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BACKGROUND - alpha-Linolenic acid (ALA) is associated with a low risk of cardiovascular disease; however, the underlying mechanism is not completely known.
OBJECTIVE - The objective was to examine whether habitual dietary ALA intake is associated with plasma concentrations of inflammatory biomarkers after control for shared genetic and common environmental factors.
DESIGN - We cross-sectionally studied 353 middle-aged male twins. Habitual diet was assessed with the Willett food-frequency questionnaire. Fasting plasma concentrations of interleukin-6 (IL-6) and its soluble receptor (sIL-6R), high-sensitivity C-reactive protein (hsCRP), and tumor necrosis factor-alpha (TNF-alpha) were measured. Linear mixed-effect regression analysis was used to partition the overall association into within- and between-pair associations.
RESULTS - A 1-g increment in habitual dietary ALA intake was associated with 11.0% lower concentrations of sIL-6R (P = 0.004) but not of IL-6 (P = 0.31), TNF-alpha (P = 0.16), or hsCRP (P = 0.36) after adjustment for energy intake, nutritional factors, known cardiovascular disease risk factors, and medications. After further control for shared genetic and common environmental factors by comparison of brothers within a twin pair, a twin with a 1-g higher ALA intake was likely to have 10.9% (95% CI: 3.7%, 17.6%; P = 0.004) lower sIL-6R concentrations than his co-twin with a low intake, whereas ALA intake was not significantly associated with plasma concentrations of IL-6, TNF-alpha, or hsCRP. These results were validated by using 1000 bootstrap samples.
CONCLUSIONS - Habitual dietary ALA intake is inversely associated with plasma sIL-6R concentrations independent of shared genetic and common environmental influences. Lowering sIL-6R may be a mechanism underlying the cardioprotective properties of habitual dietary ALA. This study was registered at clinicaltrials.gov as NCT00017836.
Anabaena sp. PCC 7120 is one of the few prokaryotes harboring a lipoxygenase (LOX) gene. The sequence resides in an open reading frame encoding a fusion protein of a catalase-like hemoprotein with an unusually short LOX (approximately 49 kDa) at the C terminus. The recombinant mini-LOX contains a non-heme iron in the active site and is highly active with linoleic and alpha-linolenic acids (which occur naturally in Anabaena) giving the respective 9R-hydroperoxides, the mirror image of the 9S-LOX products of plants. Using stereospecifically labeled [11-(3)H]linoleic acids we show that reaction is catalyzed via a typical antarafacial relationship of initial hydrogen abstraction and oxygenation. The mini-LOX oxygenated C16/C18:2-phosphatidylcholine with 9R specificity, suggesting a "tail first" mode of fatty acid binding. Site-directed mutagenesis of an active site Ala (Ala215), typically conserved as Gly in R-LOX, revealed that substitution with Gly retained 9R specificity, whereas the larger Val substitution switched oxygenation to 13S, implying that Ala215 represents the functional equivalent of the Gly in other R-LOX. Metabolism studies using a synthetic fatty acid with extended double bond conjugation, 9E,11Z,14Z-20:3omega6, showed that the mini-LOX can control oxygenation two positions further along the fatty acid carbon chain. We conclude that the mini-LOX, despite lacking the beta-barrel domain and much additional sequence, is catalytically complete. Interestingly, animal and plant LOX, which undoubtedly share a common ancestor, are related in sequence only in the catalytic domain; it is possible that the prokaryotic LOX represents a common link and that the beta-barrel domain was then acquired independently in the animal and plant kingdoms.
Data on the association between dairy consumption and blood pressure have been inconsistent. We sought to examine the relation between dairy consumption and prevalent hypertension (HTN) among 4797 participants of the National Heart, Lung, and Blood Institute Family Heart Study. We used generalized estimating equations to estimate prevalence odds ratios of HTN across categories of dairy consumption. From the lowest to the highest sex-, age-, and energy-adjusted quartile of dairy consumption, there was an inverse association between dairy intake and prevalent HTN: odds ratios (95% CIs) were 1.0 (reference), 0.82 (0.64 to 1.05), 0.68 (0.53 to 0.89), and 0.62 (0.45 to 0.84), respectively, in a model adjusting for age, sex, energy intake, field center, body mass index, dietary linolenic acid, saturated and monounsaturated fat, sodium intake, potassium, caffeine, fiber, and fruits and vegetables (P for trend = 0.002). This association was independent of calcium intake and was mainly observed among subjects consuming fewer calories from saturated fat (P for interaction = 0.014). Dairy consumption was inversely associated with systolic (P for trend = 0.003) but not diastolic (P for trend = 0.09) blood pressure. Although subjects consuming > or = 2 servings per day of dairy products and higher total linolenic acid had the lowest prevalence odds of HTN, there was no evidence for interaction between linolenic acid and dairy consumption on HTN (P for interaction = 0.65). In conclusion, our data indicate an inverse association between dairy consumption and prevalent HTN that was independent of dietary calcium, mainly among individuals consuming less saturated fat. This suggests that consumption of low-fat dairy products might be more beneficial for preventing HTN.
Palm oil and soybean oil are the 2 most widely used cooking oils in the world. Palm oil is consumed mainly in developing countries, where morbidity and mortality due to cardiovascular disease (CVD) are on the rise. Although claims about adverse or protective effects of these oils are commonly made, there are no epidemiologic studies assessing the association between these oils and cardiovascular disease endpoints. We examined whether consumption of palm oil relative to soybean oil and other unsaturated oils (predominantly sunflower) is associated with myocardial infarction (MI) in Costa Rica. The cases (n = 2111) were survivors of a first acute MI and were matched to randomly selected population controls (n = 2111). Dietary intake was assessed with a validated semiquantitative FFQ. Adipose tissue profiles of essential fatty acids were assessed to validate cooking oil intake and found to be consistent with self-reported major oils used for cooking. The data were analyzed using conditional logistic regression. Palm oil users were more likely to have an MI than users of soybean oil [odds ratio (OR) = 1.33; 95% CI: 1.08-1.63] or other cooking oils (OR = 1.23; CI: 0.99-1.52), but they did not differ from users of soybean oil with a high trans-fatty acid content (OR = 1.14; CI: 0.84-1.56). These data suggest that as currently used in Costa Rica, and most likely in many other developing countries, the replacement of palm oil with a polyunsaturated nonhydrogenated vegetable oil would reduce the risk of MI.
Cyclopentenone (A2/J2) isoprostanes (IsoPs) are a group of prostaglandin (PG)-like compounds generated in vivo from the free radical-induced peroxidation of arachidonic acid. Unlike other classes of IsoPs, cyclopentenone IsoPs contain highly reactive unsaturated carbonyl moieties on the prostane ring analogous to cyclooxygenase-derived PGA2 and PGJ2 that readily adduct relevant biomolecules such as thiols via Michael addition. The purpose of this review is to summarize our knowledge of the A2/J2-IsoPs. As a starting point, we will briefly discuss the formation and biological properties of PGA2 and PGJ2. Next, we will review studies definitively showing that cyclopentenone IsoPs are formed in large amounts in vivo. This is in marked contrast to cyclopentenone PGs, for which little evidence exists that they are endogenously produced. Subsequently, we will discuss studies related to the chemical syntheses of the 15-A2-IsoP series of cyclopentenone IsoPs. The successful synthesis of these compounds provides the recent impetus to explore the metabolism and biological properties of A-ring IsoPs, particularly as modulators of inflammation, and this work will be discussed. Finally, the formation of cyclopentenone IsoP-like compounds from other fatty acids such as linolenic acid and docosahexaenoic acid will be detailed.
Theoretical calculations were carried out to provide a framework for understanding the free radical oxidation of unsaturated lipids. The carbon[bond]hydrogen bond dissociation enthalpies (BDEs) of organic model compounds and oxidizable lipids (R[bond]H) and the carbon[bond]oxygen bond dissociation enthalpies of peroxyl radical intermediates (R[bond]OO*) have been calculated. The carbon[bond]hydrogen BDEs correlate with the rate constant for propagation of free radical autoxidation, and the carbon[bond]oxygen BDEs of peroxyl radicals correlate with rate constants for beta-fragmentation of these intermediates. Oxygen addition to intermediate carbon radicals apparently occurs preferentially at centers having the highest spin density. The calculated spin distribution therefore provides guidance about the partitioning of oxygen to delocalized carbon radicals. Where the C[bond]H BDEs are a function of the extent of conjugation in the parent lipid and the stability of the carbon radical derived therefrom, C[bond]OO* BDEs are also affected by hyperconjugation. This gives way to different rates of beta-fragmentation of peroxyl radicals formed from oxygen addition at different sites along the same delocalized radical. We have also studied by both theory and experiment the propensity for benzylic radicals to undergo oxygen addition at their ortho and para carbons which, combined, possess an equivalent unpaired electron spin density as the benzylic position itself. We find that the intermediate peroxyl radicals in these cases have negative C[bond]OO* BDEs and, thus, have rate constants for beta-fragmentation that exceed the diffusion-controlled limit for the reaction of a carbon-centered radical with oxygen.
BACKGROUND - Alpha-linolenic acid may protect against cardiovascular disease. We examined the association between adipose tissue alpha-linolenic acid and nonfatal acute myocardial infarction (MI) in a population-based case-control study in Costa Rica.
METHODS AND RESULTS - The 482 case patients with a first nonfatal acute MI and 482 population control subjects were matched by age, sex, and area of residence. Fatty acids were assessed by gas-liquid chromatography in adipose tissue samples collected from all subjects. ORs and 95% CIs were calculated from multivariate conditional logistic regression models. Subjects in the top quintiles of adipose tissue alpha-linolenic acid had a lower risk of MI than those in the lowest quintile: OR (95% CI), 1.00; 0.80 (0.52 to 1.24); 0.53 (0.34 to 0.82); 0.44 (0.28 to 0.67); and 0.37 (0.24 to 0.59); test for trend, P<0.0001. This association was strengthened after adjustment for established MI risk factors, including smoking, physical activity, income, and adipose tissue linoleic acid and trans fatty acids (OR for the top versus lowest quintile, 0.23; 95% CI, 0.10 to 0.50; test for trend, P<0.0001). Further adjustment for the intake of saturated fat, fiber, alcohol, and vitamin E did not change this association (OR for the top versus lowest quintile, 0.23; 95% CI, 0.10 to 0.55; test for trend, P<0.0001).
CONCLUSIONS - The inverse association observed between alpha-linolenic acid and nonfatal acute MI suggests that consumption of vegetable oils rich in alpha-linolenic acid confers important protection against cardiovascular disease.
BACKGROUND - Biomarkers can provide a more accurate measure of long-term intake than can dietary questionnaires.
OBJECTIVE - The objective was to identify which adipose tissue fatty acids are suitable biomarkers of intake as assessed with a validated food-frequency questionnaire.
DESIGN - Costa Rican men with a mean (+/- SD) age of 56 +/- 11 y (n = 367) and women aged 60 +/- 10 y (n = 136) completed a 135-item food-frequency questionnaire and provided an adipose tissue sample. Fifty fatty acids were identified by capillary gas chromatography. Correlation coefficients were calculated after adjustment for age, sex, body mass index, and smoking status.
RESULTS - The best adipose tissue marker for total intake of saturated fatty acids was 15:0 + 17:0 (r = 0.18). Both 15:0 and 17:0 were also the best correlates of dairy product intake (r = 0.31 for each). The diet-adipose tissue correlations for n-3 fatty acids were r = 0.34 for 18:3, r = 0.15 for 20:5, and r = 0.18 for 22:6. Fish intake correlated significantly with these adipose tissue n-3 fatty acids. Dietary and adipose tissue n-6 fatty acids were highly correlated: 18:2 (r = 0.58) and 18:3 (r = 0.24). The best indicators of total trans fatty acid intake were ct18:2n-6 and tc18:2n-6 (r = 0.58 for each); total 18:1 trans fatty acid (r = 0.45) and 16:1 trans fatty acid (r = 0.16) were the next best indicators.
CONCLUSIONS - Adipose tissue is a suitable biomarker of dietary fatty acid intake, particularly for n-3 and n-6 cis polyunsaturated fatty acids and trans fatty acids. Ideally, adipose tissue and dietary questionnaires should complement, rather than substitute for, each other in epidemiologic studies.
A novel member of the plant cytochrome P450 CYP74 family of fatty acid hydroperoxide metabolizing enzymes has been cloned from melon fruit (Cucumis melo). The cDNA is comprised of 1,446 nucleotides encoding a protein of 481 amino acids. The homology at the amino acid level to other members of the CYP74 family is 35-50%, the closest relatives being allene oxide synthases. The cDNA was expressed in Escherichia coli, and the corresponding protein was purified by affinity column chromatography. The native enzyme showed a main Soret band at 418 nm, indicative of a low spin ferric cytochrome P450, and a 447-nm peak appeared in the CO-difference spectrum. Using [U-14C]radiolabeled substrate, HPLC, UV, and GC-MS, the products of conversion of 9S-hydroperoxy-linoleic acid were identified as 9-oxo-nonanic acid and 3Z-nonenal. Kinetic analysis of this hydroperoxide lyase showed the highest rate of reaction with 9-hydroperoxy-linolenic acid followed by 9-hydroperoxy-linoleic acid and then the corresponding 13-hydroperoxides. Overall, the newly characterized cytochrome P450 enzyme is a fatty acid hydroperoxide lyase with a preference, but not absolute specificity for the 9-positional hydroperoxides of linoleic and linolenic acids.
Polyunsaturated fatty acid (PUFA) peroxyl radicals play a crucial role in lipid oxidation. ESR spectroscopy with the spin-trapping technique is one of the most direct methods for radical detection. There are many reports of the detection of PUFA peroxyl radical adducts; however, it has recently been reported that attempted spin trapping of organic peroxyl radicals at room temperature formed only alkoxyl radical adducts in detectable amounts. Therefore, we have reinvestigated spin trapping of the linoleic, arachidonic, and linolenic acid-derived PUFA peroxyl radicals. The slow-flow technique allowed us to obtain well-resolved ESR spectra of PUFA-derived radical adducts in a mixture of soybean lipoxygenase, PUFA, and the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO). However, interpretation of the ESR spectra was complicated by the overlapping of the PUFA-derived alkoxyl radical adduct spectra. In order to understand these spectra, PUFA-derived alkoxyl radical adducts were modeled by various alkoxyl radical adducts. For the first time, we synthesized a wide range of DMPO adducts with primary and secondary alkoxyl radicals. It was found that many ESR spectra previously assigned as DMPO/peroxyl radical adducts based on their close similarity to the ESR spectrum of the DMPO/superoxide radical adduct, in conjunction with their insensitivity to superoxide dismutase, are indeed alkoxyl radical adducts. We have reassigned the PUFA alkylperoxyl radical adducts to their corresponding alkoxyl radical adducts. Using hyperfine coupling constants of model DMPO/alkoxyl radical adducts, the computer simulation of DMPO/PUFA alkoxyl radical adducts was performed. It was found that the trapped, oxygen-centered PUFA-derived radical is a secondary, chiral alkoxyl radical. The presence of a chiral carbon atom leads to the formation of two diastereomers of the DMPO/PUFA alkoxyl radical adduct. Therefore, attempted spin trapping of the PUFA peroxyl radical by DMPO at room temperature leads to the formation of the PUFA alkoxyl radical adduct.