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Diabetes 53:1841-1850, 2004
© 2004 by the American Diabetes Association, Inc.

Regulation of Inducible Nitric Oxide Synthase Expression in Advanced Glycation End Product–Stimulated RAW 264.7 Cells

The Role of Heme Oxygenase-1 and Endogenous Nitric Oxide

Daigo Sumi, and Louis J. Ignarro

From the Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Center for Health Sciences, Los Angeles, California

Advanced glycation end products (AGEs) are closely linked to the development of diabetic atherosclerosis. The current study examines the induction of inducible nitric oxide (NO) synthase (iNOS) and heme oxygenase (HO)-1 expression by AGEs, as well as the signaling pathways involved and the interplay between these two enzymes. The stimulation of RAW 264.7 cells with 6.64 or 33.2 µg/ml AGEs leads to HO-1 protein expression, iNOS protein expression, and nitrite accumulation. AGEs lead to the phosphorylation of p42/44 and p38 mitogen-activated protein kinase (MAPK). The inhibition of p42/44 MAPK and protein kinase C prevented, whereas inhibition of p38 MAPK augmented, AGE-induced nitrite release and iNOS expression. In contrast, HO-1 expression was downregulated by inhibition of p38 MAPK. Furthermore, the expression of both proteins was prevented by coincubation with acetovanillone (NADPH oxidase inhibitor). AGE-induced iNOS expression was negatively regulated by stimulation of HO-1 expression with cadmium chloride or endogenous NO. Tin-protoporphyrin IX (HO-1 inhibitor) partially reversed the cadmium chloride–mediated downregulation of iNOS expression. The current study demonstrates that multiple signaling molecules are involved in AGE-stimulated iNOS and HO-1 expression. There also exists a downregulation of iNOS by its own product as well as the products of HO-1.

Address correspondence and reprint requests to Louis J. Ignarro, David Geffen School of Medicine at UCLA, Department of Molecular and Medical Pharmacology, Center for Health Sciences, 23-305, Los Angeles, CA 90095-1735. E-mail: lignarro{at}mednet.ucla.edu

Abbreviations: AGE, advanced glycation end product; apo, apolipoprotein; DMEM, Dulbecco’s modified Eagle’s medium; ELISA, enzyme-linked immunosorbent assay; HO, heme oxygenase; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; L-NAME, N{omega}-nitro-L-arginine methyl ester; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; NF-{kappa}B, nuclear factor-{kappa}B; NIH, National Institutes of Health; PKC, protein kinase C; RAGE, receptor for AGEs; Tin-PP, Tin-protoporphyrin IX


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2004 by the American Diabetes Association.