Biomedical subjects

M Toborek

Publications and source records attributed to M Toborek.

At least 37 records · Page 2Linked to original sources

PubMed1999

4-Hydroxynonenal induces dysfunction and apoptosis of cultured endothelial cells.

Lipolytic products of triglyceride-rich lipoproteins, i.e., free fatty acids, may cause activation and dysfunction of the vascular endothelium. Mechanisms of these effects may include lipid peroxidation. One of the major and biologically active products of peroxidation of n-6 fatty acids, such as linoleic acid or arachidonic acid, is the aldehyde 4-hydroxynonenal (HNE). To study the hypothesis that HNE may be a critical factor in endothelial cell dysfunction caused by free fatty acids, human umbilical endothelial cells (HUVEC) were treated with up to160 microM of linoleic or arachidonic acid. HNE formation was detected by immunocytochemistry in cells treated for 24 h with either fatty acid, but more markedly with arachidonic acid. To study the cellulareffects of HNE, HUVEC were treated with different concentrations of this aldehyde, and several markers of endothelial cell dysfunction were determined. Exposure to HNE for 6 and 9 h resulted in increased cellular oxidative stress. However, short time treatment with HNE did not cause activation of nuclear factor-kappaB (NF-kappaB). In addition, HUVEC exposure to HNE caused a dose-dependent decrease in production of both interleukin-8 (IL-8) and intercellular adhesion molecule-1 (ICAM-1). On the other hand, HNE exerted prominent cytotoxic effects in cultured HUVEC, manifested by morphological changes, diminished cellular viability, and impaired endothelial barrier function. Furthermore, HNE treatment induced apoptosis of HUVEC. These data provide evidence that HNE does not contribute to NF-kappaB-related mechanisms of the inflammatory response in HUVEC, but rather to endothelial dysfunction, cytotoxicity, and apoptotic cell death.

Aldehydes↗

PubMed1999

Linoleic acid amplifies polychlorinated biphenyl-mediated dysfunction of endothelial cells.

Selected dietary lipids may increase the atherogenicity of environmental chemicals, such as polychlorinated biphenyls (PCBs), by cross-amplifying mechanisms leading to dysfunction of the vascular endothelium. To investigate this hypothesis, cultured endothelial cells were treated with 90 microM linoleic acid (18:2n-6), followed by either one of two PCBs, 3,3',4,4'-tetrachlorobiphenyl (PCB 77) or 2,2'4,4',5,5'-hexachlorobiphenyl (PCB 153). These PCBs were selected for their varying binding activities with the aryl hydrocarbon (Ah) receptor and differences in their induction of cytochrome P450. PCB 77 disrupted endothelial barrier function by allowing an increase in albumin transfer across endothelial monolayers. Prior cellular enrichment with 18:2 before PCB treatment further diminished endothelial barrier function, as compared to cells treated only with the PCB. This phenomenon appears to be mediated by increased oxidative stress, which is supported by enhanced 2,7-dichlorofluorescein fluorescence, activation data of the oxidative stress-sensitive nuclear transcription factor-kappaB (NF-kappaB), as well as an observed decrease in vitamin E content in the culture media. Similar to the endothelial permeability data, pre-enrichment of cells with 18:2 further increased the PCB-mediated induction of cytochrome P450 1A. In contrast to PCB 77, PCB 153 (or 18:2 plus PCB 153) had little or no effect on endothelial barrier function. Our results suggest that certain unsaturated fatty acids can potentiate PCB-mediated endothelial cell dysfunction and that oxidative stress and activation of the cytochrome P450 1A subfamily may be, in part, responsible for these metabolic events. These findings have implications for understanding the involvement of certain environmental contaminants in diseases that involve dysfunction of the vascular endothelium.

Animals↗

PubMed1999

13-HPODE and 13-HODE modulate cytokine-induced expression of endothelial cell adhesion molecules differently.

Expression of cellular adhesion molecules (CAMs) at endothelial surfaces represents a physiological response to vascular damage and mediates the initiation of inflammation and possibly of atherogenesis. The cytokines TNF alpha and IL-1 are potent inducers of CAMs in endothelial cells. Reactive oxygen species comprising lipid oxidation products have been implicated in the signaling pathways of both TNF alpha and IL-1 and accordingly could modulate atherogenic events. We, therefore, investigated the potential role of the lipoxygenase product, 13-hydroperoxyoctadecadienoic acid (13-HPODE), which has also been identified in oxidized low density lipoproteins on CAM expression in HUVEC. 13-HPODE induced the expression of ICAM-1 in a concentration dependent manner up to 75 microM. Higher concentrations were toxic. Similar effects were observed with H2O2 and phosphatidylcholine hydroperoxide. VCAM-1 and E-selectin were not induced by 13-HPODE. 13-HPODE administered simultaneously with IL-1 or TNF alpha induced ICAM-1 additively, suggesting that hydroperoxides and cytokines act on the same signaling pathways. In contrast, pretreatment of cells with 50 microM 13-HPODE for 1 hour rather inhibited subsequent cytokine-induced ICAM-1 and E-selectin expression. Surprisingly, the reduction product of 13-HPODE, 13-hydroxyoctadecadienoic acid (13-HODE) proved to be an even better inducer of ICAM-1 than 13-HPODE. Pretreatment with 13-HODE did not show any inhibitory effect on ICAM-1 expression. Our data show that lipoxygenase products differentially affect CAM expression. 13-HPODE is stimulatory by itself and can positively or negatively affect cytokine signaling depending on time of exposure. 13-HODE induces CAM expression by itself but does not inhibit cytokine signaling. Thus, the interplay of lipoxygenase products with proinflammatory cytokines can not simply be explained by an oxidant-mediated facilitation of cytokine signaling.

Cell Adhesion Molecules↗

PubMed1999

Endothelial cell functions. Relationship to atherogenesis.

The vascular endothelium plays a critical role in the preservation of normal vessel wall structure and function. In particular, endothelial cells control vascular permeability, vessel tone, coagulation, fibrinolysis, and inflammatory responses. These functions are accomplished by production of a variety of biologically active substances. However, endothelial cell-mediated reactions may also lead to the development of pathological stages within the vessel wall. The current review is focused on endothelial cell metabolism in relationship to the development of atherosclerosis.

Animals↗

PubMed1999

Zinc nutrition and apoptosis of vascular endothelial cells: implications in atherosclerosis.

Little is known about the requirements and function of zinc in maintaining endothelial cell integrity, especially during stressful conditions, such as the inflammatory response in cardiovascular disease. There is evidence that zinc requirements of the vascular endothelium are increased during inflammatory conditions such as atherosclerosis, where apoptotic cell death is also prevalent. Apoptosis is a morphologically distinct mechanism of programmed cell death which involves the activation of a cell-intrinsic suicide program, and there is evidence that factors such as inflammatory cytokines (e.g., tumor necrosis factor [TNF]) and pure or oxidized lipids are necessary to induce the cell death pathway. Because of its constant exposure to blood components, including prooxidants, diet-derived fats, and their derivatives, the endothelium is very susceptible to oxidative stress and to apoptotic injury mediated by blood lipid components, prooxidants, and cytokines. Thus, it is likely that the cellular lipid environment, primarily polyunsaturated fatty acids, can potentiate the overall endothelial cell injury by increasing cellular oxidative stress and cytokine release in proximity to the endothelium, which then could further induce apoptosis and disrupt endothelial barrier function. Our data suggest that zinc deficiency exacerbates the detrimental effects of specific fatty acids (e.g., linoleic acid) and inflammatory cytokines, such as TNF, on vascular endothelial functions. We propose that a major mechanism of zinc protection against disruption of endothelial cell integrity during inflammatory conditions, is by the ability of zinc to inhibit the pathways of signal transduction leading to apoptosis and especially mechanisms that lead to upregulation of caspase genes.

Antioxidants↗

PubMed1999

Arachidonic acid-induced oxidative injury to cultured spinal cord neurons.

Spinal cord trauma can cause a marked release of free fatty acids, in particular, arachidonic acid (AA), from cell membranes. Free fatty acids, and AA by itself, may lead to secondary damage to spinal cord neurons. To study this hypothesis, cultured spinal cord neurons were exposed to increasing concentrations of AA (0.01-10 microM). AA-induced injury to spinal cord neurons was assessed by measurements of cellular oxidative stress, intracellular calcium levels, activation of nuclear factor-KB (NF-kappaB), and cell viability. AA treatment increased intracellular calcium concentrations and decreased cell viability. Oxidative stress increased significantly in neurons exposed to 1 and 10 microM AA. In addition, AA treatment activated NF-kappaB and decreased levels of the inhibitory subunit, IKB. It is interesting that manganese superoxide dismutase protein levels and levels of intracellular total glutathione increased in neurons exposed to this fatty acid for 24 h, consistent with a compensatory response to increased oxidative stress. These results strongly support the hypothesis that free fatty acids contribute to the tissue injury observed following spinal cord trauma.

Animals↗

PubMed1999

Antioxidant-like properties of zinc in activated endothelial cells.

OBJECTIVE: The objective of this study was to test the hypothesis that zinc deficiency in endothelial cells may potentiate the inflammatory response mediated by certain lipids and cytokines, possibly via mechanisms associated with increased cellular oxidative stress. Our experimental approach was to compare conditions of cellular zinc deficiency and zinc supplementation with oxidative stress-mediated molecular and biochemical changes in vascular endothelial cells. METHODS: To investigate our hypothesis, porcine pulmonary artery-derived endothelial cells were depleted of zinc by culture in media containing 1% fetal bovine serum for eight days. Subsequently, endothelial cells were exposed to media enriched with or without zinc (10 microM) for two days, followed by exposure to either tumor necrosis factor-alpha (TNF, 500 U/mL) or linoleic acid (90 microM), before measurement of oxidative stress (DCF fluorescence), activation of nuclear factor kappaB (NF-kappaB) or activator protein-1 (AP-1) and production of the inflammatory cytokine interleukin 6 (IL-6). RESULTS: Oxidative stress was increased markedly in zinc-deficient endothelial cells following treatment with fatty acid or TNF. This increase in oxidative stress was partially blocked by prior zinc supplementation. The oxidative stress-sensitive transcription factor NF-kappaB was up-regulated by zinc deficiency and fatty acid treatment. The up-regulation mediated by fatty acids was markedly reduced by zinc supplementation. Similar results were obtained with AP-1. Furthermore, endothelial cell production of IL-6 was increased in zinc-deficient endothelial cells following treatment with fatty acids or TNF. This increase in production of inflammatory cytokines was partially blocked by zinc supplementation. DISCUSSION: Our previous data clearly show that zinc is a protective and critical nutrient for maintenance of endothelial integrity. The present data suggest that zinc may in part be antiatherogenic by inhibiting oxidative stress-responsive events in endothelial cell dysfunction. This may have implications in understanding mechanisms of atherosclerosis.

Animals↗

PubMed1999

Antioxidant protection against PCB-mediated endothelial cell activation.

Certain environmental contaminants such as polyhalogenated aromatic hydrocarbons may be implicated in diseases of the vasculature by compromising normal functions of vascular endothelial cells. We have shown previously that 3,3',4,4'-tetrachlorobiphenyl (PCB 77), an aryl hydrocarbon (Ah) receptor agonist, can cause disruption of endothelial barrier function. This was supported by an increase in oxidative stress as measured by enhanced 2',7'-dichlorofluorescein (DCF) fluorescence and activation of the oxidative stress-sensitive transcription factor NF-kappaB. We have now tested the protective effects of antioxidants vitamin E (alpha-tocopherol) and pyrrolidine dithiocarbamate (PDTC) on endothelial cell activation induced by PCB 77. Only vitamin E completely blocked PCB 77-mediated endothelial barrier dysfunction. This protective effect by vitamin E was associated with a decrease in both oxidative stress, as measured by DCF fluorescence, as well as in NF-kappaB activation. Furthermore, vitamin E decreased PCB 77-mediated production of the inflammatory cytokine IL-6. Although pretreatment of endothelial cells with PDTC prevented the induction of NF-kappaB by PCB 77, this inhibition was not associated with a decrease in DCF levels or protection against endothelial barrier dysfunction. Pretreatment with alpha-naphthoflavone (alpha-NF), an Ah receptor partial antagonist and specific inhibitor of cytochrome P450 1A, partially protected against PCB 77-induced endothelial barrier dysfunction. This observation was paralleled by the fact that alpha-NF did not fully antagonize the PCB-induced increase in DCF in endothelial cells. Furthermore, PCB-mediated induction of NF-kappaB and production of IL-6 were only partially blocked by alpha-NF. Of all the tested compounds (vitamin E, PDTC and alpha-NF), vitamin E was most potent in blocking PCB 77-mediated endothelial cell activation. These data give an insight into the potential use of vitamin E and related antioxidants to limit PCB-mediated cell injury and into the use of alpha-NF to explore mechanisms underlying the injurious potential of Ah receptor agonists.

Albumins↗

PubMed1998

The role of linoleic acid in endothelial cell gene expression. Relationship to atherosclerosis.

There is evidence that linoleic acid plays a critical role in gene expression and vascular function as it relates to the pathogenesis of atherosclerosis. The lipid environment, particularly linoleic acid and its derivatives, of the vascular endothelium may profoundly influence the inflammatory response mediated by cytokines. Modulations in the level of activity of a select set of endothelial transcription factors appear to provide a mechanism for linking lipid/cytokine-mediated vessel wall dysfunction, including endothelial cell activation, altered proteoglycan metabolism, and endothelial barrier dysfunction, with the onset of atherosclerotic lesion formation. The activity of endothelial transcription factors is in part regulated by the balance of cellular oxidative stress and antioxidant status. Our data suggest that linoleic acid can activate the vascular endothelium and may thus be an atherogenic fatty acid. Furthermore, nutrients/chemicals with antioxidant properties can protect endothelial cells against lipid-mediated cell injury, suggesting that oxidative stress is a critical component in linoleic acid-mediated gene expression. Our discoveries that linoleic acid can influence significantly the cytokine-mediated inflammatory response may open new fields in dietary intervention of atherosclerosis.

Animals↗

PubMed1998

Effect of linoleic acid on endothelial cell inflammatory mediators.

Selected lipids may influence the inflammatory cascade within the vascular endothelium. To test this hypothesis, endothelial cells were treated with linoleic acid (18:2, n - 6) for 12 hours and/or tumor necrosis factor-alpha (TNF) for 4 hours. For a combined exposure to 18:2 and TNF (18:2 + TNF), cells were first preenriched with 18:2 for 8 hours before exposure to TNF for an additional 4 hours. Exposure to 18:2 increased cellular oxidative stress, activated nuclear factor-kappaB (NF-kappaB), increased interleukin-8 (IL-8) production, and elevated intercellular adhesion molecule-1 (ICAM-1) levels. A combined exposure to 18:2+ TNF resulted in decreased NF-kappaB activation compared with TNF treatment alone. In addition, preexposure to 18:2 altered TNF-mediated IkappaB-alpha signaling. Within the first 15 minutes of a 90-minute period, cytoplasmic levels of IkappaB-alpha decreased more rapidly in cells treated with 18:2 + TNF compared with TNF, suggesting translocation and activation of NF-kappaB in cultures that were pretreated with 18:2 before TNF exposure. A combined exposure to 18:2+TNF had various effects on IL-8 production and ICAM-1 levels depending on the time of exposure. For example, 18:2 + TNF treatment increased ICAM-1 levels at 12 hours but decreased ICAM-1 levels at 24 hours compared with treatment with TNF alone. These data suggest that selected fatty acids such as 18:2 can exert proinflammatory effects and, in addition, may markedly alter TNF-mediated inflammatory events.

Cells, Cultured↗

PubMed1997

Polyamine regulatory processes and oxidative stress in monocrotaline-treated pulmonary artery endothelial cells.

Alterations in polyamine metabolism may be a critical mechanism of monocrotaline (MCT)-induced structural remodeling of the pulmonary vasculature. In the present study, the hypothesis that MCT, through the induction of oxidative stress, modulates cellular polyamine regulatory mechanisms which in turn might be involved in the upregulation of fibronectin production in pulmonary artery endothelial cells (PAEC) was examined. A 24-h treatment with MCT significantly increased PAEC polyamine concentrations as compared to vehicle-treated cells. In addition, exposure to MCT caused an increase in abundance of ornithine decarboxylase (ODC) mRNA, upregulation of ODC activity and enhancement of spermidine import into PAEC. Inhibition of de novo polyamine synthesis further increased spermidine uptake in MCT-treated cells. The depletion of cellular polyamine contents through the blockade of both de novo polyamine biosynthesis and polyamine transport prevented MCT-induced increases in the medium level of fibronectin. In addition, PAEC treatment with MCT stimulated cellular oxidative stress as determined by increased levels of thiobarbituric acid reactive substances, enhanced dichlorofluorescein fluorescence and activation of NF-kappa B. A co-treatment with dimethylthiourea, an oxygen radical scavenger, prevented MCT-induced increases in cellular oxidation and attenuated disturbances in polyamine metabolism. These data suggest that MCT can stimulate polyamine regulatory processes in PAEC possibly through an increase in cellular oxidative stress. The present study may have significant implication in understanding mechanisms of MCT-induced pulmonary hypertension and remodeling of pulmonary vasculature.

Animals↗

PubMed1997

Oxidative stress mediates monocrotaline-induced alterations in tenascin expression in pulmonary artery endothelial cells.

Oxidative stress may be involved in monocrotaline (MCT)-induced endothelial cell injury and upregulation of extracellular matrix proteins in the pulmonary vasculature. To test this hypothesis, cytotoxicity, expression and distribution of tenascin (TN) as well as cellular oxidation were determined in porcine pulmonary artery endothelial cells (PAECs) exposed to MCT and/or to an oxygen radical scavenger, dimethylthiourea (DMTU). Relative to controls, treatment with 2.5 mM MCT for 24 hr produced cytotoxicity as evidenced by changes in cellular morphology, cell detachment, hypertrophy, reduction in cellular proliferation and severe cytoplasmic vacuolization. Parallel studies showed that MCT markedly altered the expression and distribution of TN in PAEC as determined by immunocytochemistry. Western analysis showed that MCT increased cellular TN content and promoted the appearance of an additional, smaller TN isoform. Northern analysis demonstrated an increase in the steady-state level of TN-specific mRNA in response to MCT treatment. Exposure to MCT also increased the synthesis of cell-associated and media-associated TN as determined by immunoprecipitation. In addition, MCT increased the intensity of cellular oxidative stress as measured by 2,7-dichlorofluorescein fluorescence. Co-treatment with DMTU prevented MCT-induced cytotoxicity, alterations in TN distribution and content, and reduced the increase in DCF fluorescence. These results suggest that MCT-induced cytotoxicity and upregulation of TN are mediated, at least in part, by induction of cellular oxidative stress.

Animals↗

PubMed1997

Amyloid beta-peptide induces cell monolayer albumin permeability, impairs glucose transport, and induces apoptosis in vascular endothelial cells.

Amyloid beta-peptide (A beta) is deposited as insoluble fibrils in the brain parenchyma and cerebral blood vessels in Alzheimer's disease (AD). In addition to neuronal degeneration, cerebral vascular alterations indicative of damage to vascular endothelial cells and disruption of the blood-brain barrier occur in AD. Here we report that A beta25-35 can impair regulatory functions of endothelial cells (ECs) from porcine pulmonary artery and induce their death. Subtoxic exposures to A beta25-35 induced albumin transfer across EC monolayers and impaired glucose transport into ECs. Cell death induced by A beta25-35 was of an apoptotic form, characterized by DNA condensation and fragmentation, and prevented by inhibitors of macromolecular synthesis and endonucleases. The effects of A beta25-35 were specific because A beta1-40 also induced apoptosis in ECs with the apoptotic cells localized to the microenvironment of A beta1-40 aggregates and because astrocytes did not undergo similar changes after exposure to A beta25-35. Damage and death of ECs induced by A beta25-35 were attenuated by antioxidants, a calcium channel blocker, and a chelator of intracellular calcium, indicating the involvement of free radicals and dysregulation of calcium homeostasis. The data show that A beta induces increased permeability of EC monolayers to macromolecules, impairs glucose transport, and induces apoptosis. If similar mechanisms are operative in vivo, then A beta and other amyloidogenic peptides may be directly involved in vascular EC damage documented in AD and other disorders that involve vascular amyloid accumulation.

Amyloid beta-Peptides↗

PubMed1997

Aortic antioxidant defense and lipid peroxidation in rabbits fed diets supplemented with different animal and plant fats.

OBJECTIVE: To test the hypothesis that dietary fats, depending on the fat source, may modulate aortic lipid peroxidation and antioxidant protection. METHODS: Rabbits were fed a low fat (LF, 2 g/100 g corn oil) diet or LF enriched with 16 g/100 g (w/w) of corn oil (CO), corn oil plus cholesterol (23.5 mg/100 g diet, CO + C), bovine milk fat (MF), chicken fat (CF), beef tallow (BT) or lard (L). After a 30-day feeding period, aortic lipid peroxidation, as well as antioxidant enzymes and vitamin E were measured. RESULTS: In rabbits fed CO or L, aortic TBARS (a marker of lipid peroxidation) and total glutathione concentrations were greater but vitamin E levels were lower compared with the LF treatment. Moreover, in rabbits fed CO, elevated activities of glutathione peroxidase and glutathione reductase but lowered activity of superoxide dismutase were observed. In rabbits fed the remaining high fat diets, including the CO + C diet, aortic lipid peroxidation and antioxidant activities/levels did not differ from those fed LF. Feeding rabbits high-fat diets for 30 days did not induce aortic lipid deposition. CONCLUSIONS: The present results indicate CO, and possibly L, as the fat sources which significantly increase aortic oxidative stress. Because long-term disturbances in redox status may be implicated in atherogenesis, excessive dietary intake of CO or L may significantly contribute to the injury of the vessel wall.

Animal Nutritional Physiological Phenomena↗

PubMed1997

Zinc attenuates tumor necrosis factor-mediated activation of transcription factors in endothelial cells.

OBJECTIVE: The objective of the study was to test the hypothesis that zinc can protect against endothelial dysfunction by interfering with oxidative stress-mediated cellular signaling and subsequent inhibition of an endothelial cell inflammatory response. Our approach was to compare alterations on molecular and biochemical levels with changes in endothelial barrier function that occur in zinc deficient conditions. METHODS: To investigate our hypothesis, endothelial cells were exposed to zinc deficient media for 2 to 10 days to deplete cellular zinc stores. Following this, half of the groups received zinc supplementation (9.2 microM) for 48 hours. The other half served as zinc deficient controls. These cells were then challenged with tumor necrosis factor-alpha (TNF) for varying time periods. Nuclear extracts were prepared from cells and analyzed for nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1) binding. Media from cells were analyzed for interleukin 8 (IL-8) production, and cellular proteins were determined. RESULTS: Zinc supplementation resulted in a 74% increase in cellular zinc content. It was also shown that a 1.5 hour exposure to TNF (100 U/mL medium) significantly increased NF-kappa B and AP-1 binding, which was lowered considerably when cells were supplemented with physiological levels of zinc. Zinc supplementation also caused a marked attenuation in IL-8 expression by endothelial cells in response to TNF-mediated cell activation. DISCUSSION: Our previous data clearly show that zinc is a protective and critical nutrient for maintenance of endothelial integrity. The present data suggest that zinc may protect against cytokine-mediated activation of oxidative stress sensitive transcription factors, upregulation of inflammatory cytokines and endothelial cell dysfunction. This may have implications in understanding mechanisms of atherosclerosis.

Animals↗

PubMed1997

Linoleic acid potentiates TNF-mediated oxidative stress, disruption of calcium homeostasis, and apoptosis of cultured vascular endothelial cells.

Diet-derived lipids may influence cytokine-mediated endothelial cell dysfunction, including TNF-induced apoptosis. To test this hypothesis, oxidative stress, intracellular calcium levels, endothelial barrier function, cell viability, and apoptosis were measured in vascular endothelial cells treated with 90 microM linoleic acid (18:2, n-6) and/or 20 ng/mL TNF (100 U/mL). For short-term exposure, endothelial cells were exposed to 18:2 for 6 h or to TNF for 1.5 h. For long-term exposure, endothelial cultures were treated with 18:2 for 24 h and with TNF for 19.5 h. In cells exposed to 18:2 + TNF, pretreatment with 18:2 began 4.5 h before additional exposure to TNF for either 1.5 h (short-term exposure) or 19.5 h (long-term exposure). After treatment, endothelial cultures were washed and incubated with maintenance medium for up to 4 days. Although initial treatment with TNF or 18:2 significantly increased oxidative stress and intracellular calcium levels, only exposure to TNF induced apoptosis in cultured endothelial cells. Furthermore, the combined exposure to 18:2 + TNF potentiated TNF-induced apoptosis. Additional treatments with BAPTA-AM, n-propyl gallate, vitamin E, and with aurintricarboxylic acid partially protected against TNF- or 18:2 + TNF-induced apoptosis. The present study suggests that changes in the cellular lipid environment may markedly influence local TNF-induced events in the vascular endothelium, including endothelial cell apoptosis. Such mechanisms may play a role in the damage and death of vascular endothelial cells in atherosclerosis.

Animals↗

PubMed1996

Is endothelial cell autocrine production of tumor necrosis factor a mediator of lipid-induced endothelial dysfunction?

Injury or dysfunction of the vascular endothelium is one of the first events in the development of atherosclerosis. Individual lipids, e.g. fatty acids or lipoproteins, are among the most critical factors which may induce injury to the endothelium. Selected fatty acids, such as linoleic acid, can disrupt endothelial barrier function and increase the inflammatory response of the vascular endothelium. The mechanisms of these processes are not fully understood. It is hypothesized that selected fatty acids can mediate the autocrine production of tumor necrosis factor-alpha in endothelial cells. This will activate a variety of intracellular signaling pathways and further potentiate endothelial injury initially induced by fatty acids.

Animals↗

PubMed1996

Antiatherogenic properties of zinc: implications in endothelial cell metabolism.

Zinc is an essential component of biomembranes and is necessary for maintenance of membrane structure and function. There is evidence that zinc can provide antiatherogenic properties by preventing metabolic physiologic derangements of the vascular endothelium. Because of its antioxidant and membrane-stabilizing properties, zinc appears to be crucial for the protection against cell-destabilizing agents such as polyunsaturated lipids and inflammatory cytokines. Zinc also may be antiatherogenic by interfering with signaling pathways involved in apoptosis. Most importantly, we have evidence that zinc can protect against inflammatory cytokine-mediated activation of oxidative stress-responsive transcription factors, such as nuclear factor kappa B and AP-1. It is very likely that certain lipids and zinc deficiency may potentiate the cytokine-mediated inflammatory response and endothelial cell dysfunction in atherosclerosis. Thus, the antiatherogenic role of zinc appears to be in its ability to inhibit oxidative stress-responsive factors involved in disruption of endothelial integrity and atherosclerosis. We discuss antiatherogenic properties of zinc with a focus on endothelial cell metabolism.

Animals↗