Specificity and uniqueness of endothelial cell stress responses

Tucci, Marisa; McDonald, Robert J.; Aaronson, R.; Graven, Krista K.; Farber, Harrison W.

doi:10.1152/ajplung.1996.271.3.l341

Cited by 10 publications

(10 citation statements)

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“…Furthermore, unlike other cell types, endothelial cells are able to withstand considerable stress such as hypoxia, prolonged glucose deprivation, and sustained heat shock (36). This is of particular significance in the survival and resistance to cytotoxic drugs of tumor vessels and presents an obstacle to some anti-cancer drugs that damage the vasculature.…”

Section: The Effect Of Lack Of Endopdi and Pdi Expression On The Secrmentioning

confidence: 99%

EndoPDI, a Novel Protein-disulfide Isomerase-like Protein That Is Preferentially Expressed in Endothelial Cells Acts as a Stress Survival Factor

Sullivan

Huminiecki

Moore

et al. 2003

Journal of Biological Chemistry

166

141

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We have identified a novel protein-disulfide isomerase and named it endothelial protein-disulfide isomerase (EndoPDI) because of its high expression in endothelial cells. Isolation of the full-length cDNA showed EndoPDI to be a 48 kDa protein that has three APWCGHC thioredoxin motifs in contrast to the two present in archetypal PDI. Ribonuclease protection and Western analysis has shown that hypoxia induces EndoPDI mRNA and protein expression. In situ hybridization analysis showed that EndoPDI expression is rare in normal tissues, except for keratinocytes of the hair bulb and syncytiotrophoblasts of the placenta, but was present in the endothelium of tumors and in other hypoxic lesions such as atherosclerotic plaques. We have compared the function of EndoPDI to that of PDI in endothelial cells using specific siRNA. PDI was shown to have a protective effect on endothelial cells under both normoxia and hypoxia. In contrast, EndoPDI has a protective effect only in endothelial cells exposed to hypoxia. The loss of EndoPDI expression under hypoxia caused a significant decrease in the secretion of adrenomedullin, endothelin-1, and CD105; molecules that protect endothelial cells from hypoxia-initiated apoptosis. The identification of an endothelial PDI further extends this increasing multigene family and EndoPDI, unlike archetypal PDI, may be a molecule with which to target tumor endothelium.Protein-disulfide isomerase (PDI) 1 is a ubiquitously expressed multifunctional protein found in the endoplasmic reticulum (ER). It constitutes around 0.8% of total cellular protein and can reach near millimolar concentrations in the ER lumen of some tissues. PDI plays a role in protein folding because of its ability to catalyze the formation of native disulfide bonds and disulfide bond rearrangement (1). Proteins targeted for secretion by the cell are inserted into and translocated across the ER membrane and enter the ER lumen in an unfolded state. PDI, together with a variety of other folding factors and molecular chaperones resident in the ER correctly fold the proteins ready for secretion (2). The accumulation of misfolded proteins in the ER, known as the Unfolded Protein Response, results in increased transcription of chaperones and folding catalysts. Proteins that fail to fold correctly are relocated to the cytosol for proteasomal degradation.PDI is a modular protein consisting of a, b, bЈ, aЈ, and c domains (3). The a and aЈ domains show sequence and structural homology to thioredoxin (Trx) and both contain the active site WCGHCK motif, constituting two independent catalytic sites for thiol-disulfide bond exchange reactions (4 -7). A ratelimiting step in the folding of many newly synthesized proteins is the formation of disulfide bridges (1) and the presence of WCGHCK in PDI is essential for this process, as confirmed by the loss of PDI activity following mutation of the cysteine residues within these motifs (5, 8). The b and bЈ domains also have the thioredoxin structural fold but lack the active site motif. Thus, PDI conta...

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Section: The Effect Of Lack Of Endopdi and Pdi Expression On The Secrmentioning

confidence: 99%

EndoPDI, a Novel Protein-disulfide Isomerase-like Protein That Is Preferentially Expressed in Endothelial Cells Acts as a Stress Survival Factor

Sullivan

Huminiecki

Moore

et al. 2003

Journal of Biological Chemistry

166

141

View full text Add to dashboard Cite

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“…The Zucker diabetic fat (ZDF) rat is a model of insulin resistance characterized by hyperinsulinemia, hyperglycemia, hyperlipidemia, moderate hypertension, and obesity 9. In the present study, we hypothesize that upregulation of the HO system with the HO-1 inducer cobalt protoporphyrin (CoPP) would increase adiponectin levels, improve insulin sensitivity via increased AMP kinase (AMPK) phosphorylation, decrease adipose tissue volumes, and cause adipose tissue redistribution and remodeling in the ZDF model of obesity-induced insulin resistance.…”

mentioning

confidence: 99%

Heme Oxygenase-1 Induction Remodels Adipose Tissue and Improves Insulin Sensitivity in Obesity-Induced Diabetic Rats

et al. 2009

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Obesity-associated inflammation causes insulin resistance. Obese adipose tissue displays hypertrophied adipocytes and increased expression of the cannabinoid-1 receptor. Cobalt protoporphyrin (CoPP) increases heme oxygenase-1 (HO-1) activity, increasing adiponectin and reducing inflammatory cytokines. We hypothesize that CoPP administration to Zucker diabetic fat (ZDF) rats would improve insulin sensitivity and remodel adipose tissue. Twelve-week-old Zucker lean and ZDF rats were divided into 4 groups: Zucker lean, Zucker lean–CoPP, ZDF, and ZDF–CoPP. Control groups received vehicle and treatment groups received CoPP (2 mg/kg body weight) once weekly for 6 weeks. Serum insulin levels and glucose response to insulin injection were measured. At 18 weeks of age, rats were euthanized, and aorta, kidney, and subcutaneous and visceral adipose tissues were harvested. HO-1 expression was measured by Western blot analysis and HO-1 activity by serum carbon monoxide content. Adipocyte size and cannabinoid-1 expression were measured. Adipose tissue volumes were determined using MRI. CoPP significantly increased HO-1 activity, phosphorylated AKT and phosphorylated AMP kinase, and serum adiponectin in ZDF rats. HO-1 induction improved hyperinsulinemia and insulin sensitivity in ZDF rats. Subcutaneous and visceral adipose tissue volumes were significantly decreased in ZDF rats. Adipocyte size and cannabinoid-1 expression were both significantly reduced in ZDF–CoPP rats in subcutaneous and visceral adipose tissues. This study demonstrates that HO-1 induction improves insulin sensitivity, downregulates the peripheral endocannabinoid system, reduces adipose tissue volume, and causes adipose tissue remodeling in a model of obesity-induced insulin resistance. These findings suggest HO-1 as a potential therapeutic target for obesity and its associated health risks.

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“…In addition to GAPDH, the level of nonneuronal enolase protein was also increased in endothelial cells exposed to SH (1). However, it should be noted that HAPs are distinct from the stress proteins evoked in response to either heat shock (i.e., HSPs) or glucose deprivation (i.e., glucose-regulated proteins) (1,25,27,86,93). GAPDH, in addition to its role in energy production in the cytosol, also has been shown to be involved in translational regulation and endocytosis in the membrane compartment (60,79,80).…”

Section: Proteins Of Energy Metabolismmentioning

confidence: 99%

Analysis of expression and posttranslational modification of proteins during hypoxia

Kumar

Klein²

2004

Journal of Applied Physiology

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The cellular responses to hypoxia are complex and characterized by alterations in the expression of a number of genes, including stress-related genes and corresponding proteins that are necessary to maintain homeostasis. The purpose of this article is to review previous and recent studies that have examined the changes in the expression and posttranslational modification of proteins in response to chronic sustained and intermittent forms of hypoxia. A large number of studies focused on the analysis of either the single protein or a subset of related proteins using one-dimensional gel electrophoresis to separate a complex set of proteins from solubilized tissues or cell extracts, followed by immunostaining of proteins using antibodies that are specific to either native or posttranslationally modified forms. On the other hand, only a limited number of studies have examined the global perturbations on protein expression by hypoxia using proteomics approach involving two-dimensional electrophoresis coupled with mass spectrometry. Results derived from specific protein analysis of a variety of tissues and cells showed that hypoxia, depending on the duration and severity of the stimulus, affects the level and the state of posttranslational modification of a subset of proteins that are associated with energy metabolism, stress response, cell injury, development, and apoptosis. Some of these earlier findings are further corroborated by recent studies that utilize a global proteomics approach, and, more importantly, results from these proteomics investigations on the effects of hypoxia provide new protein targets for further functional analysis. The anticipated new information stems from the analysis of expression, and posttranslational modification of these novel protein targets, along with gene expression profiles, offers exciting new opportunities to further define the mechanisms of cellular responses to hypoxia and to control more effectively the clinical consequences of prolonged or periodic lack of oxygen.

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Specificity and uniqueness of endothelial cell stress responses

Cited by 10 publications

References 0 publications

EndoPDI, a Novel Protein-disulfide Isomerase-like Protein That Is Preferentially Expressed in Endothelial Cells Acts as a Stress Survival Factor

EndoPDI, a Novel Protein-disulfide Isomerase-like Protein That Is Preferentially Expressed in Endothelial Cells Acts as a Stress Survival Factor

Heme Oxygenase-1 Induction Remodels Adipose Tissue and Improves Insulin Sensitivity in Obesity-Induced Diabetic Rats

Analysis of expression and posttranslational modification of proteins during hypoxia

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