Increased Expression of Thrombospondin-1 in Vessel Wall of Diabetic Zucker Rat

Stenina, Olga I.; Krukovets, Irene; Wang, Kai; Zhou, Zhongmin; Forudi, Farhad; Penn, Marc S.; Topol, Eric J.; Plow, Edward F.

doi:10.1161/01.cir.0000074223.56882.97

Cited by 131 publications

(155 citation statements)

References 32 publications

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“…Moreover, in this same study, it was observed that glucose incubations stimulated the expression and secretion of TSP-1 in cultured endothelial cells [39]. This stimulation seems to be mediated by glycosylation of specific nuclear proteins that participate in the hexosamine pathway of glucose catabolism [34].…”

Section: Discussionmentioning

confidence: 64%

“…The authors proposed that this post-transcriptional suppression was controlled by untranslated regions of TSP-1. This mechanism would not be present in vascular smooth cells and fibroblasts, where the levels of TSP-1 mRNA expression correlate positively with the increased secretion of this protein as a result of HG exposure [39].…”

Section: Discussionmentioning

confidence: 97%

“…More recently, this protein has been studied as a potential link between vasculature mechanisms and hyperglycemia [2,39]. An increase in TSP-1 production has been related with atherogenesis and restenosis in diabetes, since this increase could be a response of vascular cells to higher levels of glucose [39].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, it has been described that the expression of TSP-1 in blood vessels is increased in diabetes, perhaps by a direct effect of the elevated glucose levels in blood [39]. Nevertheless, no effects of glucose incubation have been studied so far in adipocytes from obese specimens.…”

Section: Introductionmentioning

confidence: 99%

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Glucose and insulin modify thrombospondin 1 expression and secretion in primary adipocytes from diet-induced obese rats

et al. 2011

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Thrombospondin 1 (TSP-1), an anti-angiogenic factor and TGF-β activity regulator, has been recently recognized as an adipokine that correlates with obesity, inflammation and insulin-resistance processes. In the present study, epididymal adipocytes of rats that were fed a chow (C) or a high fat diet (HFD) for 50 days, were isolated and incubated (24-72 h) in low (LG; 5.6 mM) or high (HG; 25 mM) glucose, in presence or absence of 1.6 nM insulin. Rats fed the HF diet showed an established obesity state. Serum TSP-1 levels and TSP-1 mRNA basal expression of adipocytes from HFD rats were higher than those from controls. Adipocytes from HFD animals presented an insulin-resistance state, as suggested by the lower insulin-stimulated glucose uptake as compared to controls. TSP-1 expression in culture was higher in adipocytes from obese animals at 24 h, but when the adipocytes were treated with HG, these expression levels dropped dramatically. Later at 72 h, TSP-1 expression was lower in adipocytes from HFD rats, and no effects of the other treatments were observed. Surprisingly, the secretion levels of this protein at 72 h were increased significantly by the HG treatment in both types of adipocytes, although they were even higher in adipocytes from obese animals. Finally, cell viability was significantly reduced by HG treatment in both types of adipocytes. In summary, TSP-1 expression/secretion was modulated in an in vitro model of insulinresistant adipocytes. The difference between expression and secretion patterns suggests a post-transcriptional regulation. The present study confirms that TPS-1 is closely associated with obesity-related mechanisms.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glucose and insulin modify thrombospondin 1 expression and secretion in primary adipocytes from diet-induced obese rats

et al. 2011

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“…A peptide blocking the activation of transforming growth factor-␤ activation by TSP-1 prevented progression of cardiac fibrosis and improved cardiac function in a rat model, implicating TSP-1 in development of diabetic cardiomyopathy (25). Recently, we reported increased levels of TSP-1 in macrovessels of diabetic Zucker rats (26). Moreover, the major cell types present in large vessels responded to stimulation with high glucose concentrations by increasing their expression of TSP-1.…”

mentioning

confidence: 97%

Cell Type-specific Post-transcriptional Regulation of Production of the Potent Antiangiogenic and Proatherogenic Protein Thrombospondin-1 by High Glucose

Bhattacharyya

Marinic

Krukovets

et al. 2008

Journal of Biological Chemistry

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Hyperglycemia is an independent risk factor for development of vascular diabetic complications. Vascular dysfunction in diabetics manifests in a tissue-specific manner; macrovasculature is affected by atherosclerotic lesions, and microvascular complications are described as "aberrant angiogenesis": in the same patient angiogenesis is increased in some tissues (e.g. retinal neovascularization) and decreased in others (e.g. in skin). Molecular cell-and tissue-specific mechanisms regulating the response of vasculature to hyperglycemia remain unclear. Thrombospondin-1 (TSP-1), a potent antiangiogenic and proatherogenic protein, has been implicated in the development of several vascular diabetic complications (atherosclerosis, nephropathy, and cardiomyopathy). This study examines cell type-specific regulation of production of thrombospondin-1 by high glucose. We previously reported the increased expression of TSP-1 in the large arteries of diabetic animals. mRNA and protein levels were up-regulated in response to high glucose. Unlike in macrovascular cells, TSP-1 protein levels are dramatically decreased in response to high glucose in microvascular endothelial cells and retinal pigment epithelial cells (RPE). This downregulation is post-transcriptional; mRNA levels are increased. In situ mRNA hybridization and immunohistochemistry revealed that the level of mRNA is up-regulated in RPE of diabetic rats, whereas the protein level is decreased. This cell type-specific posttranscriptional suppression of TSP-1 production in response to high glucose in microvascular endothelial cells and RPE is controlled by untranslated regions of TSP-1 mRNA that regulate coupling of TSP-1 mRNA to polysomes and its translation. The cellspecific regulation of TSP-1 suggests a potential mechanism for the aberrant angiogenesis in diabetics and TSP-1 involvement in development of various vascular diabetic complications.Despite the significant advances in the therapeutic methods to control blood glucose and insulin levels in diabetic patients, the precise regulation of these levels remains a problem. Vascular diabetic complications remain most prevalent and dangerous and account for the greatest numbers of deaths and hospitalizations in diabetic patients. The molecular basis for the vascular complications of diabetes is not well understood. Recent reports indicate that both microvascular and macrovascular complications of diabetes correlate directly with glucose levels in both patients and animal models (1-5). Some of these reports revealed the pathogenic role of impaired glucose tolerance and post-prandial hyperglycemia even in the absence of diabetes, e.g. (6). In vascular cells, glucose regulates expression of many genes that have been linked to the development of atherosclerosis or abnormal angiogenesis (reviewed in Ref. 7). One of them is thrombospondin-1 (TSP-1), 3 a cell matrix protein implicated in both atherogenesis (8 -12) and angiogenesis (13)(14)(15)(16)(17)(18)(19). Several lines of evidence indicate that TSP-1 may represent a lin...

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In Search of Biomarkers for Drug‐Induced Vascular Injury

Turk¹

2010

Biomarkers

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Increased Expression of Thrombospondin-1 in Vessel Wall of Diabetic Zucker Rat

Cited by 131 publications

References 32 publications

Glucose and insulin modify thrombospondin 1 expression and secretion in primary adipocytes from diet-induced obese rats

Glucose and insulin modify thrombospondin 1 expression and secretion in primary adipocytes from diet-induced obese rats

Cell Type-specific Post-transcriptional Regulation of Production of the Potent Antiangiogenic and Proatherogenic Protein Thrombospondin-1 by High Glucose

In Search of Biomarkers for Drug‐Induced Vascular Injury

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