13-hydroxy-9-11-octadecadienoic-acid and Atherosclerosis

Chemokines are a diverse group of molecules with important implications for the development of solid tissues and normal function of the immune system. However, change of the conditions for such a complex system can have important and dangerous consequences leading to diseases. The specific implications of the various chemokines in diseases have been elucidated in the last few years, prompting hope of manipulating this system for therapy or prevention of diseases. On the other hand, inflammatory lipids are biologically active molecules with crucial impacts on the function of various cell types, including immune cells in health and disease. Here, we describe how these lipids affect the chemokine system and how they interact with chemokines to shape chronic inflammation in the case of atherosclerosis.

Topics: Animals; Atherosclerosis; Chemokines; Dendritic Cells; Humans; Linoleic Acids; Linoleic Acids, Conjugated; Lipids; Lipoproteins, LDL; Lysophospholipids; Receptors, Chemokine; Sphingosine

Chronic inflammation plays a major role in atherogenesis and understanding the role of inflammation and its resolution will offer novel approaches to interfere with atherogenesis. The 15(S)-lipoxygenase (15-LOX) plays a janus-role in inflammation with pro-inflammatory and anti-inflammatory effects in cell cultures and primary cells and even opposite effects on atherosclerosis in two different animal species. There is evidence for a pro-atherosclerotic effect of 15-LOX including the direct contribution to LDL oxidation and to the recruitment of monocytes to the vessel wall, its role in angiotensin II mediated mechanisms and in vascular smooth muscle cell proliferation. In contrast to the pro-atherosclerotic effects of 15-LOX, there is also a broad line of evidence that 15-LOX metabolites of arachidonic and linoleic acid have anti-inflammatory effects. The 15-LOX arachidonic acid metabolite 15-HETE inhibits superoxide production and polymorphonuclear neutrophil (PMN) migration across cytokine-activated endothelium and can be further metabolized to the anti-inflammatory lipoxins. These promote vasorelaxation in the aorta and counteract the action of most other pro-inflammatory factors like leukotrienes and prostanoids. Anti-atherogenic properties are also reported for the linoleic acid oxidation product 13-HODE through inhibition of adhesion of several blood cells to the endothelium. Furthermore, there is evidence that 15-LOX is involved in the metabolism of the long-chain omega-3 fatty acid docosahexaenoic acid (DHA) leading to a family of anti-inflammatory resolvins and protectins. From these cell culture and animal studies the role of the 15-LOX in human atherosclerosis cannot be predicted. However, recent genetic studies characterized the 15-LOX haplotypes in Caucasians and discovered a functional polymorphism in the human 15-LOX promoter. This will now allow large studies to investigate an association of 15-LOX with coronary artery disease and to answer the question whether 15-LOX is pro- or anti-atherogenic in humans.

Topics: Animals; Arachidonate 15-Lipoxygenase; Atherosclerosis; CD59 Antigens; Docosahexaenoic Acids; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Isoenzymes; Linoleic Acids; Lipoproteins; Lipoxins; Monocytes; Muscle, Smooth; Oxidation-Reduction; Signal Transduction

Population-based studies have demonstrated that subclinical hypothyroidism (SCH) is an independent risk factor for atherosclerosis (OR = 1.9). However, this connection cannot be entirely explained by dyslipidemia accompanied by SCH. Lipid peroxidation also plays an important role in the development of atherosclerosis. In this study, we aimed to evaluate oxidative stress in SCH patients, as measured according to concentrations of hydroxy-octadecadienoic acids (HODEs) and hydroxy-eicosatetraenoic acids (HETEs) in both plasma and low density lipoproteins (LDL).. The concentrations of HODEs and HETEs in both LDL and plasma were examined in euthyroid (n = 10), mild SCH (4.5 ≤ TSH < 10 mU/L, n = 10), and significant SCH (TSH ≥ 10 mU/L, n = 10) subjects, using a liquid chromatograph-electrospray ionization- mass spectrometer. Then, we explored the relationship among LDL oxidation, TSH levels, and carotid intima-media thickness (IMT), a biomarker of subclinical atherosclerosis.. Serum LDL-C levels and mean-IMT in the significant SCH group were higher than in the euthyroid group (p < 0.05). The HODE and HETE concentrations clearly increased in the significant SCH patients compared with the euthyroid subjects, but there was no difference between the mild SCH and euthyroid groups. Among all subjects, linear and significant positive correlations were identified between TSH and mean-IMT after adjustment for confounding factors (r = 0.480, p = 0.018). Both 9-HODE (r = 0.376, p = 0.041) and 13-HODE (r = 0.447, p = 0.013) in LDL were linearly and positively correlated with TSH. The concentrations of HODEs (both 9-HODE and 13-HODE) in LDL were much higher in the thickened IMT group than in the normal IMT group (p =  .017 and 0.015, respectively). HODEs in LDL were also positively associated with mean-IMT.. Our findings showed that lipid peroxidation was higher in the significant SCH patients than in the euthyroid subjects, which suggested that qualitative as well as quantitative changes in serum lipids resulting from SCH may add to atherosclerosis risk.

Topics: Asymptomatic Diseases; Atherosclerosis; Body Mass Index; Carotid Intima-Media Thickness; Female; Humans; Hydroxyeicosatetraenoic Acids; Hypothyroidism; Linoleic Acids; Linoleic Acids, Conjugated; Lipid Peroxidation; Lipoproteins, LDL; Male; Middle Aged; Oxidative Stress; Risk; Thyroxine

To determine in vivo if L-4F differentially alters plasma levels of oxidized fatty acids resulting in more anti-inflammatory HDL. Injecting L-4F into apoE null mice resulted in a significant reduction in plasma levels of 15-HETE, 5-HETE, 13-HODE and 9-HODE. In contrast, plasma levels of 20-HETE were not reduced and plasma levels of 14,15-EET, which are derived from the cytochrome P450 pathway, were elevated after injection of L-4F. Injection of 13(S)-HPODE into wild-type C57BL/6J mice caused an increase in plasma levels of 13-HODE and 9-HODE and was accompanied by a significant loss in the anti-inflammatory properties of HDL. The response of atherosclerosis resistant C3H/HeJ mice to injection of 13(S)-HPODE was similar but much more blunted. Injection of L-4F at a site different from that at which the 13(S)-HPODE was injected resulted in significantly lower plasma levels of 13-HODE and 9-HODE and significantly less loss of HDL anti-inflammatory properties in both strains. i) L-4F differentially alters plasma levels of oxidized fatty acids in vivo. ii) The resistance of the C3H/HeJ strain to atherosclerosis may in part be mediated by a reduced reaction of this strain to these potent lipid oxidants.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Anti-Inflammatory Agents; Apolipoproteins E; Atherosclerosis; Chromatography, Liquid; Enzyme-Linked Immunosorbent Assay; Fatty Acids; Female; Hydroxyeicosatetraenoic Acids; Injections, Subcutaneous; Linoleic Acids; Linoleic Acids, Conjugated; Lipid Peroxides; Lipoproteins, HDL; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Oxidation-Reduction; Peptides; Species Specificity; Tandem Mass Spectrometry; Time Factors; Up-Regulation