Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques (LPPCM)

Professor - Hospital Practitioner
Head of Cardiology Unit
Team Co-leader

Centre Hospitalier Universitaire
14 Rue Paul Gaffarel
21079 DIJON Cedex

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Catherine VERGELY
Physiopathology & Genetics
Team Co-leader

Facultés de Médecine et Pharmacie
7 Bd Jeanne d’Arc
21079 DIJON Cedex

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Host Laboratory for Master 2R and PhD students

Master 2 Recherche « Signalisation Cellulaire et Moléculaire »
Université de Bourgogne-Franche-Comté, Dijon et Besançon

Master 2 Recherche « Régulations Cardiovasculaires, Métaboliques et Nutritionnelles »
Université Claude Bernard, Lyon 1

Master 2 Recherche « Biologie, Physiopathologie et Pharmacologie du Cœur et de la Circulation »
Université Paris Diderot-Paris Descartes

Nitro-oxidative stress and cardiometabolic risk: clinical and fundamental interplay

The research work carried out in our Laboratory has focused on the pathophysiological conditions associated with cardiovascular diseases, which we aimed to examine in both their experimental and clinical aspects.

Cardiovascular disease is one of the most common causes of death in the Western world and accounts for up to a third of all deaths worldwide. Cardiovascular disease is multifactorial and involves complex interplay between fixed (genotype, age, menopausal status, gender) and modifiable (diet, smoking, exercise, alcohol consumption) causative factors. The initiating step in cardiovascular disease is endothelial damage, which exposes these cells and the underlying cell layers to a deleterious inflammatory process which ultimately leads to the formation of atherosclerotic lesions. Cellular oxidative or nitrating stress is intrinsic to lesion formation, and is due to the production of damaging reactive oxygen (ROS) and nitrogen species (RNS) by many cell types including endothelial cells, vascular smooth muscle cells, cardiomyocytes and monocytes/macrophages. In physiological conditions, there is a balance between mechanisms that generate and scavenge ROS and RNS, the latter being generally referred to antioxidant defenses. An imbalance in the system leads to oxidative stress.

The main part of our research work in the past four years has been centered on the identification of modulators of oxidative stress involved in cardiovascular pathologies and their fundamental and clinical interplays.

Our research themes :

Coronary artery disease, including acute myocardial infarction (AMI), is one of the leading causes of death in France and in most developed countries. Paradoxically, few data are available on the features, management and outcomes of AMI in routine clinical practice.

Since January 1st 2001, the “obseRvatoire des Infarctus de Côte d’Or” (RICO)),a unique French regional survey, has collected data concerning all patients hospitalized with AMI in the six public and private hospitals of Côte-d’Or, a French region with a population of approximately 500,000 inhabitants. These hospitals account for the totality of cardiology and coronary care units of the region. Data are collected at each site by a study coordinator trained in completing the core record form and in extracting data from medical records, using a standardized case report form. Data on demographics, cardiovascular risk factors and treatments along with clinical data and reperfusion therapy are collected prospectively. Patients are enrolled in the survey if they are ≥18 years of age and are admitted to participating hospitals within 24 hours of the onset of symptoms with a diagnosis of AMI as defined by the European Society of Cardiology and the American College of Cardiology. Follow-up data are also collected at 12 days, 30 days and one year. More than 13,000 patients are currently included in the RICO database.

As a unique federative network, RICO is a reliable tool for the assessment of epidemiologic data and trends of AMI. It has also been used to measure the impact of various innovative therapies and to specifically address the clinical relevance of new cardiovascular biomarkers in AMI. Moreover, the RICO survey may bring to light data that challenge the value of new diagnostic tools in the setting of cardiovascular prevention. Given its prospective and continuous data collection, RICO offers a unique opportunity to assess routine clinical data. Analyses based on these data have been validated by numerous high-quality international publications. Moreover, various scientific collaborations developed from the RICO working group have provided some significant insights into patho-physiological mechanisms involved in the development of coronary artery disease.

The Côte-d’Or is the only region of France to have, through RICO, comprehensive, real-world indicators, which are so valuable in public health regarding the evolution of treatments for myocardial infarction and cardiovascular risk factors. Innovative fields of research are continuously being developed from the RICO survey, in particular in the setting of novel biomarkers for cardiovascular risk and risk stratification.

Bibliography :

  • ZELLER M, STEG PG, RAVISY J, LORGIS L, LAURENT Y, SICARD P, JANIN-MANIFICAT L, BEER JC, MAKKI H, LAGROST AC, ROCHETTE L, COTTIN Y; for the RICO Survey Working Group.Relation Between Body Mass Index, Waist Circumference, and Death After Acute Myocardial Infarction. Circulation. 2008;118:482-90.
  • LORGIS L, ZELLER M, DENTAN G, SICARD P, BUFFET P, L’HUILLIER I, BEER JC, VINCENT-MARTIN M, MAKKI H, GAMBERT P, COTTIN Y, on behalf of the RICO survey working group. Prognostic value of NT-Pro BNP in the elderly with acute myocardial infarction. Data from the RICO survey. BMJ, 2009, May 6;338:b1605. doi: 10.1136/bmj.b1605.
  • HENROTIN JB, ZELLER M, LORGIS L, COTTIN Y, GIROUD M, BÉJOT Y. Evidence of the role of short-term exposure to low levels of ozone on ischemic cerebral and cardiac events. The Dijon Vascular Project (DIVA). Heart 2010;96(24):1990-6.
  • COCHET A, LALANDE A, LORGIS L, ZELLER M, BEER JC, WALKER PM, TOUZERY C, WOLF JE, COTTIN Y, BRUNOTTE F. Prognostic Value of Microvascular Damage Determined by Cardiac Magnetic Resonance in Non ST-Segment Elevation Myocardial Infarction: Comparison Between First-Pass and Late Gadolinium-Enhanced Images. Invest Radiol. 2010; 45(11):725-32.
  • ZELLER M, DANCHIN N, SIMON D, VAHANIAN A, LORGIS L, COTTIN Y, BERLAND J, GUERET P, WYART P, DETURCK R, TABONE X, MACHECOURT J, LECLERCQ F, DROUET E, MULAK G, BATAILLE V, CAMBOU JP, FERRIERES J, SIMON T; for the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction investigators. Impact of Type of Preadmission Sulfonylureas on Mortality and Cardiovascular Outcomes in Diabetic Patients with Acute Myocardial Infarction. J Clin Endocrinol Metab. 2010 ;95(11):4993-5002.
  • LORGIS L, COTTIN Y, DANCHIN N, MOCK L, SICARD P, BUFFET P, L’HUILLIER I, RICHARD C, BEER J, TOUZERY C, GAMBERT P, ZELLER M. on behalf of the RICO survey working group. Impact of obesity in the prognostic value of the n-terminal pro-b-type natriuretic peptide (NT-proBNP) in patients with acute myocardial infarction. Heart 2011; 97(7):551-556.
  • COUTINHO T, GOEL K, CORRÊA DE SÁ D, KRAGELUND C, KANAYA AM., ZELLER M, PARK JS, KOBER LARS, TORP-PEDERSEN C, COTTIN Y, LORGIS L, LEE SH, KIM YJO, THOMAS R, L. ROGER V, SOMERS V., AND LOPEZ-JIMENEZ F. Central Obesity and Survival in Subjects With Coronary Artery Disease: A Systematic Review of the Literature and Collaborative Analysis With Individual Subject Data . J Am Coll Cardiol 2011;57 1877-1886.
  • SALIQUES S, TEYSSIER JR, VERGELY C, LORGIS L, LORIN J, DONZEL A, SICARD P, BERCHOUD J, RAGOT S, TOUZERY C, COTTIN Y, ROCHETTE L, ZELLER M. Smoking and FOS expression from blood leukocyte transcripts in patients with coronary artery disease. Atherosclerosis. 2011;219::931-936.
  • SALIQUES S, TEYSSIER JR, VERGELY C, LORGIS L, LORIN J, FARNIER M, DONZEL A, SICARD P, BERCHOUD J, LAGROST AC, TOUZERY C, RAGOT S, COTTIN Y, ROCHETTE L, ZELLER M. Circulating leukocyte telomere length and oxidative stress: A new target for statin therapy. Atherosclerosis. 2011;219:753:760.
  • ROMAGNA C, DUFOUR L, TROISGROS O, LORGIS L, RICHARD C, BUFFET P, SOULAT G, CASILLAS JM, RIOUFOL G, TOUZERY C, ZELLER M, LAURENT Y, COTTIN Y. Periodontal disease: a new factor associated with the presence of multiple complex coronary lesions. J Clin Periodontol. 2012; 39(1):38-44.
  • BÉJOT Y, ZELLER M, LORGIS L, TROISGROS O, ABOA-EBOULÉ C, OSSEBY GV, GIROUD M, COTTIN Y. Secondary prevention in patients with vascular disease. A population based study on the underuse of recommended medications. J Neurol Neurosurg Psychiatry. 2013;84(3):348-53.
  • COUTINHO T, GOEL K, CORRÊA DE SÁ D, CARTER RE, HODGE DO, KRAGELUND C, KANAYA AM, ZELLER M, PARK JS, KOBER L, TORP-PEDERSEN C, COTTIN Y, LORGIS L, LEE SH, KIM YJ, THOMAS R, ROGER V, SOMERS VK, LOPEZ-JIMENEZ F. Combining Body Mass Index With Measures of Central Obesity in the Assessment of Mortality in Subjects With Coronary Disease: Role of Normal Weight Central Obesity . J Am Coll Cardiol. 2013;61(5):553-560.
  • LORGIS L, GUDJONCIKA A, RICHARD C, MOCK L, BUFFET P, BRUNEL P, JANIN-MANIFICAT L, BEER JC, BRUNET D, TOUZERY C, ROCHETTE L, COTTIN Y AND ZELLER M. Pre-infarction angina and outcomes in non-ST-segment elevation myocardial infarction: Data from the RICO survey. PlosOne, 2012;7(12):e48513. doi: 10.1371/journal.pone.0048513.
  • LORGIS L, MOREAU D, MOCK L, DAUMAS B, POTARD D, TOUZERY C, COTTIN Y, ZELLER M. High N-terminal pro-B-type natriuretic Peptide levels are associated with reduced heart rate variability in acute myocardial infarction. PLoS One. 2012;7(10):e44677. doi: 10.1371/journal.pone.0044677.
  • LORGIS L, COTTENET J, MOLINS G, BENZENINE E, ZELLER M, AUBE H, TOUZERY C, HAMBLIN J, GUDJONCIK A, COTTIN Y, QUANTIN C. Outcomes after acute myocardial infarction in HIV-infected patients. Analysis of data from a French nationwide hospital medical information database. Circulation, 2013, Apr 30;127(17):1767-74.

Soutiens :

Within the endothelial cells of the intima of vessels, physical (shear) or chemical stimuli may initiate the synthesis of nitric oxide (NO) from L-arginine via enzymes called NO synthases (NOS). Once synthesized, the NO diffuses freely into the underlying smooth muscle cells (SMC), where it induces vascular relaxation and inhibits SMC proliferation and fibrosis. Within the vascular system, NO inhibits the adhesion of polynuclear neutrophils to the endothelium and platelet aggregation. Certain situations of cardio-metabolic risk are associated with endothelial dysfunction, characterised by a fall in the bioavailability of NO, and are accompanied by an increase in vasoconstriction, SMC proliferation, fibrosis, platelet aggregation, thrombosis and oxidative stress.

One of the factors that could explain the fall in NO bioavailability in these situations, could be linked to the presence of a molecule, Asymmetric DiMethyl Arginine, ADMA, which is the methylated derivative of L-arginine and is a competitive endogenous inhibitor of NO synthases. ADMA is fabricated in cells from proteins that contain L-arginine. ADMA inhibits NO synthesis by competing with L-Arginine not only as a substrate for NOS, but also with regard to membrane transfer . The L-arginine /ADMA ratio is thus considered a marker of NO bioavailability .

An increase in plasma levels of ADMA has been seen in a certain number of pathological situations associated with endothelial dysfunction, such as atherosclerosis, arterial hypertension, hyperlipidemia and diabetes. In our team, we showed that the plasma level of ADMA was a predictor of cardiovascular mortality in patients with myocardial infarction and that the level of ADMA correlated strongly with a low level of HDL in patients in the acute phase of myocardial infarction.

However, intra-endothelial ADMA may come not only from endogenous ADMA synthesis, by also from the penetration of ADMA into the cell from the extracellular compartment. Though ADMA present in the plasma comes from many tissues (liver, kidney, muscles, …), recent studies have shown that erythrocytes are also able to synthesize, store and transport ADMA.

Our current ambition is to improve our knowledge about the formation and role of erythrocytic ADMA , its involvement in the regulation of vascular homeostasis and its value in the determination of cardio-metabolic risk..

Bibliography :

  • Lorin J., Guilland J. C., Korandji C., Touzery C., Bichat F., Chagnon A., Cottin Y., Rochette L., Vergely C. and Zeller M. High Levels of Asymmetric Dimethylarginine Are Strongly Associated with Low HDL in Patients with Acute Myocardial Infarction. PLoS One 2013 8(6): e64796.
  • Lorin J., Zeller M., Guilland J. C., Cottin Y., Vergely C. and Rochette L. Arginine and nitric oxide synthase: Regulatory mechanisms and cardiovascular aspects. Mol Nutr Food Res 2013.
  • Korandji C., Zeller M., Guilland J. C., Collin B., Lauzier B., Sicard P., Duvillard L., Goirand F., Moreau D., Cottin Y., Rochette L. and Vergely C. Time course of asymmetric dimethylarginine (ADMA) and oxidative stress in fructose-hypertensive rats: a model related to metabolic syndrome. Atherosclerosis 2011 214(2): 310-5.
  • Zeller M., Korandji C., Guilland J. C., Sicard P., Vergely C., Lorgis L., Beer J. C., Duvillard L., Lagrost A. C., Moreau D., Gambert P., Cottin Y. and Rochette L. Impact of Asymmetric Dimethylarginine on Mortality After Acute Myocardial Infarction. Arteriosclerosis Thrombosis & Vascular Biology 2008 28(5): 954-60.
  • Korandji C., Zeller M., Guilland J. C., Vergely C., Sicard P., Duvillard L., Gambert P., Moreau D., Cottin Y. and Rochette L. Asymmetric dimethylarginine (ADMA) and hyperhomocysteinemia in patients with acute myocardial infarction. Clinical Biochemistry 2007 40(1-2): 66-72.

In recent years, our team has taken an interest in the impact of postnatal overfeeding on cardiometabolic risk and oxydative stress.

Diseases linked to overweight combine cardiovascular disorders with major metabolic disorders. The multifactorial origins of these disorders stem from the fact that our genetic heritage is incompatible with the profound modifications in our dietary habits and our levels of physical activity. Changes in early nutrition are likely to durably affect trends in body weight, and metabolic and cardiovascular risk. Certain recent studies have tended to show that postnatal overfeeding in expressly-reduced litters of rodents could be a factor in the onset of overweight in adulthood, high blood pressure and altered metabolism of carbohydrates and lipids. Recent results from our laboratory have shown that postnatal overfeeding induced not only increased levels of oxidative stress in blood and cardiac tissues, but also greater myocardial susceptibility to ischemia-reperfusion insult in adult rats and mice.

In most mammals, during the immediate postnatal period, there is still a certain plasticity of the genome. The development of a certain number of organs is not complete at birth and continues during maternal feeding. Environmental, physical, psychic and nutritional stimuli can thus affect gene expression in the offspring, thus, in theory, allowing the offspring to adapt to the environment. In the longer term, however, these changes may prove to be inappropriate or even deleterious, as they make the adult prone to metabolic and/or cardiovascular disorders. It therefore seems essential to determine, in the case of modified post-natal nutritional status, what genes are modified with regard to heart tissue, when these modifications occur and whether the modifications are permanent or transient.

It seems essential today to explore a number of major points concerning the cardio-metabolic and nitro-oxidative consequences of early modifications in diet:

  • The expression of which cardiac genes is modified early or late, transiently or permanently?
  • What role does vascular reactivity play in the increased sensitivity of the myocardium to ischemia and reperfusion, and what is the role of impaired NO bioavailability in this context?
  • Can these alterations be reversed in adulthood by moderate calorie restriction or by pharmacological treatment?

Bibliography :

  • Habbout A., Guenancia C., Lorin J., Rigal E., Fassot C., Rochette L. and Vergely C. Postnatal overfeeding causes early shifts in gene expression in the heart and long-term alterations in cardiometabolic and oxidative parameters. PLoS One 2013 8(2): e56981.
  • Habbout A., Li N., Rochette L. and Vergely C. Postnatal Overfeeding in Rodents by Litter Size Reduction Induces Major Short- and Long-Term Pathophysiological Consequences. J Nutr 2013: In press.
  • Habbout A., Delemasure S., Goirand F., Guilland J. C., Chabod F., Sediki M., Rochette L. and Vergely C. Postnatal overfeeding in rats leads to moderate overweight and to cardiometabolic and oxidative alterations in adulthood. Biochimie 2012 94(1): 117-24.

The aim of this theme is to study, from a fundamental and clinical point of view, the consequences of treatment with anticancer agents, particularly anthracyclines and trastuzumab or a combination of the two, in terms of oxidative stress and cardiotoxicity. The presence of metabolic syndrome as an aggravating factor of this cardiotoxicity is included in one of the facets explored.

The anti-tumoral efficacy of anthracyclines, which are intercalating agents and inhibitors of topoisomerase II, has made them essential in the treatment of many cancers. However, as well as the adverse side effects common to all chemotherapy drugs, anthracyclines also have extremely deleterious cardiotoxic effects, which limit their use in clinical practice. Anthracyclines can cause rhythm disturbances and cardiac contractility disorders, and even the onset of cardiomyopathy, and this even several years after the last course of treatment. It is now accepted that mechanisms underlying the anti-tumoral activity and the cardiotoxicity are distinct, and that oxidative stress is a key factor in this cardiotoxicity. Many studies have been carried out to determine the different processes leading to the anthracycline-related impairment of cardiac function and the means to limit it. More particularly, our team has set out to explore the pharmacological interactions between the level of iron in tissues, and cardiotoxicity induced by treatment with Doxorubicin.

Trastuzumab is a humanized monoclonal antibody directed against Human Epidermal Growth Factor Receptor 2 (HER2 ), a transmembrane receptor with activity on tyrosine kinase, the activation of which causes alterations in cell metabolism and cell growth. Tyrosine kinase is an oncogen, which is amplified in 25 to 30% of breast cancers and is currently a therapeutic target in the treatment of breast cancer. Though preclinical studies did not reveal any cardiotoxicity, subsequent studies showed an unexpected incidence of cardiac adverse effects of treatment with trastuzumab. The exact mechanisms of trastuzumab-induced cardiotoxicity are not yet known. Identifying the pathways by which trastuzumab deteriorates cardiomyocytes is essential in the search for new treatments to protect the heart.

It is now well established that patients with metabolic syndrome have an increased risk of cardiovascular disease, and certain stusies have shown that obese patients or rats fed a high-fat diet are more sensitive to the cardiotoxic effets of anticancer agents such as doxorubicin. However, few data are available today on the impact of overweight on sensitivity of the heart to treatment with trastuzumab, combined or not with anthracyclines. The question we wish to answer concerns the impact of overweight associated with metabolic syndrome on the onset of nitro-oxidative damage in the heart induced by anticancer drugs.

Bibliography :

  • Ghibu S., Delemasure S., Richard C., Guilland J. C., Martin L., Gambert S., Rochette L. and Vergely C. General oxidative stress during doxorubicin-induced cardiotoxicity in rats: absence of cardioprotection and low antioxidant efficiency of alpha-lipoic acid. Biochimie 2012 94(4): 932-9.
  • Cochet A., Quilichini G., Dygai-Cochet I., Touzery C., Toubeau M., Berriolo-Riedinger A., Coudert B., Cottin Y., Fumoleau P. and Brunotte F. Baseline diastolic dysfunction as a predictive factor of trastuzumab-mediated cardiotoxicity after adjuvant anthracycline therapy in breast cancer. Breast Cancer Res Treat 2011 130(3): 845-54.
  • Richard C., Ghibu S., Delemasure-Chalumeau S., Guilland J. C., Des Rosiers C., Zeller M., Cottin Y., Rochette L. and Vergely C. Oxidative stress and myocardial gene alterations associated with Doxorubicin-induced cardiotoxicity in rats persist for 2 months after treatment cessation. J Pharmacol Exp Ther 2011 339(3): 807-14.
  • Richard C., Lauzier B., Delemasure S., Talbot S., Ghibu S., Collin B., Senecal J., Menetrier F., Vergely C., Couture R. and Rochette L. Effects of angiotensin-1 converting enzyme inhibition on oxidative stress and bradykinin receptor expression during doxorubicin-induced cardiomyopathy in rats. Journal of Cardiovascular Pharmacology 2008 52(3): 278-85.
  • Vergely C., Delemasure S., Cottin Y. and Rochette L. Preventing the cardiotoxic effects of anthracyclines: from basic concepts to clinical data. Heart & Metabolism 2007 35: 27-33.
  • Delemasure S., Vergely C., Zeller M., Cottin Y. and Rochette L. Prévention de la cardiotoxicité des anthracyclines : approche fondamentale des mécanismes mis en jeu ; relations avec les données cliniques. Annales de Cardiologie et d'Angéiologie 2006 55(2): 104-12.
  • Cottin Y., L'Huillier I., Casasnovas O., Geoffroy C., Caillot D., Zeller M., Solary E., Guy H. and Wolf J. Dobutamine stress echocardiography identifies anthracycline cardiotoxicity. European Journal of Echocardiography 2000 1(3): 180-3.
  • Dalloz F., Maingon P., Cottin Y., Briot F., Horiot J.-C. and Rochette L. Effects of combined irradiation and doxorubicin treatment on cardiac function and antioxidant defenses in the rat. Free Radical Biology & Medicine 1999 26(7-8): 785-800.
  • Cottin Y., Touzery C., Dalloz F., Coudert B., Toubeau M., Riedinger A., Louis P., Wolf J.-E. and Brunotte F. Comparison of epirubicin and doxorubicin cardiotoxicity induced by low doses: evolution of the diastolic and systolic parameters studied by radionuclide angiography. Clinical Cardiology 1998 21(9): 665-70.
  • Cottin Y., Touzery C., Coudert B., Richebourg S., Toubeau M., Louis P., Wolf J.-E. and Brunotte F. Diastolic or systolic left and right ventricular impairment at moderate dose of anthracycline? A one year follow-up of women. European Journal of Nuclear Medicine 1996 23(5): 511-6.
  • Cottin Y., Touzery C., Coudert B., Gilles A., Walker P. M., Massing J.-L., Toubeau M., Riedinger-Berriolo A., Louis P., Wolf J.-E. and Brunotte F. Impairment of diastolic function during short-term anthracycline chemotherapy. British Heart Journal 1995 73(1): 61-4.
  • Institut National de la Santé Et de la Recherche Médicale
  • Tirets de séparation
  • L'Inserm en région Grand-Est
Support :

Agence Nationale de la Recherche Agrosup Dijon Fondation ARC pour la recherche sur le cancer Cent Pour Sang La Vie CHU Dijon Centre Georges François LECLERC
Conseil Régional de Bourgogne Délégation régionale à la recherche et à la technologie Institut National du Cancer ELA Association Européenne contre les leucodystrophies EPHE : Dijon - Université de Bourgogne Faculté de Médecine de Dijon
UFR Pharmacie - uB, Dijon Fondation de France Fondation pour la Recherche Médicale en France Laboratoire d’excellence - LipSTIC Dijon La Ligue Contre le Cancer Société française d'hématologie