Jeremy Bellien

Centre Hospitalier Universitaire Rouen, Rouen, Haute-Normandie, France

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Publications (51)168.42 Total impact

  • Aurélien Lorthioir, Jérémy Bellien
    Kidney International 04/2015; 87(4):857. DOI:10.1038/ki.2014.421 · 8.52 Impact Factor
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    ABSTRACT: This study addressed the hypothesis that inhibiting the soluble This study addressed the hypothesis that inhibiting the soluble epoxide hydrolase (sEH)-mediated degradation of epoxy-fatty acids, notably epoxyeicosatrienoic acids, has an additional impact against cardiovascular damage in insulin resistance, beyond its previously demonstrated beneficial effect on glucose homeostasis. The cardiovascular and metabolic effects of the sEH inhibitor t-AUCB (10 mg/l in drinking water) were compared to those of the sulfonylurea glibenclamide (80 mg/l), both administered for 8 weeks in FVB mice subjected to a high-fat diet (HFD, 60% fat) for 16 weeks. Mice on control chow diet (10% fat) and non-treated HFD mice served as controls. Glibenclamide and t-AUCB similarly prevented the increased fasting glycemia in HFD mice but only t-AUCB improved glucose tolerance and decreased gluconeogenesis, without modifying weight gain. Moreover, t-AUCB reduced adipose tissue inflammation, plasma free fatty acids and LDL cholesterol, and prevented hepatic steatosis. Furthermore, only the sEH inhibitor improved endothelium-dependent relaxations to acetylcholine, assessed by myography in isolated coronary arteries. This improvement was related to a restoration of epoxyeicosatrienoic acid and nitric oxide pathways, as shown by the increased inhibitory effects of the NO-synthase and cytochrome P450 epoxygenase inhibitors, L-NA and MSPPOH, on these relaxations. Moreover, t-AUCB decreased cardiac hypertrophy, fibrosis and inflammation, and improved diastolic function, as demonstrated by the increased E/A ratio (echocardiography) and decreased slope of the end-diastolic pressure-volume relation (invasive hemodynamics). These results demonstrate that sEH inhibition improves coronary endothelial function and prevents cardiac remodeling and diastolic dysfunction in obese insulin-resistant mice. Copyright © 2014, American Journal of Physiology - Heart and Circulatory Physiology.
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    ABSTRACT: Objective To assess the role of Toll-like receptors (TLRs) in antiphospholipid antibody (aPL)-mediated vascular abnormalities in patients with primary arterial antiphospholipid syndrome (APS).Methods Forty-eight subjects participated in the study. Arterial function and structure and TLR pathway activation were determined in patients with primary arterial APS and matched controls. The pathogenic effects of aPL isolated from patients were assessed in wild-type (WT) and TLR-knockout mice.ResultsAPS patients had endothelial dysfunction, arterial stiffening, and hypertrophy, as evidenced by decreased brachial artery endothelium-dependent flow-mediated dilation (FMD) and increased aortic pulse wave velocity and carotid intima-media thickness (IMT), as compared with controls. Plasma samples from APS patients revealed decreased nitric oxide (NO) availability and a pro-oxidative, proinflammatory, and prothrombotic state illustrated by a decrease in nitrite and an increase in lipid peroxidation, tumor necrosis factor α levels, and tissue factor (TF) levels. Furthermore, TLR pathway activation was found in APS patients with increased TLR-2 and TLR-4 messenger RNA expression and increased protein levels of the activated TLR transduction protein interleukin-1 receptor-associated kinase 1 in peripheral blood mononuclear cells. Moreover, agonist-stimulated cell-surface expression of TLR-2 and TLR-4 in circulating monocytes was higher in APS patients than in controls. These changes were positively associated with IMT and negatively associated with FMD. Finally, aPL injection decreased mesenteric endothelium-dependent relaxation and increased TF expression in WT mice but not in TLR-2- or TLR-4-knockout mice.Conclusion This translational study supports the notion that TLR-2 and TLR-4 play a role in mediating vascular abnormalities in patients with primary arterial APS. TLRs thus constitute a promising pharmacologic target for preventing cardiovascular complications in APS.
    11/2014; 66(11). DOI:10.1002/art.38785
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    ABSTRACT: Numerous autoimmune-inflammatory rheumatic diseases have been associated with accelerated atherosclerosis or other types of vasculopathy leading to an increase in cardiovascular disease incidence. In addition to traditional cardiovascular risk factors, endothelial dysfunction is an important early event in the pathogenesis of atherosclerosis, contributing to plaque initiation and progression. Endothelial dysfunction is characterized by a shift of the actions of the endothelium toward reduced vasodilation, a proinflammatory and a proadhesive state, and prothrombic properties. Therefore, assessment of endothelial dysfunction targets this vascular phenotype using several biological markers as indicators of endothelial dysfunction. Measurements of soluble adhesion molecules (ICAM-1, VCAM-1, E-selectin), pro-thrombotic factors (thrombomodulin, von Willebrand factor, plasminogen activator inhibitor-1) and inflammatory cytokines are most often performed. Regarding the functional assessment of the endothelium, the flow-mediated dilatation of conduit arteries is a non-invasive method widely used in pathophysiological and interventional studies. In this review, we will briefly review the most relevant information upon endothelial dysfunction mechanisms and explorations. We will summarize the similarities and differences in the biological and functional assessments of the endothelium in different autoimmune diseases.
    La Revue de Médecine Interne 08/2014; DOI:10.1016/j.revmed.2013.12.010 · 1.32 Impact Factor
  • Dominique Guerrot, Jeremy Bellien
    Cardiovascular & Haematological Disorders - Drug Targets(Formerly Current Drug Targets - Cardiovascular & Hematological Disorders) 07/2014; 14(1). DOI:10.2174/1871529X1401140724093325
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    ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is a renal hereditary disorder associated with increased cardiovascular mortality, due to mutations in polycystin-1 and polycystin-2 genes. Endothelial polycystin-deficient cells have an altered mechanosensitivity to fluid shear stress and subsequent deficit in calcium-induced nitric oxide release, prevented by dopamine receptor stimulation. However, the impact of polycystin deficiency on endothelial function in ADPKD patients is still largely unknown. Here we assessed endothelium-dependent flow-mediated dilatation in 21 normotensive ADPKD patients and 21 healthy control subjects, during sustained (hand skin heating) and transient (postischemic hyperemia) flow stimulation. Flow-mediated dilatation was less marked in ADPKD patients than in controls during heating, but it was similar during postischemic hyperemia. There was no difference in endothelium-independent dilatation in response to glyceryl trinitrate. Local plasma nitrite, an indicator of nitric oxide availability, increased during heating in controls but not in patients. Brachial infusion of dopamine in a subset of ADPKD patients stimulated plasma nitrite increase during heating and improved flow-mediated dilatation. Thus, ADPKD patients display a loss of nitric oxide release and an associated reduction in endothelium-dependent dilatation of conduit arteries during sustained blood flow increase. The correction of these anomalies by dopamine suggests future therapeutic strategies that could reduce the occurrence of cardiovascular events in ADPKD.Kidney International advance online publication, 16 July 2014; doi:10.1038/ki.2014.241.
    Kidney International 07/2014; DOI:10.1038/ki.2014.241 · 8.52 Impact Factor
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    ABSTRACT: Objective Epoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid, notably in endothelial cells, and display attractive metabolic, vasodilatory and anti-inflammatory properties. We demonstrated previously that inhibiting EET degradation mediated by soluble epoxide hydrolase (sEH) reduces hypertension and heart failure, and others reported that it improves glucose homeostasis in type 2 diabetes. However, the impact of such strategy on target organ damage in diabetes remains to be clarified. Materials and methods The pharmacological sEH inhibitor t-AUCB (10 mg/l in drinking water) was administered for 8 weeks in mice subjected to a high-fat diet (HFD, 60% fat) for 16 weeks. Mice on control chow diet (10% fat), non-treated HFD mice and HFD mice treated with glibenclamide (80 mg/l) served as controls. Results Glibenclamide and t-AUCB similarly prevented the increased fasting glycemia in HFD mice (Control: 5.4±0.2; HFD: 8.0±0.8; HFD+GLI: 5.1±0.3; HFD+t-AUCB: 5.6±0.2 mmol/L; p<0.05). However, only t-AUCB improved glucose tolerance and decreased gluconeogenesis. In parallel, t-AUCB prevented adipose tissue activation and dyslipidemia. Moreover, t-AUCB improved coronary endothelial function and prevented diastolic dysfunction, as shown by echocardiography (E/A ratio; Control: 1.25±0.02; HFD: 1.05±0.03; HFD+GLI: 1.07±0.04; HFD+t-AUCB: 1.23±0.04; p<0.05) and invasive hemodynamics (LVEDPVR; Control: 1.9±0.55; HFD: 3.8±0.61; HFD+GLI: 3.1±0.8; HFD+t- AUCB: 1.88±0.2 mmHg/RVU; p<0.05). Finally, t-AUCB prevented the increased urinary albumine-to-creatinine ratio and decreased renal inflammation. Discussion These results demonstrate that beyond its glucose-lowering effects sEH inhibition improves coronary endothelial function, diastolic dysfunction and prevents early kidney damage in a murine model of type 2 diabetes. This positive impact on target organ damage and metabolic homeostasis prompts sEH inhibition as a promising therapeutic perspective in type 2 diabetes.
    Archives of Cardiovascular Diseases Supplements 04/2014; 6:14. DOI:10.1016/S1878-6480(14)71300-X
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    ABSTRACT: Introduction: Cardiovascular diseases are a leading cause of death in developed countries. Increasing evidence shows that the alteration in the normal functions of the vascular endothelium plays a major role in the development of cardiovascular diseases. However, specific agents designed to prevent endothelial dysfunction and related cardiovascular complications are still lacking. One emerging strategy is to increase the bioavailability of epoxyeicosatrienoic acids (EETs), synthesized by cytochrome P450 epoxygenases from arachidonic acid. EETs are endothelium-derived hyperpolarising and relaxing factors and display attractive anti-inflammatory and metabolic properties. Genetic polymorphism studies in humans, and experiments in animal models of diseases, have identified soluble epoxide hydrolase (sEH), the major enzyme involved in EET degradation, as a potential pharmacological target. Areas covered: This review presents EET pathway and its functions and summarises the data supporting the development of sEH inhibitors for the treatment of cardiovascular and metabolic diseases. Furthermore, the authors present the different chemical families of sEH inhibitors developed and their effects in animal models of cardiovascular and metabolic diseases. Expert opinion: Several generations of sEH inhibitors have now been designed to treat endothelial dysfunction and cardiovascular complications for a variety of diseases. The safety of these drugs remains to be carefully investigated, particularly in relation to carcinogenesis. The increasing knowledge of the biological role of each of the EET isomers and of their metabolites may improve their pharmacological profile. This, in turn, could potentially lead to the identification of new pharmacological agents that achieve the cellular effects needed without the deleterious side effects.
    Expert Opinion on Drug Discovery 02/2014; DOI:10.1517/17460441.2014.881354 · 3.47 Impact Factor
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    ABSTRACT: Numerous autoimmune-inflammatory rheumatic diseases have been associated with accelerated atherosclerosis or other types of vasculopathy leading to an increase in cardiovascular disease incidence. In addition to traditional cardiovascular risk factors, endothelial dysfunction is an important early event in the pathogenesis of atherosclerosis, contributing to plaque initiation and progression. Endothelial dysfunction is characterized by a shift of the actions of the endothelium toward reduced vasodilation, a proinflammatory and a proadhesive state, and prothrombic properties. Therefore, assessment of endothelial dysfunction targets this vascular phenotype using several biological markers as indicators of endothelial dysfunction. Measurements of soluble adhesion molecules (ICAM-1, VCAM-1, E-selectin), pro-thrombotic factors (thrombomodulin, von Willebrand factor, plasminogen activator inhibitor-1) and inflammatory cytokines are most often performed. Regarding the functional assessment of the endothelium, the flow-mediated dilatation of conduit arteries is a non-invasive method widely used in pathophysiological and interventional studies. In this review, we will briefly review the most relevant information upon endothelial dysfunction mechanisms and explorations. We will summarize the similarities and differences in the biological and functional assessments of the endothelium in different autoimmune diseases.
    La Revue de Médecine Interne 01/2014; · 1.32 Impact Factor
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    ABSTRACT: Middle molecular weight uraemic toxins are considered to play an important role in vascular dysfunction and cardiovascular outcomes in end-stage renal disease (ESRD) patients. Recent dialysis techniques based on convection, specifically high-efficiency on-line haemodiafiltration (HDF), enhance the removal of middle molecular weight toxins and reduce all-cause mortality in haemodialysis (HD) patients. However, the mechanisms of these improved outcomes remain to be established. This prospective study randomly assigned 42 ESRD patients to switch from high-flux HD to high-efficiency on-line HDF (n = 22) or to continue HD (n = 20). Brachial artery endothelium-dependent flow-mediated dilatation, central pulse pressure, carotid artery intima-media thickness (IMT), internal diastolic diameter and distensibility and circulating markers of uraemia, inflammation and oxidative stress were blindly assessed before and after a 4-month follow-up. Brachial flow-mediated dilatation and carotid artery distensibility increased significantly in the HDF group compared with HD, while carotid IMT and diameter remained similar. HDF decreased predialysis levels of the uraemic toxins β2-microglobulin, phosphate and blood TNFα mRNA expression. Oxidative stress markers were not different between the HD and HDF groups. Blood mRNA expression of protein kinase C β2, an endothelial NO-synthase (eNOS) inhibitor, decreased significantly with HDF. High-efficiency on-line HDF prevents the endothelial dysfunction and stiffening of the conduit arteries in ESRD patients compared with high-flux HD. HDF decreases uraemic toxins, vascular inflammation, and is associated with subsequent improvement in eNOS functionality. These results suggest that reduced endothelial dysfunction may be an intermediate mechanism explaining the beneficial outcomes associated with HDF.
    Nephrology Dialysis Transplantation 11/2013; DOI:10.1093/ndt/gft448 · 3.49 Impact Factor
  • Néphrologie & Thérapeutique 09/2013; 9(5):275. DOI:10.1016/j.nephro.2013.07.178 · 0.55 Impact Factor
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    ABSTRACT: AimsCommon carotid artery intima-media thickness (CCIMT) is widely used as a surrogate marker of atherosclerosis, given its predictive association with cardiovascular disease (CVD). The interpretation of CCIMT values has been hampered by the absence of reference values, however. We therefore aimed to establish reference intervals of CCIMT, obtained using the probably most accurate method at present (i.e. echotracking), to help interpretation of these measures.Methods and resultsWe combined CCIMT data obtained by echotracking on 24 871 individuals (53% men; age range 15-101 years) from 24 research centres worldwide. Individuals without CVD, cardiovascular risk factors (CV-RFs), and BP-, lipid-, and/or glucose-lowering medication constituted a healthy sub-population (n = 4234) used to establish sex-specific equations for percentiles of CCIMT across age. With these equations, we generated CCIMT Z-scores in different reference sub-populations, thereby allowing for a standardized comparison between observed and predicted ('normal') values from individuals of the same age and sex. In the sub-population without CVD and treatment (n = 14 609), and in men and women, respectively, CCIMT Z-scores were independently associated with systolic blood pressure [standardized βs 0.19 (95% CI: 0.16-0.22) and 0.18 (0.15-0.21)], smoking [0.25 (0.19-0.31) and 0.11 (0.04-0.18)], diabetes [0.19 (0.05-0.33) and 0.19 (0.02-0.36)], total-to-HDL cholesterol ratio [0.07 (0.04-0.10) and 0.05 (0.02-0.09)], and body mass index [0.14 (0.12-0.17) and 0.07 (0.04-0.10)].Conclusion We estimated age- and sex-specific percentiles of CCIMT in a healthy population and assessed the association of CV-RFs with CCIMT Z-scores, which enables comparison of IMT values for (patient) groups with different cardiovascular risk profiles, helping interpretation of such measures obtained both in research and clinical settings.
    European Heart Journal 08/2013; 34(30):2368-80. DOI:10.1093/eurheartj/ehs380 · 14.72 Impact Factor
  • La Revue de Médecine Interne 12/2012; 33:A31–A32. DOI:10.1016/j.revmed.2012.10.019 · 1.32 Impact Factor
  • Artery Research 12/2012; 6(4):144. DOI:10.1016/j.artres.2012.09.018
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    ABSTRACT: In young healthy subjects, epoxyeicosatrienoic acids synthesized by endothelial cytochrome P450 epoxygenases maintain basal conduit artery diameter during altered NO availability. Whether this compensatory mechanism is effective during essential hypertension is unknown. Radial artery diameter, blood flow, and mean wall shear stress were determined in 14 nontreated essential hypertensive patients and 14 normotensive control subjects during 8 minutes of brachial infusion for inhibitors of cytochrome P450 epoxygenases (fluconazole, 0.4 µmol/min) and NO synthase (N(G)-monomethyl-l-arginine, 8 µmol/min) alone and in combination. In controls, the radial artery diameter was reduced by fluconazole (-0.034 ± 0.012 mm) and N(G)-monomethyl-l-arginine (-0.037 ± 0.010 mm) and to a larger extent by their combination (-0.137 ± 0.011 mm), demonstrating a synergic effect. In contrast, the radial diameter in hypertensive patients was not affected by fluconazole (0.010 ± 0.014 mm) but was reduced by N(G)-monomethyl-l-arginine (-0.091 ± 0.008 mm) to a larger extent than in controls. In parallel, N(G)-monomethyl-l-arginine decreased local plasma nitrite to a lesser extent in hypertensive patients (-14 ± 5 nmol/L) than in controls (-50 ± 10 nmol/L). Moreover, the addition of fluconazole to N(G)-monomethyl-l-arginine did not further decrease radial diameter in patients (-0.086 ± 0.011 mm). Accordingly, fluconazole significantly decreased local epoxyeicosatrienoic acid plasma level in controls (-2.0 ± 0.6 ng/mL) but not in patients (-0.9 ± 0.4 ng/mL). Inhibitors effects on blood flow and endothelium-independent dilatation to sodium nitroprusside were similar between groups. These results show that, in contrast to normotensive subjects, epoxyeicosatrienoic acids did not contribute to the regulation of basal conduit artery diameter and did not compensate for altered NO availability to maintain this diameter in essential hypertensive patients.
    Hypertension 10/2012; 60(6). DOI:10.1161/HYPERTENSIONAHA.112.201087 · 7.63 Impact Factor
  • Jeremy Bellien, Robinson Joannides
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    ABSTRACT: In response to endothelial cell activation, arachidonic acid can be converted by cytochrome P450 (CYP) epoxygenases to epoxyeicosatrienoic acids (EETs), which have potent vasodilator and anti-inflammatory properties. EETs are rapidly degraded in vivo to the less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). Since the beginning of the 2000's, the role of EET pathway in human health and its alteration in diseases has been shown by measuring EETs/DHET levels in blood, by evaluating the relationship between CYP/sEH gene polymorphisms, which modify enzyme activity and thus EETs/DHET level, and by assessing the inhibitory effect of the local administration of CYP epoxygenase inhibitor on endothelium-dependent dilatation. By combining these functional and biological approaches, we demonstrated that EETs are the endothelial factors released by CYP epoxygenases involved in the flow-mediated dilatation of conduit arteries in healthy subjects, together with the impairment of EET availability in essential hypertensive patients at this level. The modulation of EET pathway now emerges as a new promising pharmacological target that may improve the clinical management of patients at high cardiovascular risk. In this respect, the restoration of EET availability using a new class of agents, the inhibitors of sEH, gave promising results in various animal models of cardiovascular diseases, reducing blood pressure and target organ damage, and a first product has entered clinical evaluation.
    Journal of cardiovascular pharmacology 09/2012; DOI:10.1097/FJC.0b013e318273b007 · 2.11 Impact Factor
  • Journal des Maladies Vasculaires 09/2012; 33:S54–S55. DOI:10.1016/j.revmed.2012.03.042 · 0.24 Impact Factor
  • Journal des Maladies Vasculaires 09/2012; 37(5):257. DOI:10.1016/j.jmv.2012.07.048 · 0.24 Impact Factor
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    ABSTRACT: The incidence of cardiovascular diseases remains high in diabetic patients despite the optimization of blood glucose control and the therapeutic management of risk factors. One emerging promising pharmacological approach that may help to prevent the development of diabetic cardiovascular complications is to improve endothelial function through the restoration of the bioavailability of epoxyeicosatrienoic acids (EETs). EETs are crucial eicosanoid signaling molecules synthesized by cytochrome P450 epoxygenases in the vascular endothelium and in pancreatic islets. EETs promote vasodilatation and display attractive anti-inflammatory and anti-aggregating actions together with potent effects on insulin release and sensitivity. In animal models of insulin-resistance and diabetes, a decrease in EET availability has been reported, and is a deleterious mechanism that probably contributes to multiple metabolic, cardiovascular and renal disorders in this setting. Moreover, increasing experimental evidence suggest that the use of soluble epoxide hydrolase (sEH) inhibitors, which prevent EET degradation, is a promising pharmacological approach to prevent endothelial dysfunction and to protect against target organ damage in metabolic diseases. This review presents evidence that the EET pathway is disturbed from the early stages of metabolic diseases, and analyzes the potential contribution of EETs impairment to the progression of cardiovascular diseases associated with diabetes. Pathophysiological and therapeutic perspectives are thereafter discussed, including the necessity to demonstrate the role of EET pathway alterations in endothelial dysfunction associated with diabetes in human, and the interest of sEH inhibitors to prevent the development of diabetic cardiovascular complications, with the expected result of improving patients' health.
    Cardiovascular & hematological agents in medicinal chemistry 05/2012; 10(3):212-22. DOI:10.2174/187152512802651042
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    ABSTRACT: We sought to clarify, using functional and biological approaches, the role of epoxyeicosatrienoic acids, nitric oxide (NO)/reactive oxygen species balance, and endothelin-1 in conduit artery endothelial dysfunction during essential hypertension. Radial artery diameter and mean wall shear stress were determined in 28 untreated patients with essential hypertension and 30 normotensive control subjects during endothelium-dependent flow-mediated dilatation induced by hand skin heating. The role of epoxyeicosatrienoic acids and NO was assessed with the brachial infusion of inhibitors of cytochrome P450 epoxygenases (fluconazole) and NO synthase (N(G)-monomethyl-l-arginine [L-NMMA]). Compared with controls, hypertensive patients exhibited a decreased flow-mediated dilatation in response to postischemic hyperemia as well as to heating, as shown by the lesser slope of their diameter-shear stress relationship. In controls, heating-induced flow-mediated dilatation was reduced by fluconazole, L-NMMA, and, to a larger extent, by L-NMMA+fluconazole. In patients, flow-mediated dilatation was not affected by fluconazole and was reduced by L-NMMA and L-NMMA+fluconazole to a lesser extent than in controls. Furthermore, local plasma epoxyeicosatrienoic acids increased during heating in controls (an effect diminished by fluconazole) but not in patients. Plasma nitrite, an indicator of NO availability, increased during heating in controls (an effect abolished by L-NMMA) and, to a lesser extent, in patients, whereas, inversely, reactive oxygen species increased more in patients (an effect diminished by L-NMMA). Plasma endothelin-1 decreased during heating in controls but not in patients. These results show that an impaired role of epoxyeicosatrienoic acids contributes, together with an alteration in NO/reactive oxygen species balance and endothelin-1 pathway, to conduit artery endothelial dysfunction in essential hypertension. https://www.eudract.ema.europa.eu. Unique identifier: RCB2007-A001-10-53.
    Circulation 03/2012; 125(10):1266-75. DOI:10.1161/CIRCULATIONAHA.111.070680 · 14.95 Impact Factor

Publication Stats

391 Citations
168.42 Total Impact Points

Institutions

  • 2005–2015
    • Centre Hospitalier Universitaire Rouen
      Rouen, Haute-Normandie, France
  • 2008–2014
    • Université de Rouen
      Mont-Saint-Aignan, Haute-Normandie, France
  • 2007–2014
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2012
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2009
    • Universität zu Lübeck
      Lübeck Hansestadt, Schleswig-Holstein, Germany