Mitogenic responses of vascular smooth muscle cells to lipid peroxidation-derived aldehyde 4-hydroxy-trans-2-nonenal (HNE): Role of aldose reductase-catalyzed reduction of the HNE-glutathione conjugates in regulating cell growth

Kota Ramana, Aruni Bhatnagar, Sanjay Srivastava, Umesh C. Yadav, Sanjay Awasthi, Yogesh C. Awasthi, Satish Srivastava

Research output: Contribution to journalArticle

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Abstract

Products of lipid peroxidation such as 4-hydroxy-trans-2-nonenal (HNE) trigger multiple signaling cascades that variably affect cell growth, differentiation, and apoptosis. Because glutathiolation is a significant metabolic fate of these aldehydes, we tested the possibility that the bioactivity of HNE depends upon its conjugation with glutathione. Addition of HNE or the cell-permeable esters of glutathionyl-4-hydroxynonenal (GS-HNE) or glutathionyl-1,4-dihydroxynonene (GS-DHN) to cultures of rat aortic smooth muscle cells stimulated protein kinase C, NF-κB, and AP-1, and increased cell growth. The mitogenic effects of HNE, but not GS-HNE or GS-DHN, were abolished by glutathione depletion. Pharmacological inhibition or antisense ablation of aldose reductase (which catalyzes the reduction of GS-HNE to GS-DHN) prevented protein kinase C, NF-κB, and AP-1 stimulation and the increase in cell growth caused by HNE and GS-HNE, but not GS-DHN. The growth stimulating effect of GS-DHN was enhanced in cells treated with antibodies directed against the glutathione conjugate transporters RLIP76 (Ral-binding protein) or the multidrug resistance protein-2. Overexpression of RLIP76 abolished the mitogenic effects of HNE and its glutathione conjugates, whereas ablation of RLIP76 using RNA interference promoted the mitogenic effects. Collectively, our findings suggest that the mitogenic effects of HNE are mediated by its glutathione conjugate, which has to be reduced by aldose reductase to stimulate cell growth. These results raise the possibility that the glutathione conjugates of lipid peroxidation products are novel mediators of cell signaling and growth.

Original languageEnglish (US)
Pages (from-to)17652-17660
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number26
DOIs
StatePublished - Jun 30 2006

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Aldehyde Reductase
Cell growth
Vascular Smooth Muscle
Aldehydes
Lipid Peroxidation
Smooth Muscle Myocytes
Glutathione
Muscle
Cells
Lipids
Growth
Transcription Factor AP-1
Ablation
Protein Kinase C
ral GTP-Binding Proteins
2-nonenal
4-hydroxy-2-nonenal
Cell signaling
Bioactivity
Cell culture

ASJC Scopus subject areas

  • Biochemistry

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Mitogenic responses of vascular smooth muscle cells to lipid peroxidation-derived aldehyde 4-hydroxy-trans-2-nonenal (HNE) : Role of aldose reductase-catalyzed reduction of the HNE-glutathione conjugates in regulating cell growth. / Ramana, Kota; Bhatnagar, Aruni; Srivastava, Sanjay; Yadav, Umesh C.; Awasthi, Sanjay; Awasthi, Yogesh C.; Srivastava, Satish.

In: Journal of Biological Chemistry, Vol. 281, No. 26, 30.06.2006, p. 17652-17660.

Research output: Contribution to journalArticle

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AU - Ramana, Kota

AU - Bhatnagar, Aruni

AU - Srivastava, Sanjay

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AU - Srivastava, Satish

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