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Nitric oxide regulates the polyol pathway of glucose metabolism in vascular smooth muscle cells

KOTA V. RAMANA^#, DEEPAK CHANDRA^#, SANJAY SRIVASTAVA, ARUNI BHATNAGAR and SATISH K. SRIVASTAVA^#1

^# Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas, USA; and
Division of Cardiology, Department of Medicine, University of Louisville, Louisville, Kentucky, USA

¹Correspondence: Department of Human Biological Chemistry and Genetics Room 6.644, Basic Science Building, University of Texas Medical Branch Galveston, TX 77555-0647, USA. E-mail: ssrivast{at}utmb.edu

Increased reduction of glucose via the polyol pathway enzyme aldose reductase (AR) has been linked to the development of secondary diabetic complications. Because AR is a redox-sensitive protein, which in vitro is readily modified by NO donors, we tested the hypothesis that NO may be a physiological regulator of AR. We found that administration of the NO synthase (NOS) inhibitor N^G-nitro-L-arginine methyl ester (L-NAME) increased sorbitol accumulation in the aorta of nondiabetic and diabetic rats, whereas treatment with L-arginine (a precursor of NO) or nitroglycerine patches prevented sorbitol accumulation. When incubated ex vivo with high glucose, sorbitol accumulation was increased by L-NAME and prevented by L-arginine in strips of aorta from rats or wild-type, but not eNOS-deficient, mice. Exposure to NO donors also inhibited AR and prevented sorbitol accumulation in rat aortic vascular smooth muscle cells (VSMC) in culture. The NO donors also increased the incorporation of radioactivity in the AR protein immunoprecipitated from VSMC in which the glutathione pool was prelabeled with [³⁵S]-cysteine. Based on these observations, we suggest that NO regulates the vascular synthesis of polyols by S-thiolating AR; therefore, increasing NO synthesis or bioavailability may be useful in preventing diabetes-induced changes in the polyol pathway.—Ramana, K. V., Chandra, D., Srivastava, S., Bhatnagar, A., Srivastava, S. K. Nitric oxide regulates the polyol pathway of glucose metabolism in vascular smooth muscle cells.

Key Words: aldose reductase • glutathiolation • diabetes • nitric oxide and nitrosothiols

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