Tumor Necrosis Factor-α Does Not Mediate Diabetes-Induced Vascular Inflammation in Mice

Nilsson‐Öhman, Jenny; Fredrikson, Gunilla Nordin; Berglund, Lisa M.; Gustavsson, Carin; Bengtsson, Eva; Smith, Maj‐Lis; Agardh, Carl‐David; Agardh, Elisabet; Jovinge, Stefan; Gomez, Maria F.; Nilsson, Jan

doi:10.1161/atvbaha.109.193862

Cited by 10 publications

(8 citation statements)

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“…This is in line with the proposed mechanism underlying the pathogenesis of diabetic retinopathy, namely that hyperglycemia through various pathways (including accumulation of sorbitol and advanced glycation end-products, oxidative stress, up-regulation of the renin-angiotensisn system and vascular endothelial growth factor) initiates a cascade of events leading to retinal vascular endothelial dysfunction[37]. As we demonstrated in a previous study in cerebral arteries[35], VCAM-1 is not only confined to the endothelium, but it is also expressed in smooth muscle cells surrounding the larger arteries of the retina. The fact that the effect of diabetes on VCAM-1 was predominant in small caliber vessels (<10 µm) is interesting considering that capillary degeneration begins early in diabetes retinopathy and as it advances, contributes to the large non-perfused areas of the retina.…”

Section: Discussionsupporting

confidence: 89%

Vascular Cellular Adhesion Molecule-1 (VCAM-1) Expression in Mice Retinal Vessels Is Affected by Both Hyperglycemia and Hyperlipidemia

et al. 2010

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BackgroundInflammation has been proposed to be important in the pathogenesis of diabetic retinopathy. An early feature of inflammation is the release of cytokines leading to increased expression of endothelial activation markers such as vascular cellular adhesion molecule-1 (VCAM-1). Here we investigated the impact of diabetes and dyslipidemia on VCAM-1 expression in mouse retinal vessels, as well as the potential role of tumor necrosis factor-α (TNFα).Methodology/Principal FindingsExpression of VCAM-1 was examined by confocal immunofluorescence microscopy in vessels of wild type (wt), hyperlipidemic (ApoE−/−) and TNFα deficient (TNFα−/−, ApoE−/−/TNFα−/−) mice. Eight weeks of streptozotocin-induced diabetes resulted in increased VCAM-1 in wt mice, predominantly in small vessels (<10 µm). Diabetic wt mice had higher total retinal TNFα, IL-6 and IL-1β mRNA than controls; as well as higher soluble VCAM-1 (sVCAM-1) in plasma. Lack of TNFα increased higher basal VCAM-1 protein and sVCAM-1, but failed to up-regulate IL-6 and IL-1β mRNA and VCAM-1 protein in response to diabetes. Basal VCAM-1 expression was higher in ApoE−/− than in wt mice and both VCAM-1 mRNA and protein levels were further increased by high fat diet. These changes correlated to plasma cholesterol, LDL- and HDL-cholesterol, but not to triglycerides levels. Diabetes, despite further increasing plasma cholesterol in ApoE−/− mice, had no effects on VCAM-1 protein expression or on sVCAM-1. However, it increased ICAM-1 mRNA expression in retinal vessels, which correlated to plasma triglycerides.Conclusions/SignificanceHyperglycemia triggers an inflammatory response in the retina of normolipidemic mice and up-regulation of VCAM-1 in retinal vessels. Hypercholesterolemia effectively promotes VCAM-1 expression without evident stimulation of inflammation. Diabetes-induced endothelial activation in ApoE−/− mice seems driven by elevated plasma triglycerides but not by cholesterol. Results also suggest a complex role for TNFα in the regulation of VCAM-1 expression, being protective under basal conditions but pro-inflammatory in response to diabetes.

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Section: Discussionsupporting

confidence: 89%

Vascular Cellular Adhesion Molecule-1 (VCAM-1) Expression in Mice Retinal Vessels Is Affected by Both Hyperglycemia and Hyperlipidemia

et al. 2010

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“…Diabetes is associated with a general activation of the innate immune system in which there is a chronic, cytokine‐mediated, low‐grade inflammation. Many tissues are affected by proinflammatory cytokines which cause recognizable features of diabetes, although in some instances the cytokines may have a protective effect (Nilsson‐Ohman et al 2009). Inhibition of inflammatory pathways might provide a new therapeutic option for the management of diabetes (Fernandez‐Real and Pickup, 2008).…”

Section: Discussionmentioning

confidence: 99%

Antihyperglycemic effects of baicalin on streptozotocin – nicotinamide induced diabetic rats

Huan-ting

Davey

et al. 2011

Phytotherapy Research

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The aim of the study was to investigate the effects of baicalin on blood glucose, insulin and cytokine levels. Rat diabetes was induced by intraperitoneal (i.p.) injection of nicotinamide and streptozotocin. Diabetic rats were dosed with i.p. baicalin or oral metformin daily for 8 days. Blood glucose, insulin and hepatic glycogen were determined using conventional methods. The activity of hepatic hexokinase was determined using a coupled assay with glucose-6-phosphate dehydrogenase. Serum levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and adiponectin were measured by enzyme-linked immunosorbent assay. Administration of baicalin at 50 or 100 mg/kg significantly decreased plasma glucose levels in a dose dependent manner. The serum insulin level was not increased by baicalin treatment. Administration of baicalin at a high dose (100 mg/kg) resulted in a significant increase of liver glycogen content and a reduction of serum TNF-α. The activity of hepatic hexokinase was significantly increased after dosing baicalin at 25, 50 or 10 mg/kg. Administration of baicalin (50 or 10 mg/kg) or metformin (10 mg/kg) significantly alleviated the morphological injury to the pancreas caused by STZ. The possible mechanisms contributing to the hypoglycemic effect include increasing the hepatic glycogen content and glycolysis, and reducing the serum levels of TNF-α.

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“…Early medial artery calcification is followed by progressively severe atherosclerotic disease in this model (see below)29. Furthermore, the diet- induced systemic low-grade inflammation -- characterized by low but measurable levels of circulating TNF in obese LDLR-/- mice29, 47 and diabetic humans48-50 -- is not seen and apparently does not contribute to vascular inflammation in the apoE-/- model43, 51 even when streptozotocin is administered to induce diabetes52. However, in response to other stimuli such as lipopolysaccharide administration or Klebsiella infection, apoE-/-mice exhibit exaggerated TNF induction and increased mortality53.…”

Section: Inflammatory Cytokines In the Initiation And Progressionmentioning

confidence: 99%

Inflammation and the Osteogenic Regulation of Vascular Calcification

et al. 2010

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A rterial biomineralization processes have been afflicting humans for Ն5 millennia, as realized in 2003 via the computed tomographic imaging of Ö tzi, the intriguing "ice mummy" discovered in the Tyrolean Alps. 1 Patchy abdominal atherosclerotic calcification was readily detected in the postmortem of this Ϸ40-year-old hunter of the early Copper Age, by 2000 years a predecessor of King Tutankhamen. 1 Today, an epidemic of vascular calcification is emerging within our aging and dysmetabolic populace. 2,3 Although vascular calcification was once considered only a passive process of dead and dying cells, work from laboratories worldwide has now highlighted that arterial biomineralization is an actively regulated form of calcified tissue metabolism. 4,5 Moreover, as in skeletal development -where unique biology controls matrix mineralization in membranous bone, endochondral bone, dentin, and enamel, 6,7 mechanistic diversity exists in the pathobiology of vascular calcium deposition. 2,4,5,8 Five common forms of vascular calcification, each possessing unique histoanatomic characteristics and clinical settings with overlapping yet distinct molecular mechanisms, have been described to date 4,5,9 (Table 1). Although we touch on the subject, the reader is referred to other contemporary reviews for in-depth consideration of pathogenic differences. 2,4,5 In this brief review and perspective, we recount recent data that emphasize inflammation and oxidative stress signaling as key contributors to the pathogenesis of vascular mineral deposition. 10 Furthermore, we highlight differences between the low-density lipoprotein receptor (LDLR)-deficient and apolipoprotein E (apoE)-deficient murine models ( Table 2) that help articulate the multifaceted contributions of dyslipidemia, diabetes mellitus, and uremia to arterial calcium deposition. 2,4,11 We end by summarizing the importance of considering these disease stage-and context-specific contributions arterial mineralization when crafting therapeutic strategies to address the disease burden of vascular calcification that increasingly afflicts our patients. 5 28 -32 In this section, we review this new data and also highlight distinctions between the LDLR Ϫ/Ϫ and apoE Ϫ/Ϫ murine disease models 33 ( Table 2) that provide insights into the mechanistic complexities of inflammation-dependent arterial calcium accumulation. RANKL and Atherosclerotic CalcificationReceptor Activator of Nuclear Factor B Ligand/ Osteoprotegerin Signaling and Atherosclerotic Calcification The first robust evidence for the primary contributions of inflammatory cytokine signaling to pathogenesis of vascular calcification arose from the generation and evaluation of the osteoprotegerin (OPG) Ϫ/Ϫ mouse. 34 OPG-deficient mice develop severe medial and intimal arterial calcification in conjunction with high-turnover osteoporosis driven by excessive osteoclast formation. 34 OPG was first shown to function as an antagonistic "faux receptor" of receptor activator of nuclear factor B ligand (RANKL), the TNF superfamil...

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Tumor Necrosis Factor-α Does Not Mediate Diabetes-Induced Vascular Inflammation in Mice

Cited by 10 publications

References 45 publications

Vascular Cellular Adhesion Molecule-1 (VCAM-1) Expression in Mice Retinal Vessels Is Affected by Both Hyperglycemia and Hyperlipidemia

Vascular Cellular Adhesion Molecule-1 (VCAM-1) Expression in Mice Retinal Vessels Is Affected by Both Hyperglycemia and Hyperlipidemia

Antihyperglycemic effects of baicalin on streptozotocin – nicotinamide induced diabetic rats

Inflammation and the Osteogenic Regulation of Vascular Calcification

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