Enhancement of S-Nitrosylation in Glycosylated Hemoglobin

Padrón, Julio Rodríguez; Peiró, Concepción; Cercas, Elena; Llergo, José L; Sánchez‐Ferrer, Carlos F.

doi:10.1006/bbrc.2000.2617

Cited by 30 publications

(17 citation statements)

References 21 publications

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“…Our results suggest, therefore, that oxidative stress associated with obesity may cause and/or exacerbate insulin resistance, at least in part, via enhancing iNOS-mediated IRS-1 degradation. An involvement of nitrosative stress in decreased IRS-1 expression appears to be consistent with our observation of reduced nitrotyrosine immunoreactivity, a marker of nitrosative/oxidative stress, in skeletal muscle of iNOSϪ/Ϫ ob/ob mice compared with iNOSϩ/ϩ ob/ob mice (data not shown) and also consistent with previous studies showing the increased nitrosative protein modifications in patients with diabetes (10,48,49).…”

Section: Inos-mediated Irs-1 Degradation In Skeletal Musclesupporting

confidence: 93%

Inducible Nitric-oxide Synthase and NO Donor Induce Insulin Receptor Substrate-1 Degradation in Skeletal Muscle Cells

Sugita

Fujimoto

Yasukawa

et al. 2005

Journal of Biological Chemistry

104

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Chronic inflammation plays an important role in insulin resistance. Inducible nitric-oxide synthase (iNOS), a mediator of inflammation, has been implicated in many human diseases including insulin resistance. However, the molecular mechanisms by which iNOS mediates insulin resistance remain largely unknown. Here we demonstrate that exposure to NO donor or iNOS transfection reduced insulin receptor substrate (IRS)-1 protein expression without altering the mRNA level in cultured skeletal muscle cells. NO donor increased IRS-1 ubiquitination, and proteasome inhibitors blocked NO donor-induced reduction in IRS-1 expression in cultured skeletal muscle cells. The effect of NO donor on IRS-1 expression was cGMP-independent and accentuated by concomitant oxidative stress, suggesting an involvement of nitrosative stress. Inhibitors for phosphatidylinositol-3 kinase, mammalian target of rapamycin, and c-Jun amino-terminal kinase failed to block NO donor-induced IRS-1 reduction, whereas these inhibitors prevented insulin-stimulated IRS-1 decrease. Moreover iNOS expression was increased in skeletal muscle of diabetic (ob/ob) mice compared with lean wild-type mice. iNOS gene disruption or treatment with iNOS inhibitor ameliorated depressed IRS-1 expression in skeletal muscle of diabetic (ob/ob) mice. These findings indicate that iNOS reduces IRS-1 expression in skeletal muscle via proteasome-mediated degradation and thereby may contribute to obesity-related insulin resistance.

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Section: Inos-mediated Irs-1 Degradation In Skeletal Musclesupporting

confidence: 93%

Inducible Nitric-oxide Synthase and NO Donor Induce Insulin Receptor Substrate-1 Degradation in Skeletal Muscle Cells

Sugita

Fujimoto

Yasukawa

et al. 2005

Journal of Biological Chemistry

104

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Section: James Et Al Vasorelaxation By Glycated Red Blood Cells 979mentioning

confidence: 85%

“…Enhanced formation of HbSNO and RSNO by glycosylated protein compared with nonglycosylated counterparts has been demonstrated previously in vitro (using purified proteins) and also in animals. 46 However, HbNO was not measured in these studies.The importance of inactivation of NO by glycated RBCs and the effect on regeneration of vasoactive NO under low O 2 conditions have not been considered to date. Perhaps of greater significance is the fact that 2,3-diphosphoglycerate (DPG), the endogenous cofactor modulating Hb-O 2 binding within RBCs, binds to a site on the ␤-chain of Hb that is in close proximity to the ␤-93 cysteine residue (the so-called "back pocket" HbSNO).…”

mentioning

confidence: 85%

Vasorelaxation by Red Blood Cells and Impairment in Diabetes

James

Lang

Tufnell-Barret

et al. 2004

Circulation Research

112

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Abstract-Vascular dysfunction in diabetes is attributed to lack of bioavailable nitric oxide (NO) and is postulated as a primary cause of small vessel complications as a result of poor glycemic control. Although it has been proposed that NO is bound by red blood cells (RBCs) and can induce relaxation of blood vessels distal to its site of production in the normal circulation, the effect of RBC glycation on NO binding and relaxation of hypoxic vessels is unknown. We confirm RBC-induced vessel relaxation is inversely related to tissue oxygenation and is proportional to RBC S-nitrosohemoglobin (HbSNO) content (but not nitrosylhemoglobin content Key Words: nitric oxide Ⅲ hemoglobin Ⅲ glycosylation Ⅲ relaxation T he endothelial dysfunction associated with diabetes has been attributed to a lack of bioavailable nitric oxide (NO). [1][2][3] The mechanisms proposed to explain this deficiency include reduced production of NO by NO synthase (NOS) 4,5 and inactivation of NO by reactive oxygen species (ROS) produced either by glycated proteins or directly from vascular endothelium. 6,7 However, these only incompletely explain reduced relaxant responses of microvessels to agonists such as bradykinin in the presence of glycohemoglobin (HbA1c).NO released into the vascular lumen is metabolized (1) by oxyhemoglobin to form methemoglobin and nitrate, (2) by reaction with oxygen (O 2 ) to produce nitrite and nitrate (NOx), (3) through binding to deoxyhemoglobin to produce iron nitrosyl hemoglobin (HbNO), and (4) by reaction with thiol-containing proteins in blood (RSNO) that include glutathione (GSNO) and hemoglobin (S-nitrosohemoglobin, HbSNO). 8 -11 It has been proposed that NO bioavailability in vivo may be governed in part by its reformation from these circulating metabolites as well as by the above local factors. 12,13 This NO "reserve" is likely to be critical in tissue regions where blood supply is limiting and where O 2 demand is increased. The conformational change that occurs during oxygenation of HbNO in the lungs is thought to induce transfer of the NO to an adjacent thiol on the cysteine 93 group of the ␤-chain, producing HbSNO. The levels of HbSNO in human red blood cells (RBCs) are reflected in the physiological O 2 gradient as first shown by Funai et al, 14 and the occurrence of transpulmonary gradients in HbSNO at the expense of HbNO has recently been demonstrated in normal subjects. 15 The HbSNO is thought to pass on its NO to other smaller molecular weight proteins in blood and these can donate NO to cause vasodilatation in the peripheral microvasculature. 16 -19,21 The occurrence and physiological relevance of this NO reserve in the normal circulation has been questioned 21,22 with arguments both for and against. 13,[23][24][25][26] We hypothesized that because protein glycation can produce changes in configuration and ligand binding properties, 27-29 increased HbA1c may directly influence NO metabolism in blood. In a previous study in patients with type 1 diabetes, we demonstrated increased concentrations ...

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“…Recently, it has been observed that levels of SNO-Hb are altered in several disease states characterized by disorders in tissue oxygenation (40,(44)(45)(46)(47)(48)(49). Where examined, RBCs from these patients exhibit impaired vasodilatory capacity (40,44,46).…”

mentioning

confidence: 99%

S -nitrosohemoglobin deficiency: A mechanism for loss of physiological activity in banked blood

Reynolds

Ahearn

Angelo

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

257

227

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RBCs distribute oxygen to tissues, but, paradoxically, blood transfusion does not always improve oxygen delivery and is associated with ischemic events. We hypothesized that storage of blood would result in loss of NO bioactivity, impairing RBC vasodilation and thus compromising blood flow, and that repleting NO bioactivity would restore RBC function. We report that S-nitrosohemoglobin (SNO-Hb) concentrations declined rapidly after storage of fresh venous blood and that hypoxic vasodilation by banked RBCs correlated strongly with the amounts of SNO-Hb (r 2 ‫؍‬ 0.90; P < 0.0005). Renitrosylation of banked blood during storage increased the SNO-Hb content and restored its vasodilatory activity. In addition, canine coronary blood flow was greater during infusion of renitrosylated RBCs than during infusion of S-nitrosothiol-depleted RBCs, and this difference in coronary flow was accentuated by hypoxemia (P < 0.001). Our findings indicate that NO bioactivity is depleted in banked blood, impairing the vasodilatory response to hypoxia, and they suggest that SNO-Hb repletion may improve transfusion efficacy.blood preservation ͉ blood transfusion ͉ erythrocytes ͉ hypoxic vasodilation ͉ S-nitrosylation

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Enhancement of S-Nitrosylation in Glycosylated Hemoglobin

Cited by 30 publications

References 21 publications

Inducible Nitric-oxide Synthase and NO Donor Induce Insulin Receptor Substrate-1 Degradation in Skeletal Muscle Cells

Inducible Nitric-oxide Synthase and NO Donor Induce Insulin Receptor Substrate-1 Degradation in Skeletal Muscle Cells

Vasorelaxation by Red Blood Cells and Impairment in Diabetes

S -nitrosohemoglobin deficiency: A mechanism for loss of physiological activity in banked blood

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