Dataset Information

Vascular cellular adhesion molecule-1 (VCAM-1) expression in mice retinal vessels is affected by both hyperglycemia and hyperlipidemia.

ABSTRACT:

Background

Inflammation 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-? (TNF?).

Methodology/principal findings

Expression of VCAM-1 was examined by confocal immunofluorescence microscopy in vessels of wild type (wt), hyperlipidemic (ApoE(-/-)) and TNF? deficient (TNF?(-/-), ApoE(-/-)/TNF?(-/-)) 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 TNF?, IL-6 and IL-1? mRNA than controls; as well as higher soluble VCAM-1 (sVCAM-1) in plasma. Lack of TNF? increased higher basal VCAM-1 protein and sVCAM-1, but failed to up-regulate IL-6 and IL-1? 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/significance

Hyperglycemia 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 TNF? in the regulation of VCAM-1 expression, being protective under basal conditions but pro-inflammatory in response to diabetes.

SUBMITTER: Gustavsson C

PROVIDER: S-EPMC2938334 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Vascular cellular adhesion molecule-1 (VCAM-1) expression in mice retinal vessels is affected by both hyperglycemia and hyperlipidemia.

Gustavsson Carin C Agardh Carl-David CD Zetterqvist Anna V AV Nilsson Jan J Agardh Elisabet E Gomez Maria F MF

PloS one 20100913 9

<h4>Background</h4>Inflammation 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).<h4>Methodology/principal findings ...[more]

PMID: 20856927

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Project description:Circulating triglyceride-rich lipoproteins (TGRL) from hypertriglyceridemic subjects exacerbate endothelial inflammation and promote monocyte infiltration into the arterial wall. We have recently reported that TGRL isolated from human blood after a high-fat meal can elicit a pro- or anti-atherogenic state in human aortic endothelial cells (HAEC), defined as up- or down-regulation of VCAM-1 expression in response to tumor necrosis factor alpha (TNF?) stimulation, respectively. A direct correlation was found between subjects categorized at higher risk for cardiovascular disease based upon serum triglycerides and postprandial production of TGRL particles that increased VCAM-1-dependent monocyte adhesion to inflamed endothelium. To establish how TGRL metabolism is linked to VCAM-1 regulation, we examined endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) pathways. Regardless of its atherogenicity, the rate and extent of TGRL internalization and lipid droplet formation by HAEC were uniform. However, pro-atherogenic TGRL exacerbated ER membrane expansion and stress following TNF? stimulation, whereas anti-atherogenic TGRL ameliorated such effects. Inhibition of ER stress with a chemical chaperone 4-phenylbutyric acid decreased TNF?-induced VCAM-1 expression and abrogated TGRL's atherogenic effect. Activation of ER stress sensors PKR-like ER-regulated kinase (PERK) and inositol requiring protein 1? (IRE1?), and downstream effectors including eukaryotic initiation factor-2? (eIF2?), spliced X-box-binding protein 1 (sXBP1) and C/EBP homologous protein (CHOP), directly correlated with the atherogenic activity of an individual's TGRL. Modulation of ER stress sensors also correlated with changes in expression of interferon regulatory factor 1 (IRF-1), a transcription factor of Vcam-1 responsible for regulation of its expression. Moreover, knockdown studies using siRNA defined a causal relationship between the PERK/eIF2?/CHOP pathway and IRF-1-mediated VCAM-1 expression. We conclude that ER stress and the UPR contribute to the regulation of Vcam-1 transcription as a function of the atherogenic nature of TGRL.

Project description:BackgroundMesothelium vascular cell adhesion molecule-1 (VCAM-1) expression in the metastatic epithelial ovarian cancer (EOC) microenvironment is induced by tumor and mediates tumor cell invasion. VCAM-1 imaging suggests expression during treatment is an indicator of platinum resistance. Here, we assess the potential prognostic significance of mesothelium VCAM-1 expression and prospectively evaluate whether soluble VCAM-1 (sVCAM-1) is a surrogate for mesothelium expression.MethodsA retrospective review of EOC patients was performed to evaluate outcomes with mesothelium VCAM-1 expression determined by immunohistochemistry of peritoneum or omentum specimens. A prospective cohort of EOC patients was identified and followed through primary treatment. Serum for sVCAM-1 evaluation, which was performed via enzyme-linked immunosorbent assay, was collected before surgery or neoadjuvant chemotherapy and at each treatment cycle. Peritoneal specimens were obtained during debulking to assess mesothelial VCAM-1 expression.ResultsA retrospective review identified 54 advanced-stage EOC patients. Patients expressing mesothelium VCAM-1 had shortened overall survival (44 vs 79 months, P = 0.035) and progression-free survival (18 vs 67 months, P = 0.010); the median time to platinum resistance was 36 months for VCAM-1-expressing patients and not yet determined for the VCAM-1-negative group. In our prospective observational cohort, 18 EOC patients completed primary treatment; 3 were negative for mesothelium VCAM-1 expression, and sVCAM-1 did not vary between groups.ConclusionsMesothelium VCAM-1 expression is negatively associated with progression-free and overall survival in EOC. This is especially compelling in light of previous data suggesting that persistent VCAM-1 expression during treatment is an indicator of platinum resistance. Our pilot study had insufficient cases to determine whether sVCAM-1 would substitute for mesothelium expression. Cancer 2017;123:977-84. © 2016 American Cancer Society.

Dataset Information

Vascular cellular adhesion molecule-1 (VCAM-1) expression in mice retinal vessels is affected by both hyperglycemia and hyperlipidemia.

Background

Methodology/principal findings

Conclusions/significance

Publications

Vascular cellular adhesion molecule-1 (VCAM-1) expression in mice retinal vessels is affected by both hyperglycemia and hyperlipidemia.

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