ABSTRACT
Recent studies have proposed that n-3 polyunsaturated fatty acids (n-3 PUFAs) have direct antioxidant and anti-inflammatory effects in vascular tissue, explaining their cardioprotective effects. However, the molecular mechanisms are not yet fully understood. We tested whether n-3 PUFAs showed antioxidant activity through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcriptional factor for antioxidant genes. C57BL/6 or Nrf2(-/-) mice were fed a fish-oil diet for 3 weeks. Fish-oil diet significantly increased the expression of heme oxygenase-1 (HO-1), and endothelium-dependent vasodilation in the aorta of C57BL/6 mice, but not in the Nrf2(-/-) mice. Furthermore, we observed that 4-hydroxy hexenal (4-HHE), an end-product of n-3 PUFA peroxidation, was significantly increased in the aorta of C57BL/6 mice, accompanied by intra-aortic predominant increase in docosahexaenoic acid (DHA) rather than that in eicosapentaenoic acid (EPA). Human umbilical vein endothelial cells were incubated with DHA or EPA. We found that DHA, but not EPA, markedly increased intracellular 4-HHE, and nuclear expression and DNA binding of Nrf2. Both DHA and 4-HHE also increased the expressions of Nrf2 target genes including HO-1, and the siRNA of Nrf2 abolished these effects. Furthermore, DHA prevented oxidant-induced cellular damage or reactive oxygen species production, and these effects were disappeared by an HO-1 inhibitor or the siRNA of Nrf2. Thus, we found protective effects of DHA through Nrf2 activation in vascular tissue, accompanied by intra-vascular increases in 4-HHE, which may explain the mechanism of the cardioprotective effects of DHA.
Subject(s)
Aldehydes/pharmacology , Cytoprotection/drug effects , Docosahexaenoic Acids/chemistry , Endothelial Cells/cytology , Endothelial Cells/metabolism , NF-E2-Related Factor 2/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Aldehydes/metabolism , Animals , Antioxidants/pharmacology , Aorta/drug effects , Aorta/physiology , Body Weight/drug effects , DNA Damage , Diet , Eicosapentaenoic Acid/chemistry , Endothelial Cells/drug effects , Gene Expression Regulation/drug effects , Glutamate-Cysteine Ligase/metabolism , Heme Oxygenase-1/metabolism , Human Umbilical Vein Endothelial Cells/cytology , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/enzymology , Humans , Lipid Peroxidation/drug effects , Male , Mice , Oxidation-Reduction/drug effects , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Sequestosome-1 Protein , Vasodilation/drug effectsABSTRACT
Inflammatory signaling via Toll-like receptor 4 (TLR4) has been shown to facilitate atherogenesis. Recent lines of evidence show that saturated fatty acids (SFAs) induce the inflammatory response via the TLR4 pathway in macrophages and adipocytes. The aims of this study are to confirm the role of SFAs in TLR4-mediated inflammatory signaling in vascular cells and to propose soy phosphatidylcholine (SPC) as an effective inhibitor against TLR4-mediated agonists. SFAs such as palmitate and stearate increased the expression and secretion of MCP-1 in human umbilical vein endothelial cells (HUVECs) and rat vascular smooth muscle cells (VSMCs). SFAs up-regulated the activity of MCP-1 promoter through the activation of NF-kappaB. Knockdown of TLR4 using siRNA diminished the SFA-induced MCP-1 expression in HUVECs and rat VSMCs, while PKC or ceramide signal inhibitor did not inhibit the expression. Furthermore, we found that SPC effectively inhibited the MCP-1 expression induced by palmitate or LPS in a dose-dependent manner. However, SPC did not inhibit the mRNA expression of MCP-1 induced by cytokines such as TNF-alpha and IL-1beta, or by agonists binding to TLRs other than TLR4. In addition, SPC did not affect the activity of LPS assessed by clotting activity of the Limulus amoebocyte lysate. These results clearly show that SPC specifically inhibits the inflammatory responses induced by the TLR4-dependent signal. In conclusion, we have demonstrated a role of SFAs for inflammatory response via TLR4-NF-kappaB signaling in vascular cells. Moreover, we propose that SPC can be useful as a selective inhibitor to suppress the TLR4-mediated inflammatory signaling.
Subject(s)
Chemokine CCL2/biosynthesis , Endothelium, Vascular/pathology , Gene Expression Regulation , Glycine max/metabolism , Phosphatidylcholines/metabolism , Toll-Like Receptor 4/biosynthesis , Animals , Endothelium, Vascular/metabolism , Horseshoe Crabs/metabolism , Humans , Inflammation , Male , Myocytes, Smooth Muscle/metabolism , NF-kappa B/metabolism , Rats , Rats, Sprague-Dawley , Signal TransductionABSTRACT
We report three cases showing body lateropulsion as the sole or predominant symptom of caudal lateral medullary infarction. All of them presented a small infarction on the lateral surface of the caudal medulla corresponding to the dorsal spinocerebellar tract (DSCT). Disturbed unconscious proprioception of the lower trunk and the lower limb conveyed by the DSCT might have been responsible for the isolated lateropulsion. Although lateropulsion itself improved within two weeks, one patient's condition progressed to typical lateral medullary infarction. Lateropulsion caused by DSCT infarction could be a prodromal symptom of perfusion failure of a vertebral artery or the posterior inferior cerebellar artery.
