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Introduction Rapid changes in Western diets have been identified as being responsible, at least in part, for inflation in the number of cardiovascular diseases and related pathologies (Gadiraju et al. [...], The present study was designed to ascertain the effects of 3 diets with different omega-3/6 fatty acid ratios on infarct size and the modifications that these diets induce in the lipid composition of cardiac tissue. Sprague-Dawley rats were fed omega-3/6 fatty acid diets with 1:1,1:5, or 1:20 ratios for at least 10 days, followed by occlusion of the left anterior descending artery for 40 min and 24 h of reperfusion. Infarct size was significantly smaller in the 1:1 group than in the other groups. Significantly higher concentrations of the omega-3 fatty acids eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid were found in the 1:1 group than in the other groups. Omega-6 polyunsaturated fatty acid levels were similar between groups, although they were higher in the 1:5 and 1:20 groups than in the 1:1 group. Margaric acid concentrations were higher in the 1:1 group than in the other groups. Docosahexaenoic acid levels in cardiac tissue and infarct size were significantly correlated with no other significant links being apparent. The present study indicated that a 1:1 omega-3/6 fatty acid ratio protected against ischemia and was associated with increased omega-3 fatty acid composition of cardiac tissue. Key words: omega-3, omega-6, myocardial infarction, lipids, margaric acid, reperfusion, inflammation. La presente etude a ete concue en vue de cerner les effets de 3 regimes alimentaires avec differents ratios d'acides gras omega 3/6 sur la taille de l'infarctus, ainsi que sur les modifications que ces regimes alimentaires provoquent sur la composition lipidique du tissu cardiaque. Nous avons administre a des rats Sprague-Dawley des regimes alimentaires avec des acides gras omega 3/6 a des ratios de 1:1, de 1:5 ou de 1:20 pendant au moins 10 jours, suivis de l'occlusion de l'artere interventriculaire anterieure pendant 40 minutes avec une reperfusion de 24 h. La taille de l'infarctus etait nettement moins elevee dans le groupe 1:1 que dans les autres groupes. Nous avons mesure des concentrations d'acides gras omega 3, d'acide eicosapentaenoique, d'acide docosapentaenoique et d'acide docosahexaenoique nettement plus elevees dans le groupe 1:1 que dans les autres groupes. Les taux d'acides gras omega 6 polyinsatures etaient similaires d'un groupe a l'autre, mais ils etaient plus eleves dans les groupes 1:5 et 1:20 que dans le groupe 1:1. Les concentrations d'acide margarique etaient plus elevees dans le groupe 1:1 que dans les autres groupes. Les taux d'acide docosahexaenoique dans le tissu cardiaque etaient nettement proportionnels a la taille de l'infarctus, sans autres liens apparents de facon marquee. En conclusion, la presente etude signalait que des acides gras omega 3/6 a un ratio de 1:1 permettaient de proteger de l'ischemie et qu'ils etaient associes a une augmentation de la composition du tissu cardiaque en acides gras omega 3. [Traduit par la Redaction] Mots-cles : omega 3, omega 6, infarctus du myocarde, lipides, acide margarique, reperfusion, inflammation.

The purpose of this study was to determine in vivo myocardial energy metabolism and function in a nutritional model of type 2 diabetes. Wistar rats rendered insulin-resistant and mildly hyperglycemic, hyperinsulinemic, and hypertriglyceridemic with a high-fructose/high-fat diet over a 6-wk period with injection of a small dose of streptozotocin (HFHFS) and control rats were studied using micro-PET ([micro]PET) without or with a euglycemic hyperinsulinemic clamp. During glucose clamp, myocardial metabolic rate of glucose measured with [[sup.18]F]fluorodeoxyglucose ([[sup.18]F]FDG) was reduced by ~81% (P < 0.05), whereas myocardial plasma nonesterified fatty acid (NEFA) uptake as determined by [[sup.18]F]fluorothia-6-heptadecanoic acid ([[sup.18]F]FTHA) was not significantly changed in HFHFS vs. control rats. Myocardial oxidative metabolism as assessed by [[sup.11]C]acetate and myocardial perfusion index as assessed by [[sup.13]N]ammonia were similar in both groups, whereas left ventricular ejection fraction as assessed by [micro]PET was reduced by 26% in HFHFS rats (P < 0.05). Without glucose clamp, NEFA uptake was ~40% lower in HFHFS rats (P < 0.05). However, myocardial uptake of [[sup.18]F]FTHA administered by gastric gavage was significantly higher in HFHFS rats (P < 0.05). These abnormalities were associated with reduced Glut4 mRNA expression and increased Cd36 mRNA expression and mitochondrial carnitine palmitoyltransferase 1 activity (P < 0.05). HFHFS rats display type 2 diabetes complicated by left ventricular contractile dysfunction with profound reduction in myocardial glucose utilization, activation of fatty acid metabolic pathways, and preserved myocardial oxidative metabolism, suggesting reduced myocardial metabolic efficiency. In this model, increased myocardial fatty acid exposure likely occurs from circulating triglyceride, but not from circulating plasma NEFA. type 2 diabetes; heart failure; cardiomyopathy; energy metabolism; positron emission tomography; nonesterified fatty acids; glucose metabolism; triacylglycerol doi:10.1152/ajpendo.00560.2009.

Although a shift from fatty acids (FAs) to carbohydrates (CHOs) is considered beneficial for the diseased heart, it is unclear why subjects with FA [beta]-oxidation defects are prone to cardiac decompensation under stress conditions. The present study investigated potential alterations in the myocardial utilization of CHOs for energy production and anaplerosis in 12-wk-old peroxisome proliferator-activating receptor-[alpha] (PPAR[alpha]) null mice (a model of FA [beta]-oxidation defects). Carbon-13 methodology was used to assess substrate flux through energy-yielding pathways in hearts perfused ex vivo at two workloads with a physiological substrate mixture mimicking the fed state, and real-time RT-quantitative polymerase chain reaction was used to document the expression of selected metabolic genes. When compared with that from control C57BL/6 mice, isolated working hearts from PPAR[alpha] null mice displayed an impaired capacity to withstand a rise in preload (mimicking an increased venous return as it occurs during exercise) as reflected by a 20% decline in the aortic flow rate. At the metabolic level, beyond the expected shift from FA (5-fold down) to CHO (1.5-fold up; P < 0.001) at both preloads, PPAR[alpha] null hearts also displayed 1) a significantly greater contribution of exogenous lactate and glucose and/or glycogen (2-fold up) to endogenous pyrnvate formation, whereas that of exogenous pyruvate remained unchanged and 2) marginal alterations in citric acid cycle-related parameters. The lactate production rate was the only measured parameter that was affected differently by preloads in control and PPAR[alpha] null mouse hearts, suggesting a restricted reserve for the latter hearts to enhance glycolysis when the energy demand is increased. Alterations in the expression of some glycolysis-related genes suggest potential mechanisms involved in this defective CHO metabolism. Collectively, our data highlight the importance of metabolic alterations in CHO metabolism associated with FA oxidation defects as a factor that may predispose the heart to decompensation under stress conditions even in the fed state. isolated working mouse heart perfusion; citric acid cycle; [sup.13]C isotopomer analysis; glycolysis; ATP-citrate lyase; peroxisome proliferator-activated receptor-[alpha]

The precise mechanisms underlying skeletal muscle damage in Duchenne muscular dystrophy (DMD) remain ill-defined. Functional ischemia during muscle activation, with subsequent reperfusion during rest, has been documented. Therefore, one possibility is the presence of increased oxidative stress. We applied a model of acute hindlimb ischemia/reperfusion (I/R) in mdx mice (genetic homolog of DMD) to evaluate dynamic in vivo responses of dystrophic muscles to this form of oxidative stress. Before the application of I/R, mdx muscles showed: 1) decreased levels of total glutathione (GSH) with an increased oxidized (GSSG)-to-reduced (GSH) glutathione ratio; 2) greater activity of the GSH-metabolizing enzymes glutathione peroxidase (GPx) and glutathione reductase; and 3) lower activity levels of NADP-linked isocitrate dehydrogenase (ICDH) and aconitase, two metabolic enzymes that are sensitive to inactivation by oxidative stress and also implicated in GSH regeneration. Interestingly, nondystrophic muscles subjected to UR exhibited similar changes in total glutathione, GSSG/GSH, GPx, ICDH, and aconitase. In contrast, all of the above remained stable in mdx muscles subjected to I/R. Taken together, these results suggest that mdx muscles are chronically subjected to increased oxidative stress, leading to adaptive changes that attempt to protect (although only in part) the dystrophic muscles from acute I/R-induced oxidative stress. In addition, mdx muscles show significant impairment of the redox-sensitive metabolic enzymes ICDH and aconitase, which may further contribute to contractile dysfunction in dystrophic muscles. reduced glutathione; glutathione reductase; Duchenne muscular dystrophy doi:10.1152/ajpregu.00031.2006

Decreased cardiac mitochondrial NAD[P.sup.+]-isocitrate dehydrogenase activity and expression: a marker of oxidative stress in hypertrophy development. Am J Physiol Heart Circ Physiol 287: H2122-H2131, 2004. First published July 22, 2004; doi: 10.1152/ajpheart. 00378.2004.--Mitochondrial dysfunction subsequent to increased oxidative stress and alterations in energy metabolism is considered to play a role in the development of cardiac hypertrophy and its progression to failure, although the sequence of events remains to be elucidated. This study aimed at characterizing the impact of hypertrophy development on the activity and expression of mitochondrial NAD[P.sup.+]-isocitrate dehydrogenase (mNAD[P.sup.+]-ICDH), a metabolic enzyme that controls redox and energy status. We expanded on our previous finding of its inactivation through posttranslational modification by the lipid peroxidation product 4-hydroxynonenal (HNE) in 7-wk-old spontaneously hypertensive rat (SHR) hearts before hypertrophy development (Benderdour et al. J Biol Chem 278: 45154-45159, 2003). In this study, we used 7-, 15-, and 30-wk-old SHR and Sprague-Dawley (SD) rats with abdominal aortic coarctation. Compared with age-matched control Wistar-Kyoto (WKY) rats, SHR hearts showed a significant 25% decrease of mNAD[P.sup.+]-ICDH activity, which preceded in time 1) the decline in its protein and mRNA expression levels (between 10% and 35%) and 2) the increase in hypertrophy markers. The chronic and persistent loss of mNAD[P.sup.+]-ICDH activity in SHR was associated with enhanced tissue accumulation of HNE-mNAD[P.sup.+]-ICDH and total HNE-protein adducts at all ages and contrasted with the profile of changes in the activity of other mitochondrial enzymes involved in antioxidant or energy metabolism. Two-way ANOVA of the data also revealed a significant effect of age on most parameters measured in SHR and WKY hearts. The mNAD[P.sup.+]-ICDH activity, protein, and mRNA expression were reduced between 25% and 35% in coarctated SD rats and were normalized by treatment of SHR or coarctated SD rats with renin-angiotensin system inhibitors, which prevented or attenuated hypertrophy. Altogether, our data show that cardiac mNAD[P.sup.+]-ICDH activity and expression are differentially and sequentially affected in hypertrophy development and, to a lesser extent, with aging. Decreased cardiac mNAD[P.sup.+]-ICDH activity, which is attributed at least in part to HNE adduct formation, appears to be a relevant early and persistent marker of mitochondrial oxidative stress-related alterations in hypertrophy development. Potentially, this could also contribute to the aetiology of cardiomyopathy. energy metabolism; 4-hydroxynonenal; lipoperoxidation; renin-angiotensin system; aging

Khairallah, Maya, Francois Labarthe, Bertrand Bouchard, Gawiyou Danialou, Basil J. Petrof, and Christine Des Rosiers. Profiling substrate fluxes in the isolated working mouse heart using [sup.13]C-labeled substrates: focusing on the origin and fate of pyruvate and citrate carbons. Am J Physiol Heart Circ Physiol 286: H1461-H1470, 2004. First published December 11, 2003; 10.1152/ajpheart.00942. 2003.--The availability of genetically modified mice requires the development of methods to assess heart function and metabolism in the intact beating organ. With the use of radioactive substrates and ex vivo perfusion of the mouse heart in the working mode, previous studies have documented glucose and fatty acid oxidation pathways. This study was aimed at characterizing the metabolism of other potentially important exogenous carbohydrate sources, namely, lactate and pyruvate. This was achieved by using [sup.13]C-labeling methods. The mouse heart perfusion setup and buffer composition were optimized to reproduce conditions close to the in vivo milieu in terms of workload, cardiac functions, and substrate-hormone supply to the heart (11 mM glucose, 0.8 nM insulin, 50 [micro]M carnitine, 1.5 mM lactate, 0.2 mM pyruvate, 5 nM epinephrine, 0.7 mM oleate, and 3% albumin). The use of three differentially [sup.13]C-labeled carbohydrates and a [sup.13]C-labeled long-chain fatty acid allowed the quantitative assessment of the metabolic origin and fate of tissue pyruvate as well as the relative contribution of substrates feeding acetyl-CoA (pyruvate and fatty acids) and oxaloacetate (pyruvate) for mitochondrial citrate synthesis. Beyond concurring with the notion that the mouse heart preferentially uses fatty acids for energy production (63.5 [+ or -] 3.9%) and regulates its fuel selection according to the Randle cycle, our study reports for the first time in the mouse heart the following findings. First, exogenous lactate is the major carbohydrate contributing to pyruvate formation (42.0 [+ or -] 2.3%). Second, lactate and pyruvate are constantly being taken up and released by the heart, supporting the concept of compartmentation of lactate and glucose metabolism. Finally, mitochondrial anaplerotic pyruvate carboxylation and citrate efflux represent 4.9 [+ or -] 1.8 and 0.8 [+ or -] 0.1%, respectively, of the citric acid cycle flux and are modulated by substrate supply. The described [sup.13]C-labeling strategy combined with an experimental setup that enables continuous monitoring of physiological parameters offers a unique model to clarify the link between metabolic alterations, cardiac dysfunction, and disease development. energy metabolism; citric acid cycle; [sup.13]C mass isotopomer analysis; gas chromatography-mass spectrometry: isolated working perfused heart