RAGE modulates vascular inflammation and atherosclerosis in a murine model of type 2 diabetes

Wendt, Thoralf; Harja, Evis; Bucciarelli, Loredana; Qu, Wu; Lu, Yan; Rong, Ling; Jenkins, Daniel G.; Stein, Guenther; Schmidt, Ann Marie; Yan, Shi Fang

doi:10.1016/j.atherosclerosis.2005.06.013

Cited by 209 publications

(169 citation statements)

References 25 publications

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“…In contrast, mice homozygous for the diabetes (Lepr db/db ) and obesity (Lep ob/ob ) mutations display phenotypes of obesity-induced diabetes (30). When either of these models is combined with deficiency for apoE, atherosclerosis is enhanced in double mutants fed normal rodent chow and this tendency is further aggravated by high-fat regimen (21,23,24). Atherosclerosis is also increased in Ldlr -/-Lep ob/ob mice, although to a lesser extent than in apoE -/-Lep ob/ob mice (22,23).…”

Section: Discussionmentioning

confidence: 99%

Plasma insulin levels predict the development of atherosclerosis when IRS2 deficiency is combined with severe hypercholesterolemia in apolipoprotein E-null mice

González-Navarro

Vila-Caballer²,

Pastor³

et al. 2007

Front Biosci

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Atherosclerosis is increased in type 2 diabetic patients but the precise mechanisms underlying this predisposition remain vague. Mice deficient for insulin receptor substrate 2 (IRS2) develop type 2-like diabetes and thus, provide a model to explore the molecular connection between deranged carbohydrate metabolism and atherosclerosis. To explore the relationship between defective insulin signalling and atherosclerosis, we have examined the development of atherosclerosis in the following groups of fat-fed mice: wild-type, diabetic Irs2-null (Irs2 -/-), atherosclerosis-prone apolipoprotein E-null (apoE -/-), and doubly-deficient apoE -/-Irs2 -/-. Surprisingly, glucose levels of apoE -/-Irs2 -/-mice were comparable to those seen in wild-type and apoE -/-and significantly lower than in Irs2 -/-mice. Irs2 -/-and apoE -/-Irs2 -/-were hyperinsulinemic compared to wild-type and apoE -/-mice. Atherosclerotic lesions were barely detectable in wild-type and Irs2 -/-mice, which displayed moderate hypercholesterolemia (~280 mg/dL). Notably, atherosclerosis was significantly enhanced in apoE -/-Irs2 -/-compared with apoE -/-mice, although both models displayed similar levels of severe hypercholesterolemia (>600 mg/dL). Circulating insulin levels predicted atherosclerotic lesion burden in apoE -/-Irs2 -/-mice. Our results suggest that hyperinsulinemia as a result of Irs2 genetic ablation contributes to increased atherosclerosis when combined with severe hypercholesterolemia (apoE -/-Irs2 -/-mice) in the absence of hyperglycaemia, thus implicating IRS2 as an important modulator of murine hypercholesterolemia-dependent atherosclerosis. Future studies are necessary to determine whether IRS2 dysfunction may promote atherosclerosis in normoglycemic, prediabetic patients with clinical manifestations of hyperinsulinemia and insulin resistance.

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Section: Discussionmentioning

confidence: 99%

Plasma insulin levels predict the development of atherosclerosis when IRS2 deficiency is combined with severe hypercholesterolemia in apolipoprotein E-null mice

González-Navarro

Vila-Caballer²,

Pastor³

et al. 2007

Front Biosci

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“…In a subsequent study, sRAGE stabilized established atherosclerotic lesions in STZ-treated Apoe −/− mice as shown by reduced VSMC and macrophage content in plaque [25]. These findings were recently extended into a model for type 2 diabetes using Apoe −/− db/db (these are mice which lack the receptor for leptin, an adipokine discussed below), which after sRAGE treatment displayed smaller lesions size and reduced expression of inflammatory markers like VCAM-1, tissue factor or matrix metalloproteinase-9 (MMP-9) in the vasculature [26].…”

Section: Advanced Glycation End Products (Age)mentioning

confidence: 91%

Mechanisms by which diabetes increases cardiovascular disease

Gleissner

Galkina

Nadler

et al. 2007

Drug Discovery Today: Disease Mechanisms

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Diabetes mellitus is one of the major risk factors for cardiovascular disease which is the leading cause of death in the U.S. Increasing prevalence of diabetes and diabetic atherosclerosis makes identification of molecular mechanisms by which diabetes promotes atherogenesis an important task. Targeting common pathways may ameliorate both diseases. This review focuses on well known as well as newly discovered mechanisms which may represent promising therapeutic targets.

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“…Besides, smooth muscle cells and nerves in the vessel wall showed constitutively high levels of RAGE expression that were unchanged with ageing or by the presence of vascular disease [83]. Consistent with a pathogenic role for ligand×RAGE interaction in nondiabetic atherosclerosis, sRAGE reduced atherosclerotic lesions and inflammation in normoglycaemic Apoe −/− mice without affecting plasma cholesterol and triacylglycerol levels [84][85][86][87]. Wild-type mice treated with sRAGE and Rage −/− mice also showed significantly reduced neointima expansion in femoral artery denudation-induced arterial injury models, whereas protection conferred by sRAGE was more prominent than that due to RAGE deletion [40,88].…”

Section: The Role Of Rage In Various Pathological Settingsmentioning

confidence: 96%

Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications

2009

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The pattern recognition receptor or receptor for AGE (RAGE) is constitutionally expressed in a few cell types only. However in almost all cells studied so far it is induced by reactions known to initiate inflammation. Its biological activity seems to be mainly dependent on the presence of its various ligands, including AGE, S100-calcium binding protein/calgranulins, high-mobility group protein 1, amyloid-β-peptides and the family of β-sheet fibrils, all known to be elevated in chronic metabolic, malignant and inflammatory diseases. The RAGE pathway interacts with cytokine-, lipopolysaccharide-, oxidised LDL-and glucose-triggered cellular reactions by turning a short-lasting inflammatory response into a sustained change of cellular function driven by perpetuated activation of the proinflammatory transcription factor, nuclear factor kappa-B. RAGE-mediated persistent cell activation is of pivotal importance in various experimental and clinical settings, including diabetes and its complications, neurodegeneration, ageing, tumour growth, and autoimmune and infectious inflammatory disease. Due to RAGE's central role in maintaining perpetuated cell activation, various therapeutic attempts to block RAGE or its ligands are currently under investigation. Despite broad experimental evidence for the role of RAGE in chronic disease, knowledge of its physiological function is still missing, limiting predictions about safety of long-term inhibition of RAGE×ligand interaction in chronic diseases.

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RAGE modulates vascular inflammation and atherosclerosis in a murine model of type 2 diabetes

Cited by 209 publications

References 25 publications

Plasma insulin levels predict the development of atherosclerosis when IRS2 deficiency is combined with severe hypercholesterolemia in apolipoprotein E-null mice

Plasma insulin levels predict the development of atherosclerosis when IRS2 deficiency is combined with severe hypercholesterolemia in apolipoprotein E-null mice

Mechanisms by which diabetes increases cardiovascular disease

Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications

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