth factor (PDGF-AB). The VSMC treated with AR inhibitors showed decreased nuclear translocation of NF-κB and diminished phosphorylation and proteolytic degradation of IκB-α. Under identical conditions, treatment with AR inhibitors also prevented the activation of protein kinase C (PKC) by TNF-α, bFGF, Ang-II, and PDGF-AB but not phorbol esters, indicating that AR inhibitors prevent PKC stimulation or the availability of its activator but not PKC itself. Treatment with antisense AR, which decreased the AR activity by >80%, attenuated PKC activation in TNF-α, bFGF, Ang-II, and PDGF-AB-stimulated VSMC and prevented TNF-α-induced proliferation. Collectively, these data suggest that inhibition of NF-κB may be a significant cause of the antimitogenic effects of AR inhibition and that this may be related to disruption of PKC-associated signaling in the AR-inhibited cells.

Original languageEnglish (US)
Pages (from-to)32063-32070
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number35
DOIs
StatePublished - Aug 30 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Ramana, K. V., Chandra, D., Srivastava, S., Bhatnagar, A., Aggarwal, B. B., & Srivastava, S. K. (2002). Aldose reductase mediates mitogenic signaling in vascular smooth muscle cells. Journal of Biological Chemistry, 277(35), 32063-32070. https://doi.org/10.1074/jbc.M202126200