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J. Biol. Chem., Vol. 281, Issue 26, 17652-17660, June 30, 2006

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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^*

Kota V. Ramana, Aruni Bhatnagar, Sanjay Srivastava, Umesh C. Yadav, Sanjay Awasthi^¶, Yogesh C. Awasthi, and Satish K. Srivastava¹

From the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, the Division of Cardiology, Department of Medicine, University of Louisville, Louisville, Kentucky 40202, and the ^¶Department of Chemistry & Biochemistry, University of Texas, Arlington, Texas 76019-0065

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-B, 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-B, 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.

Received for publication, January 10, 2006 , and in revised form, April 26, 2006.

^* This work was supported in part by National Institutes of Health Grants GM71036 (to K. V. R.), DK36118 and EY01677 (to S. K. S.), HL59378 (to A. B.), and HL65618 (to S. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom the correspondence should be addressed. Tel.: 409-772-3926; Fax: 409-772-9679; E-mail: ssrivast{at}utmb.Du.

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