Glycoxidation in aortic collagen from STZ-induced diabetic rats and its relevance to vascular damage

Meng, Jian; Sakata, Noriyuki; Takebayashi, Shigeo; Asano, Takashi; Futata, Tetsuhiro; Nagai, Ryoji; Ikeda, Kazuyoshi; Horiuchi, Seikoh; Myint, Theingi; Taniguchi, Naoyuki

doi:10.1016/s0021-9150(97)00238-4

Cited by 52 publications

(24 citation statements)

References 43 publications

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“…The aldehydes generated during oxidation do not remain sequestered in the LDL particle, but diffuse to distal sites [13] generating epitopes that do not colocalize with apoB [6]. In addition, antibodies against protein aldehyde adducts also stain focal areas of neointima after balloon injury [14], and VSMC of arteries with giant cell arteritis [15]; and increased formation of lipoxidation products such as HNE and MDA has been reported for diabetic aorta [16]. Nevertheless, the contribution of these aldehydes to atherogenesis remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Identification of biochemical pathways for the metabolism of oxidized low-density lipoprotein derived aldehyde-4-hydroxy trans-2-nonenal in vascular smooth muscle cells

et al. 2001

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Oxidation of low-density lipoproteins (LDL) generates high concentrations of unsaturated aldehydes, such as 4-hydroxy trans-2-nonenal (HNE). These aldehydes are mitogenic to vascular smooth muscle cells and sustain a vascular inflammation. Nevertheless, the processes that mediate and regulate the vascular metabolism of these aldehydes have not been examined. In this communication, we report the identification of the major metabolic pathways and products of [ 3 H]-HNE in rat aortic smooth muscle cells in culture. High-performance liquid chromatography separation of the radioactivity recovered from these cells revealed that a large (60-65%) proportion of the metabolism was linked to glutathione (GSH). Electrospray mass spectrometry showed that glutathionyl-1,4 dihydroxynonene (GS-DHN) was the major metabolite of HNE in these cells. The formation of GS-DHN appears to be due aldose reductase (AR)-catalyzed reduction of glutathionyl 4-hydroxynonanal (GS-HNE), since inhibitors of AR (tolrestat or sorbinil) prevented GS-DHN formation, and increased the fraction of the glutathione conjugate remaining as GS-HNE. Gas chromatography-chemical ionization mass spectroscopy of the metabolites identified a subsidiary route of HNE metabolism leading to the formation of 4-hydroxynonanoic acid (HNA). Oxidation to HNA accounted for 25-30% of HNE metabolism. The formation of HNA was inhibited by cyanamide, indicating that the acid is derived from an aldehyde dehydrogenase (ALDH)-catalyzed pathway. The overall rate of HNE metabolism was insensitive to inhibition of AR or ALDH, although inhibition of HNA formation by cyanamide led to a corresponding increase in the fraction of HNE metabolized by the GSH-linked pathway, indicating that ALDH-catalyzed oxidation competes with glutathione conjugation. These metabolic pathways may be the key regulators of the vascular effects of HNE and oxidized LDL.

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Section: Introductionmentioning

confidence: 99%

Identification of biochemical pathways for the metabolism of oxidized low-density lipoprotein derived aldehyde-4-hydroxy trans-2-nonenal in vascular smooth muscle cells

et al. 2001

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“…Elevated serum levels of CML were demonstrated in patients with diabetes (24 -25) and renal failure (26). Importantly, enhanced accumulation of CML was shown in vascular tissue, atherosclerotic lesions, and glomerular tissue retrieved from diabetic rodents and human subjects (25,(27)(28)(29)(30). In these settings, CML adducts co-localized with oxidation epitopes, such as malondialdehyde and 4-hydroxynonenal.…”

mentioning

confidence: 98%

N ε-(Carboxymethyl)Lysine Adducts of Proteins Are Ligands for Receptor for Advanced Glycation End Products That Activate Cell Signaling Pathways and Modulate Gene Expression

Kislinger

Huber

et al. 1999

Journal of Biological Chemistry

844

695

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Recent studies suggested that interruption of the interaction of advanced glycation end products (AGEs), with the signal-transducing receptor receptor for AGE (RAGE), by administration of the soluble, extracellular ligand-binding domain of RAGE, reversed vascular hyperpermeability and suppressed accelerated atherosclerosis in diabetic rodents. Since the precise molecular target of soluble RAGE in those settings was not elucidated, we tested the hypothesis that predominant specific AGEs within the tissues in disorders such as diabetes and renal failure, N ⑀ -(carboxymethyl)lysine (CML) adducts, are ligands of RAGE. We demonstrate here that physiologically relevant CML modifications of proteins engage cellular RAGE, thereby activating key cell signaling pathways such as NF-B and modulating gene expression. Thus, CML-RAGE interaction triggers processes intimately linked to accelerated vascular and inflammatory complications that typify disorders in which inflammation is an established component.Receptor for AGE 1 (RAGE), a member of the immunoglobulin superfamily, was first described as a cell surface interaction site for advanced glycation end products (AGEs), products of glycation and oxidation of proteins and lipids (1-2). AGEs are a heterogeneous class of compounds, whose accumulation in disorders such as diabetes, renal failure, Alzheimer's disease, and, indeed, natural aging, albeit to a lesser degree, has suggested their potential contribution to the pathogenesis of complications that typify these conditions (3-7). Our previous studies demonstrated that both in vitro and in vivo derived heterogeneous AGEs ligate cell surface RAGE on endothelium (ECs), mononuclear phagocytes (MPs), vascular smooth muscle (VSMC), and neurons to activate cell signaling pathways such as ERK1/ERK2 kinases and NF-B (8 -9), thereby redirecting cellular function in a manner linked to expression of inflammatory and prothrombotic genes important in the pathogenesis of chronic disorders as apparently diverse as diabetic macrovascular disease and amyloidosis (10 -20).Our recent studies suggested that interruption of the interaction of AGEs with RAGE in vivo, by administration of soluble RAGE (sRAGE), the extracellular ligand-binding domain of RAGE, reversed vascular hyperpermeability and suppressed accelerated atherosclerotic lesion development and complexity in diabetic rodents (19 -20). In the latter studies, analysis of plasma demonstrated evidence of an sRAGE⅐AGE complex; immunoprecipitation of plasma obtained from diabetic sRAGEtreated mice with anti-RAGE IgG yielded species immunoreactive with both anti-RAGE IgG or affinity purified anti-AGE IgG, suggesting that sRAGE might bind up AGEs and limit their interaction with and activation of cell surface RAGE. The beneficial effects of sRAGE were independent of alterations in other risk factors, such as hyperglycemia and hyperlipidemia, implicating a role for AGE-RAGE interaction in the development of vascular dysfunction in diabetes (20).These past studies, however, did not elucidate ...

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“…Based on the statistically significant correlation between AGE levels and lens autofluorescence, the noninvasive measurement of the latter was introduced (ex: 365 nm/em: 434 nm) as a screening test of the secondary complications in diabetic patients (30,32). The fluorometric estimation of AGE "classical" Amadori rearrangement products does not interfere with the fluorescence of lipid peroxidation products, such as malondialdehyde (ex: 390 nm/em: 460 nm) and other lipid-derived adducts (ex: 356 nm/em: 460 nm) (33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

Age-dependent accumulation of advanced glycation endproducts is accelerated in combined hyperlipidemia and hyperglycemia, a process attenuated by L-arginine

Georgescu¹,

Popov²

2000

AGE

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In this study we have investigated the occurrence of "classical" Amadori rearrangement products of AGEproteins in the vascular mesenteric bed and in the lens of Golden Syrian hamsters (12 weeks old) rendered simultaneous hyperlipidemics-diabetics (HD), or hyperlipidemics (H) for 24 weeks. For the next 4 weeks the hamsters in HD and H groups received by gavage a solution of 3 mM L-arginine, with the intent to look for the potential effects of Larginine on the fluorescence of tissular AGE-proteins. Age-matched normal hamsters were used as controls (C). The AGE-products of proteins, and the AGE-collagen isolated from the mesenteric bed were quantitated by fluorescence spectroscopy at ex: 370 nm/em: 440 nm. The results showed that: (i) compared to the fluorescence levels of AGEproteins detected at C goup, in HD group the fluorescence of AGE-proteins was found 2.78 and 7.41 fold increased in the vascular mesenteric bed and lens, respectively; (ii) in H group the fluorescence of AGEproteins was 2.36 fold augumented in the vascular mesenteric bed, and 5.43 fold in the lens (versus the C goup); (iii) the aging occurring during the 24 weeks of the experiment induced a small increase in AGE-proteins fluorescence in both mesentery (1.76 fold) and lens (3.83 fold), compared to the levels measured in C group at the inception of the study (12 weeks old hamsters); (iv) the fluorescence of AGEproteins in the vascular mesenteric bed and in the lens of hamsters in HD and H groups correlated with the increase in circulating plasma glucose and cholesterol concentrations throughout the experiment; (v) L-arginine dietary supplementation in HD and H groups, diminished the AGE-collagen fluorescence in the mesentery to ~ 35% and ~ 17%, respectively; in the lens the fluorescence of AGE-proteins was reduced to 65-70% of the levels found in HD and H groups (at 24 weeks). This study showed for the first time that simultaneous hyperlipidemia-hyperglyTo whom all correspondence should be addressed: Doina Popov, Ph.D Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, 8 B.P.Hasdeu Street 79691,Romania telephone: 40 1 411 08 60 fax: 401411 1143 e-mail: popov@ simionescu.instcellbiopath.ro cemia induced an enhanced accumulation of fluorescent AGE-proteins in the mesentery and lens (comparatively to the effect of hyperlipidemia and of chronological aging monitored during the experiment), and that in vivo L-arginine administration decreased the fluorescence of tissular AGE-proteins (AGE-collagen included). The latter observation may bring another area of potential intervention in the adjunct efforts to find out inhibitors of AGE formation, and thus to reduce the increased levels of AGEproteins accumulated in tissues when diabetes is additionally complicated with atherosclerosis.

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Glycoxidation in aortic collagen from STZ-induced diabetic rats and its relevance to vascular damage

Cited by 52 publications

References 43 publications

Identification of biochemical pathways for the metabolism of oxidized low-density lipoprotein derived aldehyde-4-hydroxy trans-2-nonenal in vascular smooth muscle cells

Identification of biochemical pathways for the metabolism of oxidized low-density lipoprotein derived aldehyde-4-hydroxy trans-2-nonenal in vascular smooth muscle cells

N ε-(Carboxymethyl)Lysine Adducts of Proteins Are Ligands for Receptor for Advanced Glycation End Products That Activate Cell Signaling Pathways and Modulate Gene Expression

Age-dependent accumulation of advanced glycation endproducts is accelerated in combined hyperlipidemia and hyperglycemia, a process attenuated by L-arginine

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