Biomedical subjects

Bernhard Hennig

Publications and source records attributed to Bernhard Hennig.

41 records · Page 3Linked to original sources

PubMed2002

PCB-induced oxidative stress in endothelial cells: modulation by nutrients.

There is an increasing body of evidence suggesting that exposure to Superfund chemicals may have adverse consequences on many organ systems, as well as carcinogenic and atherogenic effects. This is particularly true for polyhalogenated aromatic hydrocarbons such as the polychlorinated biphenyls (PCBs). The vascular endothelium, which is constantly exposed to blood components including environmental contaminants, is extremely vulnerable to chemical insult as well as necrotic and apoptotic injury. Our recent studies suggest that certain PCBs, especially coplanar PCBs, can compromise normal functions of vascular endothelial cells by activating oxidative stress-sensitive signaling pathways and subsequent proinflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. Our findings suggest that an increase in the level of cellular oxidative stress is a significant event in PCB-mediated endothelial cell dysfunction and that nutrients can modulate PCB-induced oxidative stress and endothelial toxicity. We have demonstrated that the dietary fat linoleic acid, the parent unsaturated fatty acid of the omega-6 family, can increase endothelial dysfunction induced by selected PCBs, probably by contributing to oxidative stress and as the result of the production of toxic metabolites called leukotoxins. The subsequent imbalance in the overall cellular oxidant/antioxidant status can activate oxidative stress- or redoxsensitive transcription factors, which in turn promote gene expression for inflammatory cytokines and adhesion molecules, intensifying the inflammatory response and endothelial cell dysfunction. Our data also suggest that antioxidant nutrients such as vitamin E can protect against endothelial cell damage mediated by PCBs or polyunsaturated dietary fats by interfering with oxidative stress-sensitive and proinflammatory signaling pathways. The concept that nutrition can modify or ameliorate the toxicity of Superfund chemicals is provocative and warrants further study as the implications for human health are significant. The information from such studies could be used to develop dietary recommendations and nutritional interventions for populations at high risk for exposure to PCBs, including communities living near Superfund sites and those exposed via occupation or diet.

Diet↗

PubMed2002

Unsaturated fatty acids selectively induce an inflammatory environment in human endothelial cells.

BACKGROUND: Activation of the vascular endothelium by dietary fatty acids may be among the most critical early events in the development of atherosclerosis. However, the specific effects of fatty acids on inflammatory responses in endothelial cells are not fully understood. OBJECTIVE: The present study focused on the induction of inflammatory genes in human endothelial cells exposed to individual dietary fatty acids. Because of the significance of nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1) in the regulation of inflammatory gene expression, we also determined the effects of fatty acids on NF-kappaB and AP-1 transcriptional activation. DESIGN: Human umbilical vein endothelial cells were exposed to dietary mono- and polyunsaturated 18-carbon fatty acids. Transcriptional activation of NF-kappaB and AP-1 was determined in human umbilical vein endothelial cells transfected with reporter constructs regulated by these transcription factors. Induction of the inflammatory genes was studied by use of reverse transcriptase-polymerase chain reaction. RESULTS: Of the fatty acids studied, linoleic acid stimulated NF-kappaB and AP-1 transcriptional activation the most. In addition, treatment with this fatty acid markedly enhanced messenger RNA levels of tumor necrosis factor alpha, monocyte chemoattractant protein 1, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1. Treatment with linolenic acid stimulated only a moderate induction of the genes encoding for these inflammatory mediators, and exposure to oleic acid either had no effect or resulted in decreased inflammatory gene messenger RNA. In addition, exposure to both linoleic and linolenic acids strongly stimulated induction of the phospholipid hydroperoxide glutathione peroxidase gene. CONCLUSION: Specific unsaturated dietary fatty acids, particularly linoleic acid, can selectively stimulate the development of a proinflammatory environment within the vascular endothelium.

Arteriosclerosis↗

PubMed2002

Methamphetamine-induced TNF-alpha gene expression and activation of AP-1 in discrete regions of mouse brain: potential role of reactive oxygen intermediates and lipid peroxidation.

Cellular and molecular mechanisms of methamphetamine (METH)-induced neurotoxicity may involve alterations of cellular redox status and induction of inflammatory genes. To study this hypothesis, molecular signaling pathways of METH-induced inflammatory responses via activation of redox-sensitive transcription factors were investigated in discrete regions (corpus striatum, frontal cortex, and hippocampus) of mouse brain. Intraperitoneal injection of METH at a dose of 10 mg/kg body weight resulted in a significant increase in oxidative stress, as measured by 2,7-dichlorofluorescein (DCF) fluorescence assay, thiobarbituric acid-reactive substances (TBARS), and total glutathione levels. Glutathione peroxidase activity was also significantly increased after METH exposure. In addition, DNA binding activity of activator protein-1 (AP-1), a redox-responsive transcription factor, was increased in all studied brain regions in response to METH treatment. Because AP-1 is known to regulate expression of inflammatory genes, levels of TNF-alpha mRNA were also studied. Expression of the tumor necrosis factor-alpha (TNF-alpha) gene was induced 3 h after METH injection and remained elevated for up to 6 h of METH exposure. In addition, stimulation of the TNF-alpha gene was associated with increased TNF-a protein production in the frontal cortex. These results suggest that METH-induced disturbances in cellular redox status and that activation of AP-1 can play a critical role in signaling pathways leading to upregulation of inflammatory genes in vivo. Furthermore, these data provide evidence for the role of oxidative stress in the neurotoxic effects of METH.

Animals↗

PubMed2001

Linoleic acid induces MCP-1 gene expression in human microvascular endothelial cells through an oxidative mechanism.

Linoleic acid is a dietary fatty acid that appears to play an important role in activation of the vascular endothelium under a variety of pathological conditions, including development of atherosclerosis or cancer metastasis. Evidence indicates that inflammatory responses may be an underlying cause of endothelial cell pathology induced by linoleic acid. However, the profile of inflammatory mediators and the potential mechanisms involved in inflammatory reactions stimulated by the exposure to linoleic acid are not fully understood. The present study focused on the mechanisms of linoleic acid-induced expression of monocyte chemoattractant protein-1 (MCP-1) gene in human microvascular endothelial cells (HMEC-1). Treatment of HMEC-1 with increasing doses of linoleic acid markedly activated an oxidative stress-responsive transcription factor, nuclear factor-kappaB (NF-kappaB). In addition, exposure to linoleic acid induced a time- and concentration-dependent overexpression of the MCP-1 gene. Increased MCP-1 mRNA levels were observed in HMEC-1 treated with linoleic acid at doses as low as 10 &mgr;M. Linoleic acid-induced overexpression of the MCP-1 gene was associated with a significant elevation of MCP-1 protein levels. Most importantly, preexposure of HMEC-1 to antioxidants, such as pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine (NAC), attenuated linoleic acid-induced MCP-1 mRNA expression. The obtained results indicate that linoleic acid triggers MCP-1 gene expression in human microvascular endothelial cells through oxidative stress/redox-related mechanisms.

Journal Article↗

PubMedDate not supplied

Gene expression profile in interleukin-4-stimulated human vascular endothelial cells.

Interleukin-4 (IL-4)-mediated pro-oxidative and pro-inflammatory vascular environments have been implicated in the pathogenesis of atherosclerosis. The cellular and molecular regulatory mechanisms underlying this process, however, are not fully understood. In the present study, we employed GeneChip microarray analysis to investigate global gene expression patterns in human vascular endothelial cells after treatment with IL-4. Our results showed that mRNA levels of a total of 106 genes were significantly up-regulated and 41 genes significantly down-regulated with more than a 2-fold change. The majority of these genes are critically involved in the regulation of inflammatory responses, apoptosis, signal transduction, transcription factors, and metabolism; functions of the remaining genes are unknown. The changes in gene expression of selected genes related to inflammatory reactions, such as vascular cell adhesion molecule-1 (VCAM-1), E-selectin, monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6), were verified by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) analyses. IL-4 treatment also significantly increased the adherence of inflammatory cells to endothelial cell monolayers in a dose-dependent manner. These results may help determine the molecular mechanisms of action of IL-4 in human vascular endothelium. In addition, a better understanding of IL-4-induced vascular injury at the level of gene expression could lead to the identification of new therapeutic strategies for atherosclerosis.

Apoptosis↗