Regular Article
Glycated Serum Albumin-Induced Nitric Oxide Production in Vascular Smooth Muscle Cells by Nuclear Factor κB-Dependent Transcriptional Activation of Inducible Nitric Oxide Synthase

https://doi.org/10.1006/bbrc.1999.0736Get rights and content

Abstract

Glycated proteins, including serum albumin, may be involved in the pathogenesis of diabetic vasculopathy. Recent evidence suggests that expression of inducible nitric oxide synthase (iNOS) in vascular smooth muscle cells (VSMC) may, in part, promote atherosclerosis by increasing local oxidative stress. We therefore investigated whether VSMC exposed to glycated human serum albumin (GHSA) produce nitric oxide (NO) by increasing iNOS expression through transcriptional activation of the iNOS gene and whether this process is dependent on nuclear factor κB (NF-κB) activation. Treatment of VSMC with GHSA causes activation of NF-κB and the iNOS promoter. Induction of NF-κB and the iNOS promoter by GHSA exhibited dose-dependent kinetics at concentrations ranging from 3 to 1000 μg/ml. GHSA alone was a weak inducer of NO production in VSMC as measured by determining nitrite levels, and interferon-γ alone was totally ineffective, whereas the combination of GHSA and interferon-γ was a strong stimulus. This synergy for NO production corresponded to Northern blot analyses of iNOS mRNA expression. Thus, GHSA may promote atherosclerosis in part by activation of NF-κB and upregulation of iNOS, thereby fostering local inflammation and oxidative stress.

References (42)

  • P.J. Higgins et al.

    J. Biol. Chem.

    (1981)
  • M.P. Cohen et al.

    Kidney Int.

    (1994)
  • M.P. Cohen et al.

    J. Immunol. Methods

    (1989)
  • M.P. Cohen et al.

    Kidney Int.

    (1994)
  • A. Amore et al.

    Kidney Int.

    (1997)
  • P. Chomczynski et al.

    Anal. Biochem.

    (1987)
  • S.S. Gross et al.

    J. Biol. Chem.

    (1992)
  • Y. Nunokawa et al.

    Biochem. Biophys. Res. Commun.

    (1993)
  • Q. Xie et al.

    J. Biol. Chem.

    (1994)
  • H. Negoro et al.

    Am. J. Med.

    (1988)
  • T. Peters

    Adv. Prot. Chem.

    (1985)
  • C.J. Lowenstein et al.

    Cell

    (1992)
  • A. Graham et al.

    FEBS Lett.

    (1993)
  • H. Ischiropoulos et al.

    Arch. Biochem. Biophys.

    (1992)
  • S. Krantz et al.

    Biochim. Biophys. Acta

    (1993)
  • R. Salazar et al.

    Biochim. Biophys. Acta

    (1995)
  • K.H. Winterhalter

    Prog. Clin. Biol. Res.

    (1985)
  • L. Kennedy et al.

    Diabetologia.

    (1984)
  • M. Brownlee et al.

    Ann. Int. Med.

    (1984)
  • M. Brownlee et al.

    N. Engl. J. Med.

    (1988)
  • Cited by (36)

    • Glycated human serum albumin induces NF-κB activation and endothelial nitric oxide synthase uncoupling in human umbilical vein endothelial cells

      2015, Journal of Diabetes and its Complications
      Citation Excerpt :

      This NF-κB activation could be the reason for the gHSA-induced increase in NOX4 at the mRNA level, as observed in this work, and at the protein level, as reported previously (Rodino-Janeiro et al., 2010). NF-κB activation by glycated proteins has been previously described in vascular smooth muscle cells (Hattori, Banba, Gross, & Kasai, 1999), macrophage RAW cells (Cohen, Shea, Chen, & Shearman, 2003) and human peritoneal mesothelial cells (Nevado et al., 2005). Manea et al. (2010) showed that NF-κB regulated NOX4 expression in human aortic vascular smooth muscle cells, but they did not observe an activation of NF-kB at 4 h as we did.

    • Impact of elevated serum glycated albumin levels on contrast-induced acute kidney injury in diabetic patients with moderate to severe renal insufficiency undergoing coronary angiography

      2013, International Journal of Cardiology
      Citation Excerpt :

      The increased reactive oxygen species resulting from renal ischemia could in turn augment the vasoconstrictive effects of CM [35]. This self-reinforcing pathophysiological cycle is partly triggered by nonenzymatically GA via activation of nuclear factor-κB and decreased nitric oxide dependent vasodilation [36,37]. Further studies are needed to clarify the exact mechanism of higher GA levels predisposing to CI-AKI.

    • Clinical, pathophysiological and structure/function consequences of modification of albumin by Amadori-glucose adducts

      2013, Biochimica et Biophysica Acta - General Subjects
      Citation Excerpt :

      AGA also stimulates adhesion of monocytes to endothelial cells through enhanced transcription of the cell surface adhesion molecules E-selectin, vascular adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, implicating it in the initial endothelial cell activation occurring at atherosclerosis-prone vascular sites [59–61]. In vascular smooth muscle cells, AGA activates NF-κB, AP-1, p38 MAPK and ERK, increases expression and release of MCP-1, IL-6 and IL-8, stimulates growth and migration, and induces expression of the anti-apoptotic inhibitor of apoptosis protein (IAP)-1 [62–66]. The pathophysiologic and clinical relevance of the above studies is underscored by the positive association of AGA with atherosclerosis and coronary artery disease [21,22].

    • Glycated albumin activates NADPH oxidase in rat mesangial cells through up-regulation of p47phox

      2010, Biochemical and Biophysical Research Communications
      Citation Excerpt :

      Furthermore, we demonstrated that p47phox-depdendent NADPH oxidase activity mediates glycated albumin-induced stimulation of TGF-β and resultant extracellular matrix protein production in mesangial cells. It is known that glycated albumin activated NF-κB in a variety of cell types [28–33]. NF-κB is an important redox-sensitive transcription factor and has been implicated in the development of renal diseases [34].

    • Cellular factors involved in CXCL8 expression induced by glycated serum albumin in vascular smooth muscle cells

      2010, Atherosclerosis
      Citation Excerpt :

      Promoter activation of the IL-8 gene was significantly suppressed by an ERK1/2 inhibitor, and CXCL8 release was profoundly inhibited by both ERK and p38 MAPK inhibitors. These results, along with previous reports [8,9,27], reinforce the idea that MAPKs are important molecules mediating cellular and molecular responses to GSA in VSMCs. We observed differences in the manner in which p38 MAPK inhibitor affects IL-8 up-regulation.

    View all citing articles on Scopus

    Moncada, S.Stamler, J.Gross, S.Higgs, E.A.

    1

    Corresponding author. Fax: + 81 282 (86) 4632. E-mail:[email protected].

    View full text