Biomedical subjects

B Hennig

Publications and source records attributed to B Hennig.

At least 19 recordsLinked to original sources

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

Expression of the adhesion molecules ICAM-1, VCAM-1, LFA-1 and VLA-4 in the skin is modulated in progressing stages of chronic venous insufficiency.

In inflammation and wound healing, dynamic changes in cell adhesion and migration are fundamental properties of the cells involved. Disturbed interaction of leukocytes with microvascular endothelial cells has been proposed to be a central pathogenic factor in chronic venous insufficiency. This disease may therefore serve to elucidate dysregulated modulation of adhesion molecule expression in conditions of chronic inflammation and impaired wound healing. In this study, we determined how the expression of ICAM-1/VCAM-1 on endothelial cells and their ligands LFA-1/VLA-4 on leukocytes is modulated in skin of progressing stages of chronic venous insufficiency. Immunohistochemical staining of skin biopsies revealed an increase in the expression of ICAM-1 and VCAM-1 on endothelial cells in an early stage of venous disease such as stasis dermatitis. Such protein expression correlated with an increase of corresponding mRNA in skin biopsies. Expression of these CAMs on endothelial cells was accompanied by the occurrence of a marked perivascular infiltration of leukocytes, which expressed increased levels of LFA-1 and VLA-4. In progressing stages of chronic venous insufficiency, characterized by hyperpigmentation and lipodermatosclerosis, which precede skin ulceration, all these CAMs remained upregulated on endothelial cells and infiltrating leukocytes. Our findings indicate that following an initial peak expression during stasis dermatitis, vascular ICAM-1 and VCAM-1 expression is not downmodulated to baseline levels, but remains upregulated. This possibly promotes tissue damage by a perpetuated, upregulated influx of activated leukocytes, finally leading to skin ulceration.

Adult↗

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 the fat composition of a single meal on the composition and cytotoxic potencies of lipolytically-releasable free fatty acids in postprandial plasma.

Ingestion of a meal increases plasma levels of triglyceride (TG)-rich lipoproteins through the secretion of intestine-derived chylomcirons and liver-derived very low density lipoproteins (VLDL). We have determined the effects of the fat composition of a single meal on the composition of TG in TG-rich lipoproteins (VLDL + chylomicrons) and circulating and lipolytically-releasable free fatty acids (FFA) in postprandial (PP) plasma and on the cytotoxic potencies of the lipolytically-released FFA to cultured arterial wall cells. PP lipemia was induced by feeding fasted normolipidemic human subjects with a meal rich in saturated fat (SF) and another meal rich in polyunsaturated fat (PUF), or vice versa; each meal provided 65% of energy as fat, and polyunsaturated to saturated fatty acid ratios (P/S) of the SF and PUF in the meals were 0.40 and 2.49, respectively. The mean P/S of TG in TG-rich lipoproteins (1.43) and circulating FFA (1.46) in 4 h PP plasma of PUF were significantly higher than those in PP plasma of SF (0.44 and 0.59, respectively) in fasting plasma (0.52 and 0.53, respectively). In vitro lipolysis of fasting and PP serum by purified bovine milk lipoprotein lipase (LpL) resulted in a marked (8.8-12.3-fold) increase in the serum FFA level. The P/S of serum FFA in postlipolysis fasting and PP serum were consistently higher than that of FFA or that of TG associated with TG-rich lipoproteins in prelipolysis fasting and PP serum, indicating that polyunsaturated TG in VLDL and/or chylomicrons is more susceptible than saturated TG to lipolysis. When postlipolysis serum was interacted with cultured endothelial cells and mouse peritoneal macrophages (MPM), the lipolytically-released FFA in PP serum of SF and PUF disrupted the barrier function of endothelial cells and were cytotoxic to cultured MPM; FFA in postlipolysis fasting serum was not cytotoxic. FFA in postlipolysis PP serum of PUF were consistently more potent than that in postlipolysis PP serum of SF. Further study showed that all long-chain monounsaturated FFA and polyunsaturated FFA, but not saturated FFA, incorporated into lipoproteins (LDL) were cytotoxic to cultured MPM. In conclusion, despite the generally well-accepted belief that SF is more atherogenic than PUF, the present study provides in vitro evidence that the lipolytic remnant products of TG-rich lipoproteins produced after a meal rich in PUF are more injurious to arterial wall cells than those produced after a meal rich in SF.

Adult↗

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

Oxidized lipid-mediated alterations in proteoglycan metabolism in cultured pulmonary endothelial cells.

Compared to cholesterol or linoleic acid (18:2), oxidized lipids such as cholestan-3 beta, 5 alpha, 6 beta-triol (triol) and hydroperoxy linoleic acid (HPODE) markedly impair endothelial barrier function in culture [Hennig and Boissonneault, 1987; Hennig et al. 1986]. Because proteoglycans contribute to vascular permeability properties, the effects of cholesterol and 18:2 and their oxidation products, triol and HPODE, on endothelial proteoglycan metabolism were determined. While cholesterol was without effect, a concentration-dependent decrease in cellular proteoglycans (measured by 35S incorporation) was observed after exposure to triol. Compared to control cultures, cholesterol reduced mRNA levels for the proteoglycans, perlecan and biglycan. Triol had a similar effect on biglycan but not an perlecan mRNA levels. Compared to 18:2, 1,3 and 5 microM HPODE depressed cellular proteoglycans. Perlecan mRNA levels were reduced more by HPODE when compared to 18:2. Biglycan mRNA levels were reduced by 3 microM, but not by 5 microM HPODE. These data demonstrate that oxidized lipids such as triol and HPODE can decrease cellular proteoglycan metabolism in endothelial monolayers and alter mRNA levels of major specific proteoglycans in a concentration-dependent manner. This may have implications in lipid-mediated disruption of endothelial barrier function and 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↗

PubMed1996

Growth requirements of endothelial cells in culture: variations in serum and amino acid concentrations.

Endothelial cell growth in vitro is limited to the availability of nutrients from commercially available media and added serum. Nutrients, such as amino acids, are chiefly derived from the cell culture medium, rather than from added serum, and optimal endothelial cell growth may be dependent on amino acid levels in the culture media. To test this hypothesis, porcine pulmonary artery-derived endothelial cells were exposed to culture medium 199 (M199), amino acid-deficient M199 (dM199), as well as dM199 supplemented with amino acids. Cell protein was similar in cells cultured for 3 d in M199 supplemented with 1, 3, 5 or 10% bovine calf serum, respectively. Addition of amino acid solutions (L-amino acids [Laa], DL-amino acids [DLaa], 2Laa, or Laa+glutamine) to dM199 demonstrated a cell dependence for optimal growth on the type of amino acids as well as on the total available nitrogen in the media. Compared with M199, dM199 supplemented with Laa only partially supported long-term growth of endothelial cells in culture. On the other hand, dM199 supplemented with either 2Laa, DLaa, or Laa+ glutamine was superior over M199 with regard to endothelial cell growth. The addition of Laa+glutamine to dM199 was most growth-supporting, with an increase of over 2.6-fold in total cell protein compared with cells cultured with M199. These results suggest that, in addition to the presence of essential amino acids, total available nitrogen in culture media may be a critical factor for optimal endothelial cell growth.

Amino Acids↗

PubMed1996

Susceptibility to hepatic oxidative stress in rabbits fed different animal and plant fats.

OBJECTIVE: This study was designed to determine the effect of diets enriched with plant and animal fats on oxidative stress and glutathione metabolism in rabbit liver tissues. This study was conducted to investigate whether the type of dietary fat will impact fatty acid composition and oxidant/antioxidant status in tissues. METHODS: Rabbits were fed diets containing 2 g corn oil/100 g diet (low fat diet, LF) and LF supplemented with 16 g/100 g diet of either corn oil (CO), CO with added cholesterol (CO + C), milk fat (MF), chicken fat (CF), beef tallow (BT), or lard (L) for 30 days. After the feeding period, livers were analyzed for total fatty acid composition, thiobarbituric acid reactive substances (TBARS), conjugated dienes, and reduced glutathione (GSH), as well as for activities of glutathione peroxidase (GP) and glutathione reductase (GR). Moreover, to fully determine the oxidative stability and free radical trapping capacity, TBARS levels were measured after additional exposure of liver homogenates to 10 mM 2,2(1)-azo-bis-amidinopropane- hydrochloride (AAPH) for up to 21 hours. RESULTS: CO and CF, but not saturated fats such as MF, increased liver conjugated diene and TBARS levels and decreased liver GSH levels and GP activity. In tissues additionally exposed to AAPH, the maximum oxidation, measured as TBARS, was reached between 6 and 7 hours of treatment, independent of dietary fat. In addition, there was a marked effect of AAPH on the maximum rate of TBARS formation with the following descending order: CO > CF > CO + C > L > MF > BT > LF. This high susceptibility to oxidative stress in liver tissues of rabbits fed the CO diet may be explained in part by the significant elevation in linoleic acid (18:2n-6). DISCUSSION: There appears to be an inverse correlation between dietary fat-mediated oxidative stress and antioxidant enzyme activities. The present data suggest that high levels of dietary unsaturated fat should be avoided if oxidative stress is a critical issue in nutrition-related diseases. In addition, these data support our hypothesis that diets rich in MF provide a lipid environment with low susceptibility to oxidative stress.

Amidines↗

PubMed1996

Nutritional implications in vascular endothelial cell metabolism.

Endothelial cells interact with blood components and the abluminal tissues, thus playing an active role in many aspects of vascular function. Numerous physiologic and pathophysiologic stimuli are often mediated by nutrients that can contribute to the overall functions of endothelial cells in the regulation of vascular tone, coagulation, cellular growth, immune and inflammatory responses. Therefore, nutrient-mediated functional changes of the endothelium and the underlying tissues may be significantly involved in disease processes such as atherosclerosis. There is evidence that individual nutrients or nutrient derivatives may either provoke or prevent metabolic and physiologic perturbations of the vascular endothelium. Diets high in fat and/or calories are considered a risk factor for the development of atherosclerosis. Our research has shown that certain diet-derived lipids and their derivatives can disrupt normal endothelial integrity, thus reducing the ability of the endothelium to act as a selectively permeable barrier to blood components. Mechanisms underlying fatty acid-mediated endothelial cell dysfunction may be related to changes in fatty acid composition as well as to an increase in cellular oxidative stress. Selective lipid accumulation and fatty acid changes in endothelial cells can modulate membrane fluidity, proteoglycan metabolism and signal transduction mechanisms. Most importantly, dietary fats rich in certain unsaturated fatty acids, may be atherogenic by enhancing the formation of reactive oxygen intermediates. A subsequent imbalance in cellular oxidative stress/antioxidant status can activate oxidative stress-responsive transcription factors, which in turn may promote cytokine production, expression of adhesion molecules on the surface of endothelial cells, and thus intensify an inflammatory response in atherosclerosis. Our data also suggest that certain nutrients, which have antioxidant and/or membrane stabilizing properties, can protect endothelial cells by interfering with lipid/cytokine-mediated endothelial cell dysfunction. These findings contribute to the understanding of the interactive role of dietary fats with inflammatory components, as well as with nutrients that exhibit antiatherogenic properties, in the development of atherosclerosis.

Antioxidants↗

PubMed1996

Linoleic acid activates nuclear transcription factor-kappa B (NF-kappa B) and induces NF-kappa B-dependent transcription in cultured endothelial cells.

High dietary intakes of unsaturated fats may be atherogenic by disrupting normal functions of the vascular endothelium, due in part to the ability of linoleic acid (18:2n-6) to contribute to an increase in cellular oxidative stress and related injurious events. Exposing endothelial cells to 90 micromol linoleic acid/L for 6 h resulted in a significant increase in lipid hydroperoxides that coincided wih an increase in intracellular calcium concentrations. Treatment with this fatty acid caused an initial decrease in glutathione concentrations, which was followed by an increase at later time points. Most importantly, a significant activation of the oxidative stress-sensitive nuclear transcription factor-kappa B (NF-kappa B) was achieved after a 6-h exposure to 18:2n-6, which is the time point at which maximal depletion of cellular glutathione was observed. The fatty acid-mediated NF-kappa B activation was accompanied by induction of NF-kappa B-dependent transcription, as measured by chloramphenicol acetyltransferase (CAT) assay of an NF-kappa B-responsive promoter construct. Pretreatment of endothelial cells with vitamin E and N-acetyl cysteine inhibited the fatty acid-induced activation of NF-kappa B and formation of lipid hydroperoxides. These data suggest that oxidative stress-induced cellular changes are critical early events in fatty acid-mediated endothelial cell dysfunction.

Animals↗