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CNRS Research Associate (CR1)
tel : +33 4 91 32 48 08
Key Words
- Heart
- Endothelial dysfunction
- Ischaemia-reperfusion injury
- Nitric oxide (NO)
- Long-term heart preservation
- Type 2 diabetic heart, Heart failure.

Current Research Interest and projects

My work concerns cardiovascular diseases associated with vascular endothelial dysfunction. The endothelium is an important regulator of coronary vascular tone due to its ability to release potent vasoactive substances such as the vasodilators nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), prostacyclin (PGI2) and the potent vasoconstrictor endothelin. Endothelial dysfunction has been associated with a number of cardiovascular diseases such as atherosclerosis, hypertension, diabetes mellitus, congestive heart failure and graft vasculopathy. A disturbance of endothelial function may also contribute to the adverse effects that ischaemia and reperfusion exerts on the coronary vasculature. Endothelial dysfunction is mainly caracterized by an impaired endothelium-dependent vasodilator responses to some agonists (ACh, ADP, …) and by a reduced release of nitric oxide (NO). My current research interests is to study endothelial dysfunction involved in ischemia related to cardiac transplantation, in type 2 diabetic heart and heart failure. Pathological heart is assessed by a metabolic study using P-31 magnetic resonance spectroscopy combined to a functional evaluation and a measure of cellular integrity (biochemical assays, High Performance Liquid Chromatography (HPLC) and Western Blotting in cardiac tissues and effluents). In addition, magnetic resonance methods (spectrometry (MRS) and imaging (MRI)) combined to biochemical and molecular biology assays furnish morphological, physiological, functional and metabolic informations to characterize the pathological heart. Studies initially performed on the isolated perfused rat heart are extent to the in situ heart in animal and then, to the pathological human heart.


- Université Paris-Diderot, CNRS EAC 4413, Laboratoire de Biologie et Pathologie du Pancréas Endocrine (B2PE), Unité BFA, Pr B. Portha.
- Université d’Avignon et des Pays de Vaucluse, Laboratoire Physiologie des adaptations cardiovasculaires à l’exercice, Dr C. Reboul.
- University Laboratory of Physiology, Cardiac Metabolism Research Group, Oxford (UK) : Pr. K. Clarke, Programme d’Actions Intégrées « Alliance ».



Journal Article

  • Macia, M, Pecchi, E, Desrois, M, Lan, C, Vilmen, C, Portha, B, Bernard, M, Bendahan, D & Giannesini, B 2018, “Exercise training impacts exercise tolerance and bioenergetics in gastrocnemius muscle of non-obese type-2 diabetic Goto-Kakizaki rat in vivo”, Biochimie.
    Résumé : The functional and bioenergetics impact of regular physical activity upon type-2 diabetic skeletal muscle independently of confounding factors of overweight remains undocumented. Here, gastrocnemius muscle energy fluxes, mitochondrial capacity and mechanical performance were assessed noninvasively and longitudinally in non-obese diabetic Goto-Kakizaki rats using magnetic resonance (MR) imaging and dynamic 31-phosphorus MR spectroscopy (31P-MRS) throughout a 6-min fatiguing bout of exercise performed before, in the middle (4-week) and at the end of an 8-week training protocol consisting in 60-min daily run on a treadmill. The training protocol reduced plasmatic insulin level (-61%) whereas blood glucose and non-esterified fatty acids levels remained unaffected, thereby indicating an improvement of insulin sensitivity. It also increased muscle mitochondrial citrate synthase activity (+45%) but this increase did not enhance oxidative ATP synthesis capacity in working muscle in vivo while glycolytic ATP production was increased (+33%). On the other hand, the training protocol impaired maximal force-generating capacity (-9%), total amount of force produced (-12%) and increased ATP cost of contraction (+32%) during the fatiguing exercise. Importantly, these deleterious effects were transiently worsened in the middle of the 8-week period, in association with reduced oxidative capacity and increased basal [Pi]/[PCr] ratio (an in vivo biomarker of muscle damage). These data demonstrate that the beneficial effect of regular training on insulin sensitivity in non-obese diabetic rat occurs separately from any improvement in muscle mitochondrial function and might be linked to an increased capacity for metabolizing glucose through anaerobic process in exercising muscle.
    Mots-clés : crmbm, cvs, Diabetes, Mitochondrial capacity, msk, Nuclear magnetic resonance, Regular physical activity, Skeletal muscle function.


Journal Article

  • Desrois, M, Lan, C, Movassat, J & Bernard, M 2017, “Reduced up-regulation of the nitric oxide pathway and impaired endothelial and smooth muscle functions in the female type 2 diabetic goto-kakizaki rat heart”, Nutrition & Metabolism, vol. 14, p. 6.
    Résumé : BACKGROUND: Type 2 diabetes is associated with greater relative risk of cardiovascular diseases in women than in men, which is not well understood. Consequently, we have investigated if male and female displayed differences in cardiac function, energy metabolism, and endothelial function which could contribute to increased cardiovascular complications in type 2 diabetic female. METHODS: Male and female Control and type 2 diabetic Goto-Kakizaki (GK) isolated rat hearts were perfused during 28 min with a physiological buffer before freeze-clamping for biochemical assays. High energy phosphate compounds and intracellular pH were followed using (31)P magnetic resonance spectroscopy with simultaneous measurement of contractile function. Nitric oxide (NO) pathway and endothelium-dependent and independent vasodilatations were measured as indexes of endothelial function. Results were analyzed via two-way ANOVA, p < 0.05 was considered as statistically significant. RESULTS: Myocardial function was impaired in male and female diabetic versus Control groups (p < 0.05) without modification of energy metabolism. Coronary flow was decreased in both diabetic versus Control groups but to a higher extent in female GK versus male GK rat hearts (p < 0.05). NO production was up-regulated in diabetic groups but to a less extent in female GK rat hearts (p < 0.05). Endothelium-dependent and independent vasodilatations were impaired in female GK rat compared with male GK (p < 0.05) and female Control (p < 0.05) rat hearts. CONCLUSIONS: We reported here an endothelial damage characterized by a reduced up-regulation of the NO pathway and impaired endothelial and smooth muscle functions, and coronary flow rates in the female GK rat hearts while energy metabolism was normal. Whether these results are related to the higher risk of cardiovascular complications among type 2 diabetic female needs to be further elicited in the future.
    Mots-clés : Cardiac function, crmbm, cvs, Endothelial function, Energy Metabolism, Gender differences, Type 2 diabetic heart.


Journal Article

  • Macia, M, Pecchi, E, Vilmen, C, Desrois, M, Lan, C, Portha, B, Bernard, M, Bendahan, D & Giannesini, B 2015, “Insulin Resistance Is Not Associated with an Impaired Mitochondrial Function in Contracting Gastrocnemius Muscle of Goto-Kakizaki Diabetic Rats In Vivo”, PloS One, vol. 10, no. 6, p. e0129579.
    Résumé : Insulin resistance, altered lipid metabolism and mitochondrial dysfunction in skeletal muscle would play a major role in type 2 diabetes mellitus (T2DM) development, but the causal relationships between these events remain conflicting. To clarify this issue, gastrocnemius muscle function and energetics were investigated throughout a multidisciplinary approach combining in vivo and in vitro measurements in Goto-Kakizaki (GK) rats, a non-obese T2DM model developing peripheral insulin resistant without abnormal level of plasma non-esterified fatty acids (NEFA). Wistar rats were used as controls. Mechanical performance and energy metabolism were assessed strictly non-invasively using magnetic resonance (MR) imaging and 31-phosphorus MR spectroscopy (31P-MRS). Compared with control group, plasma insulin and glucose were respectively lower and higher in GK rats, but plasma NEFA level was normal. In resting GK muscle, phosphocreatine content was reduced whereas glucose content and intracellular pH were both higher. However, there were not differences between both groups for basal oxidative ATP synthesis rate, citrate synthase activity, and intramyocellular contents for lipids, glycogen, ATP and ADP (an important in vivo mitochondrial regulator). During a standardized fatiguing protocol (6 min of maximal repeated isometric contractions electrically induced at a frequency of 1.7 Hz), mechanical performance and glycolytic ATP production rate were reduced in diabetic animals whereas oxidative ATP production rate, maximal mitochondrial capacity and ATP cost of contraction were not changed. These findings provide in vivo evidence that insulin resistance is not caused by an impairment of mitochondrial function in this diabetic model.
    Mots-clés : crmbm, cvs, msk.


Journal Article

  • Desrois, M, Piccardo, A, Zogheib, E, Dalmasso, C, Lan, C, Fourré, D, Cozzone, PJ, Caus, T & Bernard, M 2014, “Heart donation after cardiac death: preliminary study on an isolated, perfused Swine heart after 20 minutes of normothermic ischemia”, Transplantation Proceedings, vol. 46, no. 10, p. 3314-3318.
    Résumé : BACKGROUND: We measured the functional and metabolic status of hearts submitted to normothermic ischemia before preservation through the use of an ex vivo pig heart model to assess the feasibility of donation after cardiac death (DCD) in heart transplantation. METHODS: Ten pigs were separated into 2 groups: control (n = 6, brain-dead group) and DCD (n = 4, heart donation after cardiac death). In the control group, hearts were excised 20 minutes after the brachiocephalic trunk cross-clamping and were immediately reperfused. In DCD, hearts were excised 20 minutes after exsanguination and asphyxia, stored in the Centre de Résonance Magnétique Biologique et Médicale (CRMBM) solution for 2 hours, and then were reperfused. Cardioplegic arrest was induced with the use of 1 L of CRMBM solution (4°C) and the heart was reperfused for 60 minutes through the use of an ex vivo perfusion system in Langendorff mode with normothermic autologous blood. During reperfusion, functional parameters were analyzed. Biochemical assays were performed in myocardial effluents and freeze-clamped hearts. RESULTS: No electromechanical activity was found in DCD compared with control. Creatine kinase (CK) was higher at 2 minutes of reperfusion in DCD versus control (P = .005). Adenosine triphosphate was lower in DCD versus control (P = .0019). Malondialdehyde, an oxidative stress index, was present only in DCD. The nitric oxide (NO) pathway was impaired in DCD versus control, with lower eNOS expression (P < .0001) and total nitrate concentration content (P = .04). CONCLUSIONS: We reported no cardiac functional and metabolic recovery in the DCD group after normothermic ischemia and reperfusion, which indicates that a single immersion of the cardiac graft during storage does not provide an optimal protection. New strategies in heart preservation are necessary for recruiting heart donation after cardiac death.
    Mots-clés : crmbm.

  • Desrois, M, Kober, F, Lan, C, Dalmasso, C, Cole, M, Clarke, K, Cozzone, PJ & Bernard, M 2014, “Effect of isoproterenol on myocardial perfusion, function, energy metabolism and nitric oxide pathway in the rat heart – a longitudinal MR study”, NMR in Biomedicine, vol. 27, no. 5, p. 529-538, viewed 20February,2014, .
    Résumé : The chronic administration of the β-adrenoreceptor agonist isoproterenol (IsoP) is used in animals to study the mechanisms of cardiac hypertrophy and failure associated with a sustained increase in circulating catecholamines. Time-dependent changes in myocardial blood flow (MBF), morphological and functional parameters were assessed in rats in vivo using multimodal cardiac MRI. Energy metabolism, oxidative stress and the nitric oxide (NO) pathway were evaluated in isolated perfused rat hearts following 7 days of treatment. Male Wistar rats were infused for 7 days with IsoP or vehicle using osmotic pumps. Cine-MRI and arterial spin labeling were used to determine left ventricular morphology, function and MBF at days 1, 2 and 7 after pump implantation. Isolated hearts were then perfused, and high-energy phosphate compounds and intracellular pH were followed using 31P MRS with simultaneous measurement of contractile function. Total creatine and malondialdehyde (MDA) contents were measured by high-performance liquid chromatography. The NO pathway was evaluated by NO synthase isoform expression and total nitrate concentration (NOx). In IsoP-treated rats, left ventricular mass was increased at day 1 and maintained. Wall thickness was increased with a peak at day 2 and a tendency to return to baseline values at day 7. MBF was markedly increased at day 1 and returned to normal values between days 1 and 2. The rate–pressure product and phosphocreatine/adenosine triphosphate ratio in perfused hearts were reduced. MDA, endothelial NO synthase expression and NOx were increased. Sustained high cardiac function and normal MBF after 24 h of IsoP infusion indicate imbalance between functional demand and blood flow, leading to morphological changes. After 1 week, cardiac hypertrophy and decreased function were associated with impaired phosphocreatine, increased oxidative stress and up-regulation of the NO pathway. These results provide supplemental information on the evolution of the different contributing factors leading to morphological and functional changes in this model of cardiac hypertrophy and failure. Copyright © 2014 John Wiley & Sons, Ltd.
    Mots-clés : cine-MRI, crmbm, Function, Heart, isoproterenol, Metabolism, nitric oxide pathway, Perfusion, rat.


Journal Article

  • Desrois, M, Clarke, K, Lan, C, Dalmasso, C, Cole, M, Portha, B, Cozzone, PJ & Bernard, M 2010, “Upregulation of eNOS and unchanged energy metabolism in increased susceptibility of the aging type 2 diabetic GK rat heart to ischemic injury”, American Journal of Physiology - Heart and Circulatory Physiology, vol. 299, no. 5, p. H1679-H1686, viewed 21November,2013, .
    Résumé : We investigated the tolerance of the insulin-resistant diabetic heart to ischemic injury in the male Goto-Kakizaki (GK) rat, a model of type 2 diabetes. Changes in energy metabolism, nitric oxide (NO) pathway, and cardiac function were assessed in the presence of physiological substrates. Age-matched control Wistar (n = 19) and GK (n = 18) isolated rat hearts were perfused with 0.4 mM palmitate, 3% albumin, 11 mM glucose, 3 U/l insulin, 0.2 mM pyruvate, and 0.8 mM lactate for 24 min before switching to 1.2 mM palmitate (11 rats/group) during 32 min low-flow (0.5 ml·min−1·g wet wt−1) ischemia. Next, flow was restored with 0.4 mM palmitate buffer for 32 min. A subset of hearts from each group (n = 8 for control and n = 7 for GK groups) were freeze-clamped for determining baseline values after the initial perfusion of 24 min. ATP, phosphocreatine (PCr), and intracellular pH (pHi) were followed using 31P magnetic resonance spectroscopy with simultaneous measurement of contractile function. The NO pathway was determined by nitric oxide synthase (NOS) isoform expression and total nitrate concentration (NOx) in hearts. We found that coronary flow was 26% lower (P < 0.05) during baseline conditions and 61% lower (P < 0.05) during reperfusion in GK vs. control rat hearts. Rate pressure product was lower during reperfusion in GK vs. control rat hearts (P < 0.05). ATP, PCr, and pHi during ischemia-reperfusion were similar in both groups. Endothelial NOS expression was increased in GK rat hearts during baseline conditions (P < 0.05). NOx was increased during baseline conditions (P < 0.05) and after reperfusion (P < 0.05) in GK rat hearts. We report increased susceptibility of type 2 diabetic GK rat heart to ischemic injury that is not associated with impaired energy metabolism. Reduced coronary flow, upregulation of eNOS expression, and increased total NOx levels confirm NO pathway modifications in this model, presumably related to increased oxidative stress. Modifications in the NO pathway may play a major role in ischemia-reperfusion injury of the type 2 diabetic GK rat heart.
    Mots-clés : aging, Animals, Coronary Vessels, crmbm, Diabetes Mellitus, Type 2, Disease Models, Animal, Energy Metabolism, Heart, Male, Myocardial Reperfusion Injury, Nitric Oxide, Nitric Oxide Synthase Type III, Rats, Rats, Mutant Strains, Rats, Wistar, Regional Blood Flow, Up-Regulation.


Journal Article
  • Desrois, M, Caus, T, Dalmasso, C, Lan, C, Cozzone, PJ & Bernard, M 2009, “Expression of the three nitric oxide synthase isoforms and nitric oxide level in the rat heart during cold storage and blood reperfusion”, Cellular and molecular biology (Noisy-le-Grand, France), vol. 55 Suppl, p. OL1208-1214.
    Résumé : Maintenance of nitric oxide (NO) homeostasis is an important concept for myocardial protection. Here, we have investigated the NO pathway by analysing total nitrate concentration (NOx) and NO synthase (NOS) isoforms expression as well as the myocardial integrity by lactate dehydrogenase and creatine kinase contents in the rat heart graft arrested by CRMBM solution, submitted to 3 hr cold ischemia in the same solution and 24 hr blood reperfusion following heterotopic abdominal heart transplantation. NOx level was similar to baseline value after ischemia and significantly increased after 24 hr reperfusion. NOS isoforms expression was highly modulated after cold ischemia followed by blood reperfusion. Endothelial NOS expression was decreased after ischemia but restored after 24 hr reperfusion. Neuronal NOS expression was drastically decreased after ischemia and 24 hr reperfusion. Inducible NOS protein was present only after 24 hr reperfusion. Cold ischemia induced a severe loss of creatine kinase without any modification after blood reperfusion. In conclusion, we show here that CRMBM solution did not increase NO production during ischemia but induced an enhanced synthesis of NO during reperfusion which may be related to restoration of endothelial NOS expression and/or induction of inducible NOS expression.
    Mots-clés : Cold Temperature, Gene Expression Regulation, Enzymologic, Heart, Heart Transplantation, Isoenzymes, Myocardial Ischemia, Myocardial Reperfusion, Nitric Oxide, Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Rats, Rats, Inbred Lew, Tissue and Organ Harvesting.


Journal Article

  • Desrois, M, Caus, T, Belles, PM, Dalmasso, C, Lan, C, Cozzone, PJ & Bernard, M 2008, “Limitation of myocardial and endothelial injury of the rat heart graft after preservation with Centre de Résonance Magnétique Biologique et Médicale (CRMB) solution”, Transplant international: official journal of the European Society for Organ Transplantation, vol. 21, no. 3, p. 276-283.
    Résumé : Myocardial injury caused by prolonged storage compromises post-transplantation contractile performance and induces endothelial injury. The aim of this study was to compare a solution developed in our laboratory [Centre de Résonance Magnétique Biologique et Médicale (CRMBM) solution] with a widely used solution (Celsior, Genzyme, Saint Germain en Laye, France). Metabolic and contractile parameters as well as indexes of endothelial injury were measured in a heterotopic rat heart transplantation model with a 3-h ischaemia and a 1-h reperfusion. The two solutions were randomly used for cardioplegia and graft preservation in six experiments each. During reperfusion, developed pressure and rate pressure product were higher with CRMBM compared with Celsior (P = 0.0002 and P = 0.0135, respectively). Phosphocreatine and adenosine triphosphate (ATP) concentrations after reperfusion were significantly higher with CRMBM (P = 0.0069 and P = 0.0053, respectively). Endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) protein expression were decreased to the same extent after reperfusion compared with baseline with CRMBM (P = 0.0001 and P < 0.0001, respectively) and Celsior (P = 0.0007 and P < 0.0001, respectively). Total nitrate concentration (NOx) was significantly increased after reperfusion with CRMBM (P < 0.0001 versus baseline and P < 0.0001 versus Celsior). Na,K-ATPase activity was decreased in both groups versus baseline after reperfusion (P < 0.0001 for CRMBM and P < 0.0001 for Celsior). We showed limitation of both myocardial and endothelial damage with CRMBM compared with Celsior during heterotopic rat heart transplantation in vivo.
    Mots-clés : Adenosine Triphosphate, Animals, crmbm, Disaccharides, Electrolytes, Endothelium, Vascular, Glutamates, Glutathione, Heart Transplantation, Histidine, Mannitol, Nitric Oxide, Organ Preservation, Organ Preservation Solutions, Phosphocreatine, Rats, Rats, Inbred Lew, Reperfusion, Transplantation, Isogeneic.


Journal Article

  • Desrois, M, Caus, T, Belles, PM, Dalmasso, C, Lan, C, Cozzone, PJ & Bernard, M 2005, “Nitric oxide pathway after long-term cold storage and reperfusion in a heterotopic rat heart transplantation model”, Transplantation proceedings, vol. 37, no. 10, p. 4553-4555.
    Résumé : Recent studies have suggested the involvement of the nitric oxide (NO) pathway in ischemia-reperfusion injury related to cardiac transplantation. Herein, we assessed the NO pathway by quantifying endothelial (e) and inducible (i) nitric oxide synthase (NOS) expression and total NOS activity in a rat heart transplant model during cold ischemia with Celsior cardioplegia and reperfusion. Experiments were performed using a modified Lewis-Lewis heterotopic abdominal heart transplantation with 3 or 6 hours of ischemia with or without 1 hour of blood reperfusion. NOS expression and activity were determined using Western blotting and colorimetric assays, respectively, on freeze-clamped hearts after ischemia without (n = 10) or with reflow (n = 12) compared with basal values. Hearts submitted to 3 hours of ischemia and 1 hour of reperfusion showed a postischemic rate pressure product of 5190 +/- 3047 mm Hg/min (reversible ischemia), but no contractility was observed after 6 hours of ischemia. eNOS protein levels were lower after 3 hours of ischemia compared with the basal value (P = .0005) and were further decreased after 6 hours of ischemia (P < .0001 versus basal value and P = .0018 versus 3 hours of ischemia). Reperfusion did not further decrease eNOS protein levels. iNOS protein was not detected in any condition. NOS activity was increased after 3 hours of ischemia versus basal value (P = .0065) but not after 6 hours of ischemia without any effect of reperfusion. We concluded that eNOS expression was altered during ischemia and the amplitude of the alteration depended on the duration of ischemia. Reversible ischemia was associated with increased NOS activity at the end of ischemia with no variation at reperfusion.
    Mots-clés : Blood pressure, crmbm, Heart Transplantation, Models, Animal, Myocardial Contraction, Myocardial Ischemia, Nitric Oxide, Nitric Oxide Synthase, Nitric Oxide Synthase Type III, Rats, Rats, Inbred Lew, Reperfusion Injury, Transplantation, Isogeneic.
  • Iltis, I, Kober, F, Desrois, M, Dalmasso, C, Lan, C, Portha, B, Cozzone, PJ & Bernard, M 2005, “Defective myocardial blood flow and altered function of the left ventricle in type 2 diabetic rats: a noninvasive in vivo study using perfusion and cine magnetic resonance imaging”, Investigative Radiology, vol. 40, no. 1, p. 19-26.
    Résumé : OBJECTIVE: In type 2 diabetes mellitus, cardiovascular complications are related to microvascular abnormalities. In this work, we aimed at characterizing in vivo myocardial blood flow and left ventricular function of the Goto-Kakizaki (GK) rat as a nonobese model of type 2 diabetes. MATERIALS AND METHODS: We performed arterial spin labeling magnetic resonance imaging (MRI) for myocardial blood flow quantification and cine MRI for functional evaluation in free-breathing isoflurane-anesthetized animals. RESULTS: Myocardial blood flow was altered in adult female GK rats compared with age-matched female Wistar rats (4.7 +/- 1.6 vs. 7.1 +/- 1.2 mL/g/min respectively, P = 0.0022). Ejection fraction was decreased in GK compared with Wistar rats (64 +/- 7 vs. 78 +/- 8% respectively, P <0.005), mainly as a result of a loss in left ventricular longitudinal contraction. CONCLUSIONS: Adult female GK rats have defective myocardial blood flow associated with altered left ventricular function. This multiparametric MRI approach in the GK rat is of particular interest for the study of type 2 diabetic cardiomyopathy.
    Mots-clés : Animals, Coronary Circulation, crmbm, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Female, Magnetic Resonance Imaging, Cine, Rats, Rats, Wistar, Ventricular Dysfunction, Left.


Journal Article

  • Bernard, M, Robert, K, Caus, T, Desrois, M, Paganelli, F, Cozzone, PJ & Maixent, JM 2004, “Protective effect of a low K+ cardioplegic solution on myocardial Na, K-ATPase activity.”, Cellular and molecular biology (Noisy-le-Grand, France), vol. 50, no. 7, p. 841, viewed 21November,2013, .
    Mots-clés : Adenosine, Allopurinol, Cardioplegic Solutions, crmbm, Glutathione, Insulin, Myocardial Ischemia, Myocardial Reperfusion Injury, Organ Preservation Solutions, Potassium, Protective Agents, Raffinose, Rats, Rats, Sprague-Dawley, Sodium-Potassium-Exchanging ATPase, Temperature.

  • Desrois, M, Sidell, RJ, Gauguier, D, Davey, CL, Radda, GK & Clarke, K 2004, “Gender differences in hypertrophy, insulin resistance and ischemic injury in the aging type 2 diabetic rat heart”, Journal of molecular and cellular cardiology, vol. 37, no. 2, p. 547-555.
    Résumé : Aging and diabetes in women increase their susceptibility to myocardial ischemic injury, but the cellular mechanisms involved are not understood. Consequently, we studied the influence of gender on cardiac insulin resistance and ischemic injury in the aging of Goto-Kakizaki (GK) rat, a model of type 2 diabetes. Male and female GK rats had heart/body weight ratios 29% (P < 0.0001) and 53% (P < 0.0001) higher, respectively, than their sex-matched controls, with the female GK rat hearts significantly more hypertrophied than the male (P < 0.001). Glucose transporter (GLUT) 1 protein levels were the same in all hearts, but GLUT4 protein levels were 28% lower (P < 0.01) in all GK rat hearts compared with their sex-matched controls. In isolated, perfused hearts, insulin-stimulated (3)H-glucose uptake rates were decreased by 23% (P < 0.05) and 40% (P < 0.05) in male and female GK rat hearts, respectively, compared with their controls, with the female significantly more insulin resistant than the male GK rat hearts (P < 0.05). Protein kinase B protein levels and insulin-stimulated phosphorylation were the same in all hearts. During low-flow ischemia, glucose uptake was 59% lower (P < 0.001) in female, but the same as controls in male, GK rat hearts. Consequently, recovery of contractile function during reperfusion was 30% lower (P < 0.05) in female, but the same as controls in male GK rat hearts. We conclude that the aging female type 2 diabetic rat heart has increased insulin resistance and greater susceptibility to ischemic injury, than non-diabetic or male type 2 diabetic rat hearts.
    Mots-clés : aging, Biological Transport, Cardiomegaly, Diabetes Mellitus, Type 2, Glucose, Glucose Transporter Type 1, Glucose Transporter Type 4, Heart, Insulin, Insulin Resistance, Monosaccharide Transport Proteins, Muscle Proteins, Myocardial Reperfusion Injury, Myocardium, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Rats.
  • Desrois, M, Sidell, RJ, Gauguier, D, King, LM, Radda, GK & Clarke, K 2004, “Initial steps of insulin signaling and glucose transport are defective in the type 2 diabetic rat heart”, Cardiovascular research, vol. 61, no. 2, p. 288-296.
    Résumé : OBJECTIVE: Whole body insulin resistance and diabetes are risk factors for cardiovascular diseases, yet little is known about insulin resistance in the diabetic heart. The aim of this work was to define the insulin response in hearts of the Goto-Kakizaki (GK) rat, a polygenic model of spontaneous type 2 diabetes. METHODS: We measured D[2-3H]glucose uptake before and after insulin stimulation, plus initial steps of the insulin signaling pathway after insulin infusion via the caudal vena cava in hearts from the male Wistar and spontaneously diabetic GK rats. RESULTS: Despite normal basal D[2-3H]glucose uptake, insulin-stimulated glucose uptake was 50% (p<0.03) lower in GK rat hearts compared with their Wistar controls. Total GLUT4 protein was depleted by 28% (p<0.01) in GK rat hearts. We found 31% (p<0.0001) and 38% (p<0.001) decreased protein levels of insulin receptor beta (IRbeta)-subunit and insulin receptor substrate-1 (IRS-1), respectively, in GK rat hearts with 37% (p<0.02) and 45% (p<0.01) lower insulin-stimulated tyrosine phosphorylation of these proteins. Owing to the decreased IRS-1 protein levels, GK rat hearts had a 41% (p<0.0001) decrease in insulin-stimulated IRS-1 protein association with the p85 subunit of phosphatidylinositol 3-kinase, despite normal phosphatidylinositol 3-kinase protein expression. Insulin-stimulated serine phosphorylation of protein kinase B was the same in all hearts, as was protein kinase B expression. CONCLUSION: We conclude that decreased insulin receptor beta, IRS-1 and GLUT4 proteins are associated with insulin resistance in type 2 diabetic rat hearts.
    Mots-clés : Biological Transport, Cell Membrane, Diabetes Mellitus, Type 2, Glucose, Glucose Transporter Type 1, Glucose Transporter Type 4, Insulin, Insulin Receptor Substrate Proteins, Models, Animal, Monosaccharide Transport Proteins, Muscle Proteins, Myocardium, Phosphoproteins, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Rats, Rats, Inbred Strains, Rats, Wistar, Signal Transduction.

  • Kober, F, Iltis, I, Izquierdo, M, Desrois, M, Ibarrola, D, Cozzone, PJ & Bernard, M 2004, “High-resolution myocardial perfusion mapping in small animals in vivo by spin-labeling gradient-echo imaging”, Magnetic Resonance in Medicine, vol. 51, no. 1, p. 62-67.
    Résumé : An ECG and respiration-gated spin-labeling gradient-echo imaging technique is proposed for the quantitative and completely noninvasive measurement and mapping of myocardial perfusion in small animals in vivo. In contrast to snapshot FLASH imaging, the spatial resolution of the perfusion maps is not limited by the heart rate. A significant improvement in image quality is achieved by synchronizing the inversion pulse to the respiration movements of the animals, thereby allowing for spontaneous respiration. High-resolution myocardial perfusion maps (in-plane resolution=234 x 468 microm2) demonstrating the quality of the perfusion measurement were obtained at 4.7 T in a group of seven freely breathing Wistar-Kyoto rats under isoflurane anesthesia. The mean perfusion value (group average +/- SD) was 5.5 +/- 0.7 ml g(-1)min(-1). In four animals, myocardial perfusion was mapped and measured under cardiac dobutamine stress. Perfusion increased to 11.1 +/- 1.9 ml g(-1)min(-1). The proposed method is particularly useful for the study of small rodents at high fields.
    Mots-clés : Animals, Coronary Circulation, crmbm, Echo-Planar Imaging, Electrocardiography, Heart Rate, Image Processing, Computer-Assisted, Male, Rats, Rats, Wistar, Spin Labels.


Journal Article
  • Caus, T, Desrois, M, Izquierdo, M, Lan, C, LeFur, Y, Confort-Gouny, S, Métras, D, Clarke, K, Cozzone, PJ & Bernard, M 2003, “NOS substrate during cardioplegic arrest and cold storage decreases stunning after heart transplantation in a rat model”, The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation, vol. 22, no. 2, p. 184-191.
    Résumé : BACKGROUND: In this study, we evaluated how adding L-arginine to Centre de Résonance Magnétique Biologique et Médicale (CRMBM) solution affected myocardial performance during post-ischemic in vivo reperfusion. METHODS: Experiments were conducted using a modified Lewis-Lewis heterotopic heart transplantation model, with a total ischemic time of 3 hours followed by 1 or 24 hours of blood reperfusion. Heart grafts were arrested using intra-aortic injection of CRMBM solution, either supplemented or not supplemented with 2 mmol/liter L-arginine (n = 12 in each group). We measured systolic indexes and simultaneously performed phosphorus magnetic resonance spectroscopy ((31)P MRS). We quantified total endothelial nitric oxide synthase (eNOS) protein using the Western blot test of freeze-clamped hearts. RESULTS: Contractility during early reperfusion was significantly better in grafts arrested with CRMBM solution enriched with L-arginine: mean rate pressure product, 11249 +/- 1548 vs 5637 +/- 1118 mm Hg/min (p = 0.05), and maximal first derivative of the pressure signal (dP/dt(max)), 1721 +/- 177 vs 1214 +/- 321 mm Hg/sec (p = 0.013). Conversely, during late reperfusion, contractility did not relate to the nature of the preservation solution. The presence of L-arginine in the CRMBM solution did not alter time-related variations of high-energy phosphate ratios measured using in vivo (31)P MRS. The eNOS protein level decreased significantly during early compared with late reperfusion, with no effect caused by L-arginine. CONCLUSIONS: During early reperfusion, the limited myocardial stunning observed with CRMBM solution containing L-arginine does not relate to energy metabolism but to better preservation of the NO pathway.
    Mots-clés : Allopurinol, Animals, Arginine, Blotting, Western, Cardioplegic Solutions, Cold Temperature, Glutathione, Heart Arrest, Induced, Heart Transplantation, Myocardial Reperfusion, Myocardial Stunning, Nitric Oxide Synthase, Nitric Oxide Synthase Type III, Organ Preservation, Raffinose, Rats, Rats, Inbred Lew.

  • Desrois, M, Sciaky, M, Lan, C, Cozzone, PJ & Bernard, M 2003, “Preservation of amino acids during long term ischemia and subsequent reflow with supplementation of L-arginine, the nitric oxide precursor, in the rat heart”, Amino acids, vol. 24, no. 1-2, p. 141–148, viewed 21November,2013, .
    Mots-clés : Amino Acids, Arginine, Chromatography, High Pressure Liquid, Chromatography, Ion Exchange, Creatine Kinase, L-Lactate Dehydrogenase, Myocardial Ischemia, Myocardial Reperfusion, Myocardium, Nitric Oxide, Rats, Rats, Sprague-Dawley.


Journal Article
  • Desrois, M, Caus, T, Lan, C, Sciaky, M, Cozzone, PJ & Bernard, M 2002, “Comparative effects of Celsior and a new cardioplegic solution on function, energy metabolism, and intracellular pH during long-term heart preservation”, Transplantation proceedings, vol. 34, no. 4, p. 1259-1261.
    Mots-clés : Allopurinol, Cardioplegic Solutions, Coronary Circulation, Disaccharides, Electrolytes, Glutamates, Glutathione, Heart, Histidine, Mannitol, Myocardial Ischemia, Myocardial Reperfusion, Myocardium, Organ Preservation, Raffinose, Rats.
  • Sidell, RJ, Cole, MA, Draper, NJ, Desrois, M, Buckingham, RE & Clarke, K 2002, “Thiazolidinedione treatment normalizes insulin resistance and ischemic injury in the zucker Fatty rat heart”, Diabetes, vol. 51, no. 4, p. 1110-1117.
    Résumé : Obesity is associated with risk factors for cardiovascular disease, including insulin resistance, and can lead to cardiac hypertrophy and congestive heart failure. Here, we used the insulin-sensitizing agent rosiglitazone to investigate the cellular mechanisms linking insulin resistance in the obese Zucker rat heart with increased susceptibility to ischemic injury. Rats were treated for 7 or 14 days with 3 mg/kg per os rosiglitazone. Hearts were isolated and perfused before and during insulin stimulation or during 32 min low-flow ischemia at 0.3 ml small middle dot min(-1) small middle dot grams wet wt(-1) and reperfusion. D[2-(3)H]glucose was used as a tracer of glucose uptake, and phosphorus-31 nuclear magnetic resonance spectroscopy was used to follow energetics during ischemia. At 12 months of age, obese rat hearts were insulin resistant with decreased GLUT4 protein expression. During ischemia, glucose uptake was lower and depletion of ATP was greater in obese rat hearts, thereby significantly impairing recovery of contractile function during reperfusion. Rosiglitazone treatment normalized the insulin resistance and restored GLUT4 protein levels in obese rat hearts. Glucose uptake during ischemia was also normalized by rosiglitazone treatment, thereby preventing the greater loss of ATP and restoring recovery of contractile function to that of lean rat hearts. We conclude that rosiglitazone treatment, by normalizing glucose uptake, protected obese rat hearts from ischemic injury.
    Mots-clés : Blood Glucose, Blood pressure, Body Weight, Heart, Heart Rate, Hypoglycemic Agents, Insulin Resistance, Myocardial Ischemia, Myocardial Reperfusion, Obesity, Organ Size, Perfusion, Rats, Rats, Zucker, Thiazoles, Thiazolidinediones.


Journal Article

  • Desrois, M, Sciaky, M, Lan, C, Cozzone, PJ & Bernard, M 2000, “L-arginine during long-term ischemia: effects on cardiac function, energetic metabolism and endothelial damage”, The Journal of Heart and Lung Transplantation, vol. 19, no. 4, p. 367-376, viewed 21November,2013, .
    Résumé : Background: We have evaluated the addition of L-arginine, a precursor of nitric oxide, to a cardioplegic solution (named CRMBM) designed for long-term heart preservation. Methods Isolated isovolumic-perfused rat hearts (n = 22) were arrested with the CRMBM solution either with (Arg) or without L-arginine (2 mmol/L) (Arg group, n = 12, vs control group n = 10), submitted to 8 hours of cold storage (4° C) in the solution, and then reperfused for 60 minutes at 37° C. In 11 hearts, we evaluated the quality of cardiac preservation with P-31 magnetic resonance spectroscopy and the measure of function and cellular integrity. Endothelium-dependent and independent vasodilatations were measured in 11 other hearts, using 5-hydroxytryptamine and papaverine to assess endothelial and smooth muscle function. Results Adding L-arginine to the cardioplegic solution improved functional recovery during reflow, as shown by the rate pressure product (31% ± 3% for control vs 47% ± 3% for Arg, p = 0.003) together with higher coronary flow and diminished contracture. Purine release in coronary effluents during reperfusion was lower in the Arg group. During ischemia and reflow kinetics of intracellular pH and high-energy phosphates were similar in both groups. Coronary endothelium-dependent vasodilatation was similarly impaired in both groups, but smooth muscle was less altered with L-arginine. Conclusion As an additive to the CRMBM cardioplegic solution, L-arginine provides a protective effect for long-term heart preservation. Our data do not show coronary endothelial protection as the prominent mechanism.
    Mots-clés : Arginine, Cardioplegic Solutions, Coronary Circulation, Endothelium, Vascular, Hemodynamics, Myocardial Ischemia, Organ Preservation, Rats, Rats, Sprague-Dawley.


Journal Article

  • Desrois, M, Sciaky, M, Lan, C, Cozzone, PJ & Bernard, M 1999, “Metabolic and functional effects of low-potassium cardioplegic solutions for long-term heart preservation”, Magnetic Resonance Materials in Physics, Biology and Medicine, vol. 8, no. 2, p. 77–82, viewed 21November,2013, .
    Mots-clés : Blood pressure, Cardioplegic Solutions, Creatine Kinase, Heart Arrest, Induced, Heart Rate, L-Lactate Dehydrogenase, Lactic Acid, Myocardial Ischemia, Organ Preservation, Potassium, Purines, Rats, Rats, Sprague-Dawley, Reperfusion.
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