8-11-14-eicosatrienoic-acid and Coronary-Disease

14,15-Epoxyeicosatrienoic acids (14,15-EETs) generated from arachidonic acid by cytochrome P450 epoxygenases have beneficial effects in certain cardiovascular diseases, and increased 14,15-EET levels protect the cardiovascular system. 14,15-EETs are rapidly hydrolyzed by soluble epoxide hydrolase (sEH) to the corresponding 14,15-dihydroxyeicosatrienoic acids (14,15-DHETs), which are generally less biologically active but more stable metabolite. A functionally relevant polymorphism of the CYP2J2 gene is independently associated with an increased risk of coronary heart disease (CHD), and the major CYP2J2 product is 14,15-EETs. 14,15-DHETs can be considered a relevant marker of CYP2J2 activity. Therefore, the aim of the present study was to evaluate the plasma 14,15-DHET levels to reflect the 14,15-EET levels in an indirectly way in patients with CHD, and to highlight the growing body of evidence that 14,15-EETs also play a role in anti-inflammatory and lipid-regulating effects in patients with CHD. This was achieved by investigating the relationship between 14,15-DHETs and high-sensitivity C-reactive protein (hs-CRP) and blood lipoproteins.. Samples of peripheral venous blood were drawn from 60 patients with CHD and 60 healthy controls. A 14,15-DHET enzyme-linked immunosorbent assay kit (14,15-DHET ELISA kit) was used to measure the plasma 14,15-DHET levels. Hs-CRP, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein-cholesterol levels were measured.. 14,15-DHET levels (2.53 ± 1.60 ng/mL) were significantly higher in patients with CHD as compared with those of the healthy controls (1.65 ± 1.54 ng/mL, P < 0.05). There was a significant positive correlation between 14,15-DHETs and hs-CRP levels (R = 0.286, P = 0.027). However, there was no significant correlation between 14,15-DHETs and blood lipoproteins (all, P > 0.05).. Increased plasma 14,15-DHET levels reflect the decreased of 14,15-EET levels in an indirectly way. Indicated that decreased plasma 14,15-EET levels might be involved in the inflammatory reaction process in atherosclerosis.

Topics: 8,11,14-Eicosatrienoic Acid; Aged; C-Reactive Protein; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Female; Humans; Inflammation; Male; Middle Aged; Statistics, Nonparametric; Triglycerides

Cytochrome P450 (CYP) 2J2 is expressed in the vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs). The EETs are potent endogenous vasodilators and inhibitors of vascular inflammation. However, it is not known whether genetic polymorphisms of CYP2J2 are associated with increased cardiovascular risks.. All 9 exons of the CYP2J2 gene and its proximal promoter were sequenced in 132 patients to identify potential variants. Functional consequence of a single nucleotide polymorphism (SNP) in the promoter of CYP2J2 was further evaluated by use of transcription factor-binding and reporter assays. A total of 17 polymorphisms were identified. One of the most relevant polymorphisms in terms of frequency and functional importance is located at -50 (G-50T) in the proximal promoter of CYP2J2. Screening of 289 patients with coronary artery disease and 255 control subjects revealed 77 individuals with the G-50T SNP (17.3% of coronary artery disease patients, 10.6% of control subjects; P=0.026). The association of the G-50T polymorphism remained significant after adjustment for age, gender, and conventional cardiovascular risk factors (OR, 2.23; 95% CI, 1.04 to 4.79). The G-50T mutation resulted in the loss of binding of the Sp1 transcription factor to the CYP2J2 promoter and resulted in a 48.1+/-2.4% decrease in CYP2J2 promoter activity (P<0.01). Plasma concentrations of stable EET metabolites were significantly lower in individuals with the G-50T SNP.. A functionally relevant polymorphism of the CYP2J2 gene is independently associated with an increased risk of coronary artery disease.

Topics: 3' Untranslated Regions; 8,11,14-Eicosatrienoic Acid; Aged; Amino Acid Substitution; Arachidonic Acid; Base Sequence; Binding Sites; Coronary Disease; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; DNA Mutational Analysis; Eicosanoids; Exons; Female; Genetic Testing; Genotype; Germany; Humans; Hydroxyeicosatetraenoic Acids; Introns; Male; Middle Aged; Molecular Sequence Data; Oxygenases; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk; Sequence Analysis, DNA; Sp1 Transcription Factor

To prospectively investigate the relation of plasma cholesterol ester (CE) and phospholipid (PL) fatty acid (FA) composition with incidence of coronary heart disease (CHD).. 3,591 white participants in the Minneapolis field center of the Atherosclerosis Risk in Communities Study, aged 45-64 years, were studied. Plasma FA composition of CEs and PLs was quantified using gas-liquid chromatography and expressed as percentage of total FAs. Incident CHD was identified during 10.7 years of follow-up. In both CE and PL fractions, the proportions of stearic (18:0) acid, dihomo-gamma-linolenic (20:3n6) acid and total saturated fatty acids (SFAs) were significantly higher while arachidonic (20:4n6) acid and total polyunsaturated fatty acids (PUFAs) were significantly lower among participants who developed incident CHD (n = 282). After adjusting for age, gender, smoking, alcohol drinking, sports activity, and non-FA dietary factors, the incidence of CHD was significantly and positively associated with the proportion of dihomo-gamma-linolenic acid but inversely associated with arachiadonic acid. The multiply-adjusted rate ratios (RRs) of CHD incidence for the highest versus the lowest quintile were 1.31 in CE and 1.44 in PL for dihomo-gamma-linolenic acid (p for trend: 0.05 and 0.017, respectively), 0.59 in CE and 0.65 in PL for arachidonic acid (p: 0.016 and 0.024, respectively). Also significantly and positively associated with incident CHD were PL stearic acid and CE linolenic (18:3n3) acid. Only a borderline significant positive association was observed for total SFAs in CE (multivariate RRs across quintiles: 1.00, 1.15, 1.40, 1.62, 1.32; p = 0.07). Total PUFAs or monounsaturated FA were not independently associated with CHD.. Our study found a weak positive association of SFAs with incident CHD. Our findings also confirm that FA metabolism in the body, such as the activity of delta-5 desaturase, which converts dihomo-gamma-linolenic acid to arachidonic acid, may affect the development of CHD.

Topics: 8,11,14-Eicosatrienoic Acid; Arachidonic Acid; Arteriosclerosis; Cholesterol Esters; Cohort Studies; Coronary Disease; Fatty Acids, Unsaturated; Female; Health Surveys; Humans; Male; Middle Aged; Phospholipids; Prospective Studies; Risk Factors; Stearic Acids

It has been suggested that the fatty acid composition of serum phospholipids is an independent risk factor for cardiovascular disease. We examined the association of the fatty acid composition of serum phospholipids with fibrinogen, factor VII antigen (FVII:Ag), factor VII coagulant activity (FVII:C), plasminogen, and lipoprotein(a) [Lp(a)] in 338 men and 363 women 45 to 64 years old. Palmitic acid, the most abundant saturated fatty acid, was positively associated in univariate analyses with plasminogen, which explained 5.2% of its variance among men (P<.0001) and 5.8% among women (P<.0001). Linoleic acid, which is the most abundant polyunsaturated fatty acid, was negatively associated with plasminogen and fibrinogen. This explained 1.1% of the variance in fibrinogen among men (P=.04) and 3.2% among women (P=.0006) and 4.1% of the variance in plasminogen in both sexes (P<.0001). Dihomogammalinolenic acid was positively associated with FVII:Ag and explained 3.7% of its variance among men (P=.0003) and 4.6% among women (P<.0001). Furthermore, dihomogammalinolenic acid was positively and significantly associated with FVII:C, fibrinogen, and plasminogen among women but not among men. All these associations remained significant after adjustment for multiple potential confounding factors such as age, smoking, serum lipids, and body mass index. In conclusion, our findings suggest that linoleic acid, palmitic acid, and dihomogammalinoleic acid are significant independent determinants of hemostatic profile. It is not clear, however, to what extent these results reflect the effects of fatty acids on coagulation and to what extent they reflect the activity of inflammatory processes in the arteries.

Topics: 8,11,14-Eicosatrienoic Acid; Antigens; Coronary Disease; Factor VII; Fatty Acids; Female; Fibrinogen; Hemostasis; Humans; Linoleic Acid; Linoleic Acids; Lipoprotein(a); Male; Middle Aged; Palmitic Acid; Phospholipids; Plasminogen; Risk Factors

Coronary vascular injury promotes blood cell-vessel wall interactions that influence arachidonic acid metabolism and coronary blood flow patterns. Since lipoxygenase and cytochrome P-450 epoxygenase metabolites of arachidonic acid are synthesized by vascular and inflammatory cells and have a variety of important biological actions, we investigated the metabolism of arachidonic acid by these pathways in normal and stenosed, endothelially injured canine coronary arteries. We found and confirmed by gas chromatography/mass spectrometry that primarily 12- and 15-hydroxyeicosatetraenoic acids (HETEs) are synthesized by both coronary artery segments. Lesser amounts of 11-, 9-, 8-, and 5-HETEs are also produced. 15-Ketoeicosatetraenoic acid is also synthesized. The synthesis of 14C-HETEs is fivefold to 10-fold greater by the stenosed than the normal coronary artery. Specific radioimmunoassays indicated that the stenosed coronary artery synthesized 93 +/- 14 and 1,102 +/- 154 ng/g of tissue of 15- and 12-HETE, respectively, while the normal coronary artery produced 17 +/- 3 and 162 +/- 68 ng/g of tissue of 15- and 12-HETE, respectively. Products comigrating with 14,15-; 11,12-; 8,9-; and 5,6-epoxyeicosatrienoic acids (EETs) and the corresponding dihydroxyeicosatrienoic acids (DHETs) were detected predominantly in stenosed coronary arteries by high-pressure liquid chromatography. The structures of the EETs were confirmed by GC/MS. The EETs and prostaglandin I2 produced endothelium-independent, concentration-related relaxations of dog coronary artery rings. These data indicate that normal and stenotic coronary arteries metabolize arachidonic acid to HETEs, DHETs, and EETs along with prostaglandins; however, the synthesis of these metabolites is greater in the stenosed, endothelially injured vessel. The EETs may be synthesized during the development of cyclic flow variations and counteract the vasoconstrictor effects of thromboxane A2.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Arachidonic Acids; Constriction, Pathologic; Coronary Disease; Coronary Vessels; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Dogs; Hydroxyeicosatetraenoic Acids; Lipoxygenase; Oxygenases; Prostaglandins; Reference Values