Christine Des Rosiers

Montreal Heart Institute, Montréal, Quebec, Canada

Are you Christine Des Rosiers?

Claim your profile

Publications (108)404.09 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Anesthetics used in infants and children are implicated in the development of neurocognitive disorders. Although propofol induces neuroapoptosis in developing brain, the underlying mechanisms require elucidation and may have an energetic basis. We studied substrate utilization in immature swine anesthetized with either propofol or isoflurane for 4 hours. Piglets were infused with 13-Carbon-labeled glucose and leucine in the common carotid artery to assess citric acid cycle (CAC) metabolism in the parietal cortex. The anesthetics produced similar systemic hemodynamics and cerebral oxygen saturation by near-infrared spectroscopy. Compared with isoflurane, propofol depleted ATP and glycogen stores. Propofol decreased pools of the CAC intermediates, citrate, and α-ketoglutarate, while markedly increasing succinate along with decreasing mitochondrial complex II activity. Propofol also inhibited acetyl-CoA entry into the CAC through pyruvate dehydrogenase, while promoting glycolytic flux with marked lactate accumulation. Although oxygen supply appeared similar between the anesthetic groups, propofol yielded a metabolic phenotype that resembled a hypoxic state. Propofol impairs substrate flux through the CAC in the immature cerebral cortex. These impairments occurred without systemic metabolic perturbations that typically accompany propofol infusion syndrome. These metabolic abnormalities may have a role in the neurotoxity observed with propofol in the vulnerable immature brain.Journal of Cerebral Blood Flow & Metabolism advance online publication, 8 January 2014; doi:10.1038/jcbfm.2013.229.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 01/2014; · 5.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Extracorporeal membrane oxygenation (ECMO) provides a bridge to recovery after myocardial injury in infants and children, yet morbidity and mortality remain high. Weaning from the circuit requires adequate cardiac contractile function, which can be impaired by metabolic disturbances induced either by ischemia-reperfusion and/or by ECMO. We tested the hypothesis that although ECMO partially ameliorates metabolic abnormalities induced by ischemia-reperfusion, these abnormalities persist or recur with weaning. We also determined if thyroid hormone supplementation (triiodothyronine) during ECMO improves oxidative metabolism and cardiac function. Neonatal piglets underwent transient coronary ischemia to induce cardiac injury then were separated into 4 groups based on loading status. Piglets without coronary ischemia served as controls. We infused into the left coronary artery [2-(13)C]pyruvate and [(13)C6, (15)N]l-leucine to evaluate oxidative metabolism by gas chromatography-mass spectroscopy and nuclear magnetic resonance methods. ECMO improved survival, increased oxidative substrate contribution through pyruvate dehydrogenase, reduced succinate and fumarate accumulation, and ameliorated ATP depletion induced by ischemia. The functional and metabolic benefit of ECMO was lost with weaning, yet triiodothyronine supplementation during ECMO restored function, increased relative pyruvate dehydrogenase flux, reduced succinate and fumarate, and preserved ATP stores. Although ECMO provides metabolic rest by decreasing energy demand, metabolic impairments persist, and are exacerbated with weaning. Treating ECMO-induced thyroid depression with triiodothyronine improves substrate flux, myocardial oxidative capacity and cardiac contractile function. This translational model suggests that metabolic targeting can improve weaning.
    Journal of the American Heart Association. 01/2014; 3(2):e000680.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background It was demonstrated that branched-chain amino acids like leucine induce insulin resistance in muscle and adipose tissues. The mechanism proposed to explain leucine action involves mTOR/p70S6K signaling. This pathway can be activated by leucine and is implicated in the stimulation of an insulin negative feedback loop. Knowing that insulin-resistance participates in diabetic cardiomyopathy, we were interested in studying leucine effect in cardiomyocytes. Methods Primary cultured adult rat cardiomyocytes were pretreated with different concentrations of leucine (from 1 to 10 mM) during different periods of time (up to 20h) before being exposed to insulin (3x10−9 M, 30 min). Results In absence of leucine, insulin induced a 6-fold increase in glucose uptake (0.31+/−0.04 vs. 0.05+/−0.01 μmoles/mg.h). This correlated with the increase in phosphorylation state of PKB and AS160, both known to regulate glucose transport downstream of insulin. Pre-incubation with leucine for 1 h stimulated mTOR/p70S6K pathway resulting in the inhibiting phosphorylation of IRS-1 located in the proximal insulin signaling pathway. This is accompanied by a significant decrease in PKB and AS160 phosphorylation but, surprisingly, insulin-stimulated glucose uptake was preserved (0.31+/–0.05 μmoles/mg.h). On the other hand, a longer incubation (14h) with leucine induced a drastic decrease in glucose transport (0.056+/–0.01 μmoles/mg.h). The mTOR/p70S6K inhibitor rapamycin did not prevent this inhibition. Moreover, the non-metabolized leucine analog BCH was able to stimulate mTOR/p70S6K pathway but had no effect on the insulin-mediated stimulation of glucose uptake. By contrast, intermediates of leucine catabolism, alpha-ketoisocaproate, acetoacetate and betahydroxybutyrate, inhibited glucose uptake similarly to leucine. Conclusion Leucine catabolism reduces insulin-dependent glucose transport independently of insulin signaling.
    Archives of Cardiovascular Diseases Supplements 01/2014; 6:13.
  • AJP Heart and Circulatory Physiology 12/2013; · 4.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim: In mice, genetic background is known to influence various parameters, including cardiac function. Its impact on cardiac energy substrate metabolism - a factor known to be closely related to function and contributes to disease development - is, however, unclear. This was examined in this study. Methods & Results: In commonly-used control mouse substrains SJL/JCrNTac, 129S6/SvEvTac, C57Bl/6J and C57Bl/6NCrl, we assessed the functional and metabolic phenotypes of 3 month old working mouse hearts perfused ex vivo with physiological concentrations of 13C labeled carbohydrates (CHO) and a fatty acid (FA). Marked variations in various functional and metabolic flux parameters were observed among all mouse substrains, although the pattern observed differed for these parameters. For example, among all strains, C57Bl/6NCrl hearts had a greater cardiac output (+1.7 fold vs SJL/JCrNTac and C57Bl/6J; P<0.05), while at the metabolic level, 129S6/SvEvTac hearts stood out by displaying (vs. all 3 strains) a striking shift from exogenous FA (~ -3.5-fold) to CHO oxidation as well as increased glycolysis (+1.7-fold) and FA incorporation into triglycerides (+2-fold). Correlation analyses revealed, however, specific linkages between glycolysis, FA oxidation and pyruvate metabolism and cardiac work, oxygen consumption with heart rate, respectively. This implies that any genetically-determined factors affecting a given metabolic flux parameter may impact on the associated functional parameters. Conclusion: Our results emphasize the importance of selecting the appropriate control strain for cardiac metabolic studies using transgenic mice, a factor that has often been neglected. Understanding the molecular mechanisms underlying the diversity of strain-specific cardiac metabolic and functional profiles, particularly the 129S6/SvEvTac, may ultimately disclose new specific metabolic targets for interventions in heart disease.
    AJP Heart and Circulatory Physiology 11/2013; · 4.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Marine n-3 polyunsaturated fatty acids alter cardiac phospholipids and prevent cardiac pathology in rodents subjected to pressure overload. This approach has not been evaluated in humans or large animals with hypertension-induced pathological hypertrophy. We evaluated docosahexaenoic acid (DHA) in old female dogs with hypertension caused by 16 weeks of aldosterone infusion. Aldosterone-induced hypertension resulted in concentric left ventricular (LV) hypertrophy and impaired diastolic function in placebo-treated dogs. DHA supplementation increased DHA and depleted arachidonic acid in cardiac phospholipids, but did not improve LV parameters compared to placebo. Surprisingly, DHA significantly increased serum aldosterone concentration and blood pressure compared to placebo. Cardiac mitochondrial yield was decreased in placebo-treated hypertensive dogs compared to normal animals, which was prevented by DHA. Extensive analysis of mitochondrial function found no differences between DHA and placebo groups. In conclusion, DHA did not favorably impact mitochondrial or LV function in aldosterone hypertensive dogs.
    Journal of Cardiovascular Translational Research 09/2013; · 3.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Supplementation with the n3 polyunsaturated fatty acid docosahexaenoic acid (DHA) is beneficial in heart failure patients, however the mechanisms are unclear. DHA is incorporated into membrane phospholipids, which may prevent mitochondrial dysfunction. Thus we assessed the effects of DHA supplementation on cardiac mitochondria and the development of heart failure caused by aortic pressure overload. Pathological cardiac hypertrophy was generated in rats by thoracic aortic constriction. Animals were fed either a standard diet or were supplemented with DHA (2.3 % of energy intake). After 14 weeks, heart failure was evident by left ventricular hypertrophy and chamber enlargement compared to shams. Left ventricle fractional shortening was unaffected by DHA treatment in sham animals (44.1 ± 1.6 % vs. 43.5 ± 2.2 % for standard diet and DHA, respectively), and decreased with heart failure in both treatment groups, but to a lesser extent in DHA treated animals (34.9 ± 1.7 %) than with the standard diet (29.7 ± 1.5 %, P < 0.03). DHA supplementation increased DHA content in mitochondrial phospholipids and decreased membrane viscosity. Myocardial mitochondrial oxidative capacity was decreased by heart failure and unaffected by DHA. DHA treatment enhanced Ca(2+) uptake by subsarcolemmal mitochondria in both sham and heart failure groups. Further, DHA lessened Ca(2+)-induced mitochondria swelling, an index of permeability transition, in heart failure animals. Heart failure increased hydrogen peroxide-induced mitochondrial permeability transition compared to sham, which was partially attenuated in interfibrillar mitochondria by treatment with DHA. DHA decreased mitochondrial membrane viscosity and accelerated Ca(2+) uptake, and attenuated susceptibility to mitochondrial permeability transition and development of left ventricular dysfunction.
    Cardiovascular Drugs and Therapy 09/2013; · 2.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Extracorporeal membrane oxygenation (ECMO) unloads the heart, providing a bridge to recovery in children after myocardial stunning. ECMO also induces stress which can adversely affect the ability to reload or wean the heart from the circuit. Metabolic impairments induced by altered loading and/or stress conditions may impact weaning. However, cardiac substrate and amino acid requirements upon weaning are unknown. We assessed the hypothesis that ventricular reloading with ECMO modulates both substrate entry into the citric acid cycle (CAC) and myocardial protein synthesis. Sixteen immature piglets (7.8 to 15.6 kg) were separated into 2 groups based on ventricular loading status: 8-hour ECMO (UNLOAD) and postwean from ECMO (RELOAD). We infused into the coronary artery [2-(13)C]-pyruvate as an oxidative substrate and [(13)C6]-L-leucine as an indicator for amino acid oxidation and protein synthesis. Upon RELOAD, each functional parameter, which were decreased substantially by ECMO, recovered to near-baseline level with the exclusion of minimum dP/dt. Accordingly, myocardial oxygen consumption was also increased, indicating that overall mitochondrial metabolism was reestablished. At the metabolic level, when compared to UNLOAD, RELOAD altered the contribution of various substrates/pathways to tissue pyruvate formation, favoring exogenous pyruvate versus glycolysis, and acetyl-CoA formation, shifting away from pyruvate decarboxylation to endogenous substrate, presumably fatty acids. Furthermore, there was also a significant increase of tissue concentrations for all CAC intermediates (≈80%), suggesting enhanced anaplerosis, and of fractional protein synthesis rates (>70%). RELOAD alters both cytosolic and mitochondrial energy substrate metabolism, while favoring leucine incorporation into protein synthesis rather than oxidation in the CAC. Improved understanding of factors governing these metabolic perturbations may serve as a basis for interventions and thereby improve success rate from weaning from ECMO.
    Journal of the American Heart Association. 01/2013; 2(4):e000106.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective Measurements of oxidative stress biomarkers in patients with heart failure (HF) have yielded controversial results. This study aimed at testing the hypothesis that circulating levels of the lipid peroxidation product 4-hydroxynonenal bound to thiol proteins (4HNE-P) are strongly associated with those of its potential precursors, namely n-6 polyunsaturated fatty acids (PUFA).Methods & ResultsCirculating levels of 4HNE-P were evaluated by gas chromatography-mass spectrometry in 71 control subjects and 61 ambulatory symptomatic HF patients along with various other clinically- and biochemically-relevant parameters, including other oxidative stress markers, and total levels of fatty acids from all classes, which reflect both free and bound to cholesterol, phospholipids and triglycerides. All HF patients had severe systolic functional impairment despite receiving optimal evidence-based therapies. Compared to controls, HF patients displayed markedly lower circulating levels of HDL- and LDL-cholesterol, which are major PUFA carriers, as well as of PUFA of the n-6 series, specifically linoleic acid (LA; P=0.001). Circulating 4HNE-P in HF patients was similar to controls, albeit multiple regression analysis revealed that LA was the only factor that was significantly associated with circulating 4HNE-P in the entire population (R2=0.086; P=0.02). In HF patients only, 4HNE-P was even more strongly associated with LA (P=0.003) and HDL-cholesterol (p<0.0002). Our results demonstrate that 4HNE-P levels, expressed relative to HDL-cholesterol, increase as HDL-cholesterol plasma levels decrease in the HF group only.Conclusion Results from this study emphasize the importance of considering changes in lipids and lipoproteins in the interpretation of measurements of lipid peroxidation products. Further studies appear warranted to explore the possibility that HDL-cholesterol particles may be a carrier of 4HNE adducts.
    Redox Biology. 01/2013;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Endothelial dysfunction is a turning point in the initiation and development of atherosclerosis and its complications and is predictive of future cardiovascular events. Ingestion of high-carbohydrate or high-fat meals often results in postprandial hyperglycaemia and/or hypertriacylglycerolaemia that may lead to a transient impairment in endothelial function. The present review will discuss human studies evaluating the impact of high-carbohydrate and high-fat challenges on postprandial endothelial function as well as the potential role of oxidative stress in such postprandial metabolic alterations. Moreover, the present review will differentiate the postprandial endothelial and oxidative impact of meals rich in varying fatty acid types.
    Nutrition Research Reviews 12/2012; 25(2):288-301. · 5.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Extracorporeal membrane oxygenation (ECMO) provides mechanical circulatory support essential for survival in infants and children with acute cardiac decompensation. However, ECMO also causes metabolic disturbances, which contribute to total body wasting and protein loss. Cardiac stunning can also occur which prevents ECMO weaning, and contributes to high mortality. The heart may specifically undergo metabolic impairments, which influence functional recovery. We tested the hypothesis that ECMO alters oxidative . Wefocused on the amino acid leucine, and integration with myocardial protein synthesis. We used a translational immature swine model in which we assessed in heart (i) the fractional contribution of leucine (FcLeucine) and pyruvate (FCpyruvate) to mitochondrial acetyl-CoA formation by nuclear magnetic resonance and (ii) global protein fractional synthesis (FSR) by gas chromatography-mass spectrometry. Immature mixed breed Yorkshire male piglets (n = 22) were divided into four groups based on loading status (8 hours of normal circulation or ECMO) and intracoronary infusion [(13)C(6),(15)N]-L-leucine (3.7 mM) alone or with [2-(13)C]-pyruvate (7.4 mM). ECMO decreased pulse pressure and correspondingly lowered myocardial oxygen consumption (~ 40%, n = 5), indicating decreased overall mitochondrial oxidative metabolism. However, FcLeucine was maintained and myocardial protein FSR was marginally increased. Pyruvate addition decreased tissue leucine enrichment, FcLeucine, and Fc for endogenous substrates as well as protein FSR. Conclusion: The heart under ECMO shows reduced oxidative metabolism of substrates, including amino acids, while maintaining (i) metabolic flexibility indicated by ability to respond to pyruvate, and (ii) a normal or increased capacity for global protein synthesis.
    AJP Heart and Circulatory Physiology 11/2012; · 4.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: RATIONALE AND GOAL: Glutamine, the most abundant amino acid in plasma, has attracted considerable interest for its cardioprotective properties. The primary effect of glutamine in the heart is commonly believed to be mediated via its anaplerotic metabolism to citric acid cycle (CAC) intermediates; however, there is little direct evidence to support this concept. Another potential candidate is the hexosamine biosynthetic pathway (HBP), which has recently been shown to modulate cardiomyocyte function and metabolism. Therefore, the goal of this study was to evaluate the contribution of anaplerosis and the HBP to the acute metabolic effects of glutamine in the heart. METHODS: Normoxic ex vivo working rat hearts were perfused with (13)C-labeled substrates to assess relevant metabolic fluxes perfused with a physiological mixture of carbohydrates and a fatty acid (control) or under conditions of restricted pyruvate anaplerosis RESULTS: Addition of a physiological concentration of glutamine (0.5 mM) had no effect on contractile function of hearts perfused under the control condition, but improved that of hearts perfused under restricted pyruvate anaplerosis. Changes in CAC intermediate concentrations as well as (13)C-enrichment from [U-(13)C]glutamine did not support a major role of glutamine anaplerosis under any conditions. Under the control condition, however, glutamine significantly increased the contribution of exogenous oleate to β-oxidation, 1.6-fold, and triglyceride formation, 2.8-fold. Glutamine had no effect on malonyl-CoA or AMPK kinase activity levels; however, it resulted in a higher plasma membrane level of the fatty acid transporter CD36. These metabolic effects of glutamine were reversed by azaserine, which inhibits glucose entry into the HPB CONCLUSION: Our results reveal a metabolic role of physiological concentration of glutamine in the healthy working heart beyond anaplerosis. This role appears to involve the HBP and regulation of fatty acid entry and metabolism via CD36.
    Journal of Molecular and Cellular Cardiology 11/2012; · 5.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial dysfunction in heart failure includes greater susceptibility to mitochondrial permeability transition, which may worsen cardiac function and decrease survival. Treatment with a mixture of the n3 polyunsaturated fatty acids (n3 PUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is beneficial in heart failure patients, and increases resistance to mitochondrial permeability transition in animal models. We assessed if DHA and EPA have similar effects when given individually, and if they prolong survival in heart failure. Male δ-sarcoglycan null cardiomyopathic hamsters were untreated or given either DHA, EPA or a 1:1 mixture of DHA+EPA at 2.1% of energy intake. Treatment did not prolong survival: mean survival was 298±15 days in untreated hamsters, and was 335±17, 328±14 and 311±15 days with DHA, EPA and DHA+EPA, respectively (n=27-32/group). A subgroup of cardiomyopathic hamsters treated for 26 weeks had impaired LV function and increased cardiomyocyte apoptosis compared to normal hamsters, which was unaffected by n3 PUFA treatment. Evaluation of oxidative phosphorylation in isolated subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria with substrates for complex I or II showed no effect of n3 PUFA treatment. On the other hand, IFM from cardiomyopathic hamsters were significantly more sensitive to Ca(2+)-induced mitochondrial permeability transition, which was completely normalized by treatment with DHA, and partial corrected by EPA. In conclusion, treatment with DHA or EPA normalizes Ca(2+)-induced MPT in cardiomyopathic hamsters, but does not prolong survival or improve cardiac function.
    AJP Heart and Circulatory Physiology 10/2012; · 4.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: RATIONALE: Mechanical ventilation (MV) is associated with adverse effects on the diaphragm, but the cellular basis for this phenomenon, referred to as ventilator-induced diaphragmatic dysfunction (VIDD), is poorly understood. OBJECTIVES: To determine whether mitochondrial function and cellular energy status are disrupted in human diaphragms after MV, as well as the role of mitochondria-derived oxidative stress in the development of VIDD. METHODS: Diaphragm and biceps specimens obtained from brain-dead organ donors who underwent MV (15-176 hours) and age-matched controls were compared regarding mitochondrial enzymatic function, mitochondrial DNA integrity, lipid content, and metabolic gene/protein expression. In addition, diaphragmatic force and oxidative stress after exposure to MV for 6 hours were evaluated in mice under different conditions. MAIN RESULTS: In human MV diaphragms, mitochondrial biogenesis and content were downregulated, with a more specific defect of respiratory chain cytochrome c oxidase (COX). Laser capture microdissection of COX-deficient fibers revealed mitochondrial DNA deletions, consistent with damage from oxidative stress. Diaphragmatic lipid accumulation and responses of master cellular metabolic sensors (AMP-activated protein kinase and sirtuins), were consistent with energy substrate excess as a possible stimulus for the above changes. In mice, induction of hyperlipidemia worsened diaphragmatic oxidative stress during MV, whereas transgenic overexpression of a mitochondria-localized antioxidant (peroxiredoxin-3), was protective against VIDD. CONCLUSIONS: Our data suggest that mitochondrial dysfunction lies at the nexus between oxidative stress and the impaired diaphragmatic contractility which develops during MV. Energy substrate oversupply relative to demand, resulting from diaphragmatic inactivity during MV, could play an important role in this process.
    American Journal of Respiratory and Critical Care Medicine 09/2012; · 11.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondria can depolarize and trigger cell death through the opening of the mitochondrial permeability transition pore (MPTP). We recently showed that an increase in the long chain n3 polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA; 22:6n3) and depletion of the n6 PUFA arachidonic acid (ARA; 20:4n6) in mitochondrial membranes is associated with a greater Ca(2+) load required to induce MPTP opening. Here we manipulated mitochondrial phospholipid composition by supplementing the diet with DHA, ARA or combined DHA+ARA in rats for 10 weeks. There were no effects on cardiac function, or respiration of isolated mitochondria. Analysis of mitochondrial phospholipids showed DHA supplementation increased DHA and displaced ARA in mitochondrial membranes, while supplementation with ARA or DHA+ARA increased ARA and depleted linoleic acid (18:2n6). Phospholipid analysis revealed a similar pattern, particularly in cardiolipin. Tetralinoleoyl cardiolipin was depleted by 80% with ARA or DHA+ARA supplementation, with linoleic acid side chains replaced by ARA. Both the DHA and ARA groups had delayed Ca(2+)-induced MPTP opening, but the DHA+ARA group was similar to the control diet. In conclusion, alterations in mitochondria membrane phospholipid fatty acid composition caused by dietary DHA or ARA was associated with a greater cumulative Ca(2+) load required to induced MPTP opening. Further, high levels of tetralinoleoyl cardiolipin were not essential for normal mitochondrial function if replaced with very-long chain n3 or n6 PUFAs.
    PLoS ONE 01/2012; 7(3):e34402. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Triiodothyronine (T3) supplementation improves clinical outcomes in infants after cardiac surgery using cardiopulmonary bypass by unknown mechanisms. We utilized a translational model of infant cardiopulmonary bypass to test the hypothesis that T3 modulates pyruvate entry into the citric acid cycle (CAC), thereby providing the energy support for improved cardiac function after ischemia-reperfusion (I/R). Neonatal piglets received intracoronary [2-(13)Carbon((13)C)]pyruvate for 40 min (8 mM) during control aerobic conditions (control) or immediately after reperfusion (I/R) from global hypothermic ischemia. A third group (I/R-Tr) received T3 (1.2 μg/kg) during reperfusion. We assessed absolute CAC intermediate levels and flux parameters into the CAC through oxidative pyruvate decarboxylation (PDC) and anaplerotic carboxylation (PC) using [2-(13)C]pyruvate and isotopomer analysis by gas and liquid chromatography-mass spectrometry and (13)C-nuclear magnetic resonance spectroscopy. When compared with I/R, T3 (group I/R-Tr) increased cardiac power and oxygen consumption after I/R while elevating flux of both PDC and PC (∼4-fold). Although neither I/R nor I/R-Tr modified absolute CAC levels, T3 inhibited I/R-induced reductions in their molar percent enrichment. Furthermore, (13)C-labeling of CAC intermediates suggests that T3 may decrease entry of unlabeled carbons at the level of oxaloacetate through anaplerosis or exchange reaction with asparate. T3 markedly enhances PC and PDC fluxes, thereby providing potential substrate for elevated cardiac function after reperfusion. This T3-induced increase in pyruvate fluxes occurs with preservation of the CAC intermediate pool. Our labeling data raise the possibility that T3 reduces reliance on amino acids for anaplerosis after reperfusion.
    AJP Heart and Circulatory Physiology 12/2011; 302(5):H1086-93. · 4.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The impact of a high-fat diet on the failing heart is unclear, and the differences between polyunsaturated fatty acids (PUFA) and saturated fat have not been assessed. Here, we compared a standard low-fat diet to high-fat diets enriched with either saturated fat (palmitate and stearate) or PUFA (linoleic and α-linolenic acids) in hamsters with genetic cardiomyopathy. Male δ-sarcoglycan null Bio TO2 hamsters were fed a standard low-fat diet (12% energy from fat), or high-fat diets (45% fat) comprised of either saturated fat or PUFA. The median survival was increased by the high saturated fat diet (P< 0.01; 278 days with standard diet and 361 days with high saturated fat)), but not with high PUFA (260 days) (n = 30-35/group). Body mass was modestly elevated (∼10%) in both high fat groups. Subgroups evaluated after 24 weeks had similar left ventricular chamber size, function, and mass. Mitochondrial oxidative enzyme activity and the yield of interfibrillar mitochondria (IFM) were decreased to a similar extent in all TO2 groups compared with normal F1B hamsters. Ca(2+)-induced mitochondrial permeability transition pore opening was enhanced in IFM in all TO2 groups compared with F1B hamsters, but to a significantly greater extent in those fed the high PUFA diet compared with the standard or high saturated fat diet. These results show that a high intake of saturated fat improves survival in heart failure compared with a high PUFA diet or low-fat diet, despite persistent mitochondrial defects.
    Cardiovascular research 09/2011; 93(1):24-32. · 5.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The molecular mechanisms underlying doxorubicin (DOX)-induced cardiomyopathy include alterations in cardiomyocytes' oxidative stress status and in gene expression. Although such alterations have been reported during in vivo DOX treatment of animals, it remains to be clarified whether they persist after treatment cessation. To address this question, rats were injected with either saline (1 ml/kg/day i.p; control) or DOX (1 mg/kg/day i.p.) for 10 days, and 70 days later cardiac functional parameters were evaluated in vivo by left ventricular catheterization. Hearts were also harvested for histological analyses as well as measurements of oxidative stress parameters by various techniques and gene expression by quantitative polymerase chain reaction of markers of cardiac pathological remodeling, namely atrial natriuretic factor, myosin heavy chain β, vascular endothelial growth factor A (VEGF-A), and sarcoplasmic reticulum Ca(+2) ATPase. Compared with controls, DOX-treated rats displayed marked alterations in most parameters even 2 months after cessation of treatment. These included 1) lower left ventricular contractility (+dP/dt), 2) increased levels of plasma and myocardial oxidative stress markers, namely thiobarbituric acid reactive substances or dihydroethidium fluorescence, and 3) markedly altered transcript levels for all measured markers of cardiac remodeling, except VEGF-A. These changes correlated significantly with +dP/dt values assessed in the two groups of animals. In conclusion, this study demonstrated that as many as 2 months after cessation of DOX treatment cardiac alterations persisted, reflecting increased oxidative stress and pathological remodeling, the latter being linked to the development of contractile dysfunction.
    Journal of Pharmacology and Experimental Therapeutics 09/2011; 339(3):807-14. · 3.89 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The cardiac cycle imposes a mechanical stress that dilates elastic carotid arteries, while shear stress largely contributes to the endothelium-dependent dilation of downstream cerebral arteries. In the presence of dyslipidemia, carotid arteries stiffen while the endothelial function declines. We reasoned that stiffening of carotid arteries would be prevented by reducing resting heart rate (HR), while improving the endothelial function would regulate cerebral artery compliance and function. Thus we treated or not 3-mo-old male atherosclerotic mice (ATX; LDLr(-/-):hApoB(+/+)) for 3 mo with the sinoatrial pacemaker current inhibitor ivabradine (IVA), the β-blocker metoprolol (METO), or subjected mice to voluntary physical training (PT). Arterial (carotid and cerebral artery) compliance and endothelium-dependent flow-mediated cerebral dilation were measured in isolated pressurized arteries. IVA and METO similarly reduced (P < 0.05) 24-h HR by ≈15%, while PT had no impact. As expected, carotid artery stiffness increased (P < 0.05) in ATX mice compared with wild-type mice, while cerebral artery stiffness decreased (P < 0.05); this paradoxical increase in cerebrovascular compliance was associated with endothelial dysfunction and an augmented metalloproteinase-9 (MMP-9) activity (P < 0.05), without changing the lipid composition of the wall. Reducing HR (IVA and METO) limited carotid artery stiffening, but plaque progression was prevented by IVA only. In contrast, IVA maintained and PT improved cerebral endothelial nitric oxide synthase-dependent flow-mediated dilation and wall compliance, and both interventions reduced MMP-9 activity (P < 0.05); METO worsened endothelial dysfunction and compliance and did not reduce MMP-9 activity. In conclusion, HR-dependent mechanical stress contributes to carotid artery wall stiffening in severely dyslipidemic mice while cerebrovascular compliance is mostly regulated by the endothelium.
    AJP Heart and Circulatory Physiology 09/2011; 301(5):H2081-92. · 4.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Exposure to high glucose (HG) stimulates reactive oxygen species (ROS) production by NADPH oxidase in cardiomyocytes, but the underlying mechanism remains elusive. In this study, we have dissected the link between glucose transport and metabolism and NADPH oxidase activation under hyperglycaemic conditions. Primary cultures of adult rat cardiomyocytes were exposed to HG concentration (HG, 21 mM) and compared with the normal glucose level (LG, 5 mM). HG exposure activated Rac1GTP and induced p47phox translocation to the plasma membrane, resulting in NADPH oxidase (NOX2) activation, increased ROS production, insulin resistance, and eventually cell death. Comparison of the level of O-linked N-acetylglucosamine (O-GlcNAc) residues in LG- and HG-treated cells did not reveal any significant difference. Inhibition of the pentose phosphate pathway (PPP) by 6-aminonicotinamide counteracted ROS production in response to HG but did not prevent Rac-1 upregulation and p47phox translocation leading to NOX2 activation. Modulation of glucose uptake barely affected oxidative stress and toxicity induced by HG. More interestingly, non-metabolizable glucose analogues (i.e. 3-O-methyl-D-glucopyranoside and α-methyl-D-glucopyranoside) reproduced the toxic effect of HG. Inhibition of the sodium/glucose cotransporter SGLT1 by phlorizin counteracted HG-induced NOX2 activation and ROS production. Increased glucose metabolism by itself does not trigger NADPH oxidase activation, although PPP is required to provide NOX2 with NADPH and to produce ROS. NOX2 activation results from glucose transport through SGLT1, suggesting that an extracellular metabolic signal transduces into an intracellular ionic signal.
    Cardiovascular research 08/2011; 92(2):237-46. · 5.81 Impact Factor

Publication Stats

2k Citations
404.09 Total Impact Points

Institutions

  • 2007–2014
    • Montreal Heart Institute
      Montréal, Quebec, Canada
  • 2013
    • University of Alberta
      Edmonton, Alberta, Canada
    • University of Sydney
      • Discipline of Physiology
      Sydney, New South Wales, Australia
    • Seattle Children’s Research Institute
      Seattle, Washington, United States
  • 2009–2013
    • University of Maryland, Baltimore
      • Division of Cardiology
      Baltimore, MD, United States
    • University of Cambridge
      • Department of Biochemistry
      Cambridge, ENG, United Kingdom
  • 2012
    • Loyola University Maryland
      Baltimore, Maryland, United States
  • 2011
    • University of Washington Seattle
      • Division of Cardiology
      Seattle, WA, United States
  • 2003–2011
    • University of Alabama at Birmingham
      • Department of Medicine
      Birmingham, Alabama, United States
  • 1988–2011
    • Université de Montréal
      • • Department of Nutrition
      • • Department of Kinesiology
      • • Department of Biochemistry
      Montréal, Quebec, Canada
  • 1995–2009
    • Case Western Reserve University
      • • Department of Nutrition
      • • Department of Biochemistry
      • • Department of Biomedical Engineering
      Cleveland, OH, United States
  • 2008
    • University of Tours
      Tours, Centre, France
  • 2004
    • McGill University
      • Division of Experimental Medicine
      Montréal, Quebec, Canada
  • 1992–2003
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
  • 1987
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States