8-11-14-eicosatrienoic-acid and Diabetes-Mellitus

Despite the optimization of blood glucose control and the therapeutic management of risk factors, obesity- and diabetes-induced cardiovascular diseases are still major health problems in the United States. Arachidonic acid (AA), an endogenous 20-carbon polyunsaturated fatty acid, is metabolized by cytochrome P450 (CYP) epoxygenases into epoxyeicosatrienoic acids (EETs), which are important lipid mediators with many beneficial effects in type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and obesity- and diabetes-induced cardiovascular diseases. EETs can be further metabolized to less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). It has been demonstrated that the use of sEH blockers, which prevent EET degradation, is a promising pharmacological approach to promoting insulin secretion, preventing endothelial dysfunction, decreasing blood pressure, and protecting against target organ damage in obesity and metabolic diseases. This review will focus on biochemistry of CYP monooxygenase system as well as the pharmacology and physiological significance of EETs and sEH. We will also discuss the role of EETs/sEH in T1DM, T2DM, and obesity- and diabetes-induced cardiovascular diseases.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Cardiovascular Diseases; Diabetes Mellitus; Epoxide Hydrolases; Humans; Obesity; Solubility

Alpha-Lipoic acid (ALA) is a natural compound, chemically named 1,2-dithiolane-3-pentanoic acid, also referred to as thioctic acid. In humans, ALA is synthetized by the liver and other tissues with high metabolic activity: heart, kidney. ALA is both water and fat soluble and therefore, is widely distributed in both cellular membranes and cytosol. Recently, a greater deal of attention has been given to antioxidant function for ALA and its reduced formed: dihydrolipoic acid (DHLA). ALA scavenges hydroxyl radicals, hypochlorous acid and singlet oxygen. It may also exert antioxidant effects in biological systems through transitional metal chelation. Dihydrolipoic acid has been shown to have antioxidant but also pro-oxidant properties in systems in which hydroxyl radical was generated. ALA/DHLA ratio has the capacity to recycle endogenous antioxidants such as vitamin E. A number of experimental as well as clinical studies point to the usefulness of ALA as a therapeutic agent for such diverse conditions as diabetes, atherosclerosis, insulin resistance, neuropathy, neurodegenerative diseases and ischemia-reperfusion injury. ALA represents a potential agent on the vascular endothelium, recording to ALA/DHLA redox couple is one of the most powerful biological antioxidant systems.

Topics: 8,11,14-Eicosatrienoic Acid; Animal Experimentation; Animals; Antioxidants; Cardiovascular Diseases; Diabetes Mellitus; Endothelium, Vascular; Free Radical Scavengers; Humans; Hydroxyl Radical; Insulin Resistance; Neurodegenerative Diseases; Oxidation-Reduction; Randomized Controlled Trials as Topic; Rats; Thioctic Acid; Toluene; Vitamin B Complex

Cardiac hypertrophy is a key structural change in diabetic cardiomyopathy, which mechanism is unknown. 14,15-Epoxyeicosatrienoic acid (14,15-EET) generated from arachidonic acid by CYP2J2 has beneficial effects in metabolic syndrome, which also plays vital roles in inflammatory response. Peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor superfamily and have three subtypes of α, β (or δ) and γ. Studies have found that 14,15-EET can perform various biological functions by activating PPARs, but its role in diabetic cardiac hypertrophy is unknown. This study aimed to investigate the role of 14,15-EET-PPARs signaling pathway in the development of diabetic cardiac hypertrophy. Diabetic cardiac hypertrophy was developed by high-fat diet feeding combined with streptozotocin (40 mg/kg/d for 5 days, i.p.) in mice and was induced by glucose at 25.5 mmol/L (high glucose, HG) in H9c2 cells. The decreased level of 14,15-EET and the down-regulated expression of PPARα, PPARβ and PPARγ were found following diabetic cardiac hypertrophy in mice. Similarly, both the level of 14,15-EET and the PPARs expression were also reduced in HG-induced hypertrophic cardiomyocytes. Supplementation with 14,15-EET improved the cardiomyocyte hypertrophy and up-regulated PPARs expression, which were nullified by 14,15-EEZE, a 14,15-EET antagonist. Taken together, we conclude that the decreased 14,15-EET is involved in the development of diabetic cardiac hypertrophy through the down-regulation of PPARs.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Cardiomegaly; Diabetes Mellitus; Diabetic Cardiomyopathies; Glucose; Mice; Myocytes, Cardiac; PPAR gamma

The cardioprotective properties of linoleic acid (LA), a major n-6 (ω-6) polyunsaturated fatty acid (PUFA), have been recognized, but less is known about its associations with other causes of death. Relatively little is also known about how the minor n-6 PUFAs-γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA)-relate to mortality risk.. We investigated the associations of serum n-6 PUFAs, an objective biomarker of exposure, with risk of death in middle-aged and older men and whether disease history modifies the associations.. We included 2480 men from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 y at baseline in 1984-1989. The stratified analyses by baseline disease status included 1019 men with a history of cardiovascular disease (CVD), cancer, or diabetes and 1461 men without a history of disease.. During the mean follow-up of 22.4 y, 1143 deaths due to disease occurred. Of these, 575 were CVD deaths, 317 were cancer deaths, and 251 were other-cause deaths. A higher serum LA concentration was associated with a lower risk of death from any cause (multivariable-adjusted HR for the highest compared with the lowest quintile: 0.57; 95% CI: 0.46, 0.71; P-trend < 0.001) and with deaths due to CVD (extreme-quintile HR: 0.54; 95% CI: 0.40, 0.74; P-trend < 0.001) and non-CVD or noncancer causes (HR: 0.48; 95% CI: 0.30, 0.76; P-trend = 0.001). Serum AA had similar, although weaker, inverse associations. Serum GLA and DGLA were not associated with risk of death, and none of the fatty acids were associated with cancer mortality. The results were generally similar among those with or without a history of major chronic disease (P-interaction > 0.13).. Our findings showed an inverse association of a higher biomarker of LA intake with total and CVD mortality and little concern for risk, thus supporting the current dietary recommendations to increase LA intake for CVD prevention. The finding of an inverse association of serum AA with the risk of death needs replication in other populations.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Arachidonic Acid; Biomarkers; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus; Diet; Fatty Acids, Omega-6; Follow-Up Studies; gamma-Linolenic Acid; Humans; Incidence; Linoleic Acid; Male; Middle Aged; Mortality; Neoplasms; Prospective Studies; Risk Factors; Socioeconomic Factors

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

Platelet abnormalities have been suggested to be linked with vascular diseases. Diabetes mellitus has a high incidence of vascular complications. In the present study gas-liquid chromatography analyses were carried out to investigate the fatty acid composition in platelet phospholipids of Type-2 (non-insulin-dependent) diabetic patients. Fatty acid composition in platelet phospholipids was different between diabetics and age-matched control subjects. Arachidonic acid increased significantly (p less than 0.01), and both eicosatrienoic acid and eicosapentaenoic acid decreased in diabetes mellitus. A good correlation was found between fatty acid content of platelet phospholipids and that of plasma total lipids in the fatty acids examined, except for arachidonic acid. The levels of arachidonic acid in diabetic platelet phospholipids was disproportionately high to these in plasma total lipids. These results suggest that the system for arachidonic acid incorporation into platelet phospholipids is specifically accelerated in the diabetic metabolic state.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Aged; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Diabetes Mellitus; Eicosapentaenoic Acid; Fatty Acids; Fatty Acids, Unsaturated; Female; Humans; Lipids; Male; Middle Aged; Phospholipids