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

The relation between levels of n-6 polyunsaturated fatty acids (PUFAs) and cognitive function and mild cognitive impairment (MCI) in patients with coronary artery disease (CAD) is unclear. The purpose of the present study was to examine the associations between levels of n-6 PUFAs and cognitive function and MCI in patients with CAD.. We conducted a cross-sectional study of 129 patients with CAD but without probable dementia. MCI was estimated with the Japanese version of the Montreal Cognitive Assessment (MoCA-J). We classified patients into the normal cognitive group and MCI group and compared their clinical characteristics and serum levels of PUFAs. The relation between these levels and cognitive function and MCI was clarified with Pearson correlation analysis and logistic regression analysis.. The serum levels of dihomo-γ-linolenic acid (DGLA) in the CAD patients with MCI were significantly lower than those in the patients with normal cognitive function (p= 0.04). The serum levels of DGLA were positively associated with the MoCA-J score (r= 0.24, p= 0.005) and significantly associated with MCI in the univariate logistic regression analysis (odds ratio, 0.97; p= 0.035). However, in the multivariate logistic regression analysis, only age was significantly associated with MCI (odds ratio, 1.11; p < 0.001).. The serum levels of DGLA were associated with cognitive function and MCI in patients with CAD. Although not an independent predictor, DGLA might be one useful marker with which to identify early cognitive decline in these patients.

Topics: 8,11,14-Eicosatrienoic Acid; Aged; Aged, 80 and over; Cognition; Cognitive Dysfunction; Coronary Artery Disease; Cross-Sectional Studies; Female; Humans; Logistic Models; Male; Middle Aged

Objective Associations between aortic stiffness and cardiovascular disease events are mediated in part by pathways that include coronary microvascular dysfunction (CMD) and remodeling. However, the relationship between aortic stiffness and CMD remains unclear. The present study aimed to determine whether aortic stiffness causes CMD as evaluated by the hyperemic microvascular resistance index (hMVRI) in patients with non-obstructive coronary artery disease (CAD). Methods The intracoronary physiological variables in 209 coronary arteries were evaluated in 121 patients with non-obstructive CAD (fractional flow reserve >0.80) or reference vessels. The cardio-ankle vascular index (CAVI) as a measure of aortic stiffness and atherosclerotic risk factors were also measured. Results Univariate analyses showed that hMVRI correlated with age (β=0.24, p=0.007), eicosapentaenoic acid (EPA; β=-0.18, p=0.048), EPA/arachidonic acid (AA) (EPA/AA) ratio (β=-0.22, p=0.014) and CAVI (β=0.30, p=0.001). A multivariate regression analysis identified CAVI (β=0.25, p=0.007) and EPA/AA ratio (β=-0.26, SE=0.211, p=0.003) as independent determinants of hMVRI. Conclusion Aortic stiffness may cause CMD in patients with non-obstructive CAD via increased coronary microvascular resistance. Aortic stiffness is associated with CMD which is evaluated as hyperemic microvascular resistance in patients with non-obstructive CAD.

Topics: 8,11,14-Eicosatrienoic Acid; Aged; Arachidonic Acid; Cardiac Catheterization; Cardio Ankle Vascular Index; Coronary Artery Disease; Coronary Vessels; Docosahexaenoic Acids; Echocardiography; Eicosapentaenoic Acid; Female; Fractional Flow Reserve, Myocardial; Humans; Hyperemia; Male; Microcirculation; Microvascular Angina; Microvessels; Middle Aged; Multivariate Analysis; Risk Factors; Vascular Stiffness

Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating EET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with extent of CAD [no apparent CAD (N = 39), nonobstructive CAD (N = 51), and obstructive CAD (N = 72)] were evaluated. A significant relationship between free EET levels and CAD extent was observed (P = 0.003) such that the presence of obstructive CAD was associated with lower circulating EET levels. This relationship was confirmed in multiple regression analysis where CAD extent was inversely and significantly associated with EET levels (P = 0.013), and with a biomarker of EET biosynthesis (P < 0.001), independent of clinical and demographic factors. Furthermore, quantitative enrichment analysis revealed that these associations were the most pronounced compared with other eicosanoid metabolism pathways. Collectively, these findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis. Novel strategies that promote the effects of EETs may have therapeutic promise for patients with obstructive CAD.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Aged; Arachidonic Acid; Arachidonic Acids; Biomarkers; Coronary Angiography; Coronary Artery Disease; Cytochrome P-450 Enzyme System; Female; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Male; Metabolomics; Middle Aged

Preclinical and genetic epidemiologic studies suggest that modulating cytochrome P450 (CYP)-mediated arachidonic acid metabolism may have therapeutic utility in the management of coronary artery disease (CAD). However, predictors of inter-individual variation in CYP-derived eicosanoid metabolites in CAD patients have not been evaluated to date. Therefore, the primary objective was to identify clinical factors that influence CYP epoxygenase, soluble epoxide hydrolase (sEH), and CYP ω-hydroxylase metabolism in patients with established CAD.. Plasma levels of epoxyeicosatrienoic acids (EETs), dihydroxyeicosatrienoic acids (DHETs), and 20-hydroxyeicosatetraenoic acid (20-HETE) were quantified by HPLC-MS/MS in a population of patients with stable, angiographically confirmed CAD (N=82) and healthy volunteers from the local community (N=36). Predictors of CYP epoxygenase, sEH, and CYP ω-hydroxylase metabolic function were evaluated by regression.. Obesity was significantly associated with low plasma EET levels and 14,15-EET:14,15-DHET ratios. Age, diabetes, and cigarette smoking also were significantly associated with CYP epoxygenase and sEH metabolic activity, while only renin-angiotensin system inhibitor use was associated with CYP ω-hydroxylase metabolic activity. Compared to healthy volunteers, both obese and non-obese CAD patients had significantly higher plasma EETs (P<0.01) and epoxide:diol ratios (P<0.01), whereas no difference in 20-HETE levels was observed (P=NS).. Collectively, these findings suggest that CYP-mediated eicosanoid metabolism is dysregulated in certain subsets of CAD patients, and demonstrate that biomarkers of CYP epoxygenase and sEH, but not CYP ω-hydroxylase, metabolism are altered in stable CAD patients relative to healthy individuals. Future studies are necessary to determine the therapeutic utility of modulating these pathways in patients with CAD.

Topics: 8,11,14-Eicosatrienoic Acid; Age Factors; Biomarkers; Case-Control Studies; Chromatography, High Pressure Liquid; Coronary Angiography; Coronary Artery Disease; Cross-Sectional Studies; Cytochrome P-450 CYP2J2; Cytochrome P-450 CYP4A; Cytochrome P-450 Enzyme System; Diabetes Mellitus; Eicosanoids; Epoxide Hydrolases; Female; Humans; Hydroxyeicosatetraenoic Acids; Hydroxylation; Male; Middle Aged; North Carolina; Obesity; Regression Analysis; Risk Assessment; Risk Factors; Severity of Illness Index; Smoking; Tandem Mass Spectrometry

Activation of the lectin-like oxLDL receptor (LOX-1) promotes atherosclerosis. Oxidized LDL (oxLDL) increases production of reactive oxygen species (ROS) and leads to the development of endothelial dysfunction. The molecular causes for oxLDL to induce oxidative DNA damage and metabolic dysfunction remain uncertain. Here we report treatment of cultured human coronary arterial endothelial cells (HCAEC) with oxLDL to cause oxidative DNA damage as determined by a 3-fold increase in 8-OH-desoxyguanosine adduct formation and a 4-fold induction of the growth arrest and DNA damage-inducible transcripts GADD45 and GADD153. Oxidative stress resulted in activation of Oct-1, a transcriptional repressor of various vascular cytochrome P450 (CYP) monooxygenases. Activation of Oct-1 was protein kinase C (PKC)-mediated. Binding of Oct-1 to promoter sequences of CYP monooxygenases was increased upon treatment of HCAEC with oxLDL. This resulted in repressed production of endothelium-derived hyperpolarization factor 11,12-epoxyeicosatrieonic acid. Small interference RNA-mediated functional knockdown of Oct-1 prevented oxLDL-mediated silencing of CYP expression. Inhibition of LOX-1 attenuated oxLDL-mediated endothelial DNA damage, Oct-1/DNA binding, and reversed impaired production of EDHF. Taken collectively, oxLDL induced oxidative DNA damage and activation of Oct-1 to result in metabolic dysfunction of coronary arterial endothelium.

Topics: 8-Hydroxy-2'-Deoxyguanosine; 8,11,14-Eicosatrienoic Acid; Biological Factors; Cell Cycle Proteins; Cells, Cultured; Coronary Artery Disease; Coronary Vessels; Cytochrome P-450 Enzyme System; Deoxyguanosine; DNA Adducts; DNA Damage; Endothelial Cells; Endothelium, Vascular; Humans; Lipoproteins, LDL; Nuclear Proteins; Octamer Transcription Factor-1; Oxidative Stress; Protein Kinase C; Reactive Oxygen Species; Repressor Proteins; Response Elements; RNA, Small Interfering; Scavenger Receptors, Class E; Transcription Factor CHOP