Aldose reductase regulates vascular smooth muscle cell proliferation by modulating G1/S phase transition of cell cycle

Ravinder Tammali, Ashish Saxena, Satish K. Srivastava, Kota V. Ramana

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Abnormal proliferation of vascular smooth muscle cells (VSMC) is a key feature of development of cardiovascular complications, atherosclerosis, and restenosis. Patients with diabetes have higher risk for restenosis after coronary angioplasty than nondiabetic patients due to hyperglycemiainduced release of cytokines such as TNF-α. However, the molecular mechanisms regulating VSMC proliferation remain unclear. Herein, we report that inhibition of the polyol pathway enzyme aldose reductase (AR) prevents high glucose (HG)- and/or TNF-α-induced VSMC proliferation by accumulating cells at the G1 phase of the cell cycle. Treatment of VSMC with AR inhibitor sorbinil prevented HG- as well as TNF-α-induced phosphorylation of retinoblastoma protein and activation of E2F-1. Inhibition of AR also prevented HG- and TNF-α-induced phosphorylation of cyclin-dependent kinase (cdk)-2andexpression of G1/S transition regulatory proteins such as cyclin D1, cyclin E, cdk-4, c-myc, and proliferative cell nuclear antigen. More importantly, inhibition of AR prevented the increased expression of E2F-1 and proliferative cell nuclear antigen in diabetic rat aorta. Treatment of VSMC with the most abundant and toxic lipid aldehyde 4-hydroxy-trans-2-nonenal (HNE) or its glutathione conjugate [glutathionyl (GS)-HNE] or AR-catalyzed product of GS-HNE, GS-1,4-dihydroxynonane, resulted in increased E2F-1 expression. Inhibition of AR prevented HNEor GS-HNE-induced but not GS-1,4-dihydroxynonane- induced up-regulation of E2F-1. Collectively, these results show that AR could regulate HG- and TNF-α-induced VSMC proliferation by altering the activation of G1/S-phase proteins such as E2F-1, cdks, and cyclins. Thus, inhibition of AR may be a useful therapeutic approach in preventing vascular complications.

Original languageEnglish (US)
Pages (from-to)2140-2150
Number of pages11
JournalEndocrinology
Volume151
Issue number5
DOIs
StatePublished - May 1 2010

ASJC Scopus subject areas

  • Endocrinology

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