Publications by authors named "Isabelle Remy-Jouet"

33 Publications

Transient heart rate reduction improves acute decompensated heart failure-induced left ventricular and coronary dysfunction.

ESC Heart Fail 2021 Apr 20;8(2):1085-1095. Epub 2021 Jan 20.

Normandie Université, UNIROUEN, Inserm U1096 Endothelium, Valvulopathy and Heart Failure, Rouen, 76183, France.

Aims: Acute decompensated heart failure (ADHF), a live-threatening complication of heart failure (HF), associates a further decrease of the already by HF-impaired cardiac function with an increase in heart rate. We evaluated, using a new model of ADHF, whether heart rate reduction (HRR) opposes the acute decompensation-related aggravation of cardiovascular dysfunction.

Methods And Results: Cardiac output (echocardiography), cardiac tissue perfusion (magnetic resonance imaging), pulmonary wet weight, and in vitro coronary artery relaxation (Mulvany) were assessed 1 and 14 days after acute decompensation induced by salt-loading (1.8 g/kg, PO) in rats with well-established HF due to coronary ligation. HRR was induced by administration of the I current inhibitor S38844, 12 mg/kg PO twice daily for 2.5 days initiated 12 h or 6 days after salt-loading (early or delayed treatment, respectively). After 24 h, salt-loading resulted in acute decompensation, characterized by a reduction in cardiac output (HF: 130 ± 5 mL/min, ADHF: 105 ±  8 mL/min; P < 0.01), associated with a decreased myocardial perfusion (HF: 6.41 ± 0.53 mL/min/g, ADHF: 4.20 ± 0.11 mL/min/g; P < 0.01), a slight increase in pulmonary weight (HF: 1.68 ± 0.09 g, ADHF: 1.81 ± 0.15 g), and impaired coronary relaxation (HF: 55 ± 1% of pre-contraction at acetylcholine 4.5 10  M, ADHF: 27 ± 7 %; P < 0.01). Fourteen days after salt-loading, cardiac output only partially recovered (117 ± 5 mL/min; P < 0.05), while myocardial tissue perfusion (4.51 ± 0.44 mL/min; P < 0.01) and coronary relaxation (28 ± 4%; P < 0.01) remained impaired, but pulmonary weight further increased (2.06 ± 0.15 g, P < 0.05). Compared with untreated ADHF, HRR induced by S38844 improved cardiac output (125 ± 1 mL/min; P < 0.05), myocardial tissue perfusion (6.46 ± 0.42 mL/min/g; P < 0.01), and coronary relaxation (79 ± 2%; P < 0.01) as soon as 12 h after S38844 administration. These effects persisted beyond S38844 administration, illustrated by the improvements in cardiac output (130 ± 6 mL/min; P < 0.05), myocardial tissue perfusion (6.38 ± 0.48 mL/min/g; P < 0.01), and coronary relaxation (71 ± 4%; P < 0.01) at Day 14. S38844 did not modify pulmonary weight at Day 1 (1.78 ± 0.04 g) but tended to decrease pulmonary weight at Day 14 (1.80 ± 0.18 g). While delayed HRR induced by S38844 never improved cardiac function, early HRR rendered less prone to a second acute decompensation.

Conclusions: In a model mimicking human ADHF, early, but not delayed, transient HRR induced by the I current inhibitor S38844 opposes acute decompensation by preventing the decompensated-related aggravation of cardiovascular dysfunction as well as the development of pulmonary congestion, and these protective effects persist beyond the transient treatment. Whether early transient HRR induced by I current inhibitors or other bradycardic agents, i.e. beta-blockers, exerts beneficial effects in human ADHF warrants further investigation.
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http://dx.doi.org/10.1002/ehf2.13094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006644PMC
April 2021

Short-and long-term administration of imeglimin counters cardiorenal dysfunction in a rat model of metabolic syndrome.

Endocrinol Diabetes Metab 2020 Jul 16;3(3):e00128. Epub 2020 Apr 16.

UNIROUEN Inserm U1096 FHU-REMOD-VHF Normandie Univ Rouen France.

Introduction: Imeglimin, a glucose-lowering agent targeting mitochondrial bioenergetics, decreases reactive oxygen species (ROS) overproduction and improves glucose homeostasis. We investigated whether this is associated with protective effects on metabolic syndrome-related left ventricular (LV) and vascular dysfunctions.

Methods: We used Zucker rats to assess the effects on LV function, LV tissue perfusion, LV oxidative stress and vascular function induced by imeglimin administered orally for 9 or 90 days at a dose of 150 mg/kg twice daily.

Results: Compared to untreated animals, 9- and 90-day imeglimin treatment decreased LV end-diastolic pressure and LV end-diastolic pressure-volume relation, increased LV tissue perfusion and decreased LV ROS production. Simultaneously, imeglimin restored acetylcholine-mediated coronary relaxation and mesenteric flow-mediated dilation. One hour after imeglimin administration, when glucose plasma levels were not yet modified, imeglimin reduced LV mitochondrial ROS production and improved LV function. Ninety-day imeglimin treatment reduced related LV and kidney fibrosis and improved kidney function.

Conclusion: In a rat model, mimicking Human metabolic syndrome, imeglimin immediately countered metabolic syndrome-related cardiac diastolic and vascular dysfunction by reducing oxidative stress/increased NO bioavailability and improving myocardial perfusion and after 90-day treatment myocardial and kidney structure, effects that are, at least in part, independent from glucose control.
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http://dx.doi.org/10.1002/edm2.128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375119PMC
July 2020

Beneficial Effects of Remifentanil Against Excitotoxic Brain Damage in Newborn Mice.

Front Neurol 2019 24;10:407. Epub 2019 Apr 24.

INSERM U1245, Genetics and Pathophysiology of Neurodevelopment Disorders Team, Faculty of Medicine, Institute of Research and Innovation in Biomedicine, Normandy University, Rouen, France.

Remifentanil, a synthetic opioid used for analgesia during cesarean sections, has been shown in experiments to exert anti-apoptotic activity on immature mice brains. The present study aimed to characterize the impact of remifentanil on brain lesions using an model of excitotoxic neonatal brain injury. Postnatal day 2 (P2) mice received three intraperitoneal injections of remifentanil (500 ng/g over a 10-min period) or saline just before an intracortical injection of ibotenate (10 μg). Cerebral reactive oxygen species (ROS) production, cell death, labeling of cortical caspase activity, astrogliosis, inflammation mediators, and lesion size were determined at various time points after ibotenate injection. Finally, behavioral tests were performed until P18. In the injured neonatal brain, remifentanil significantly decreased ROS production, cortical caspase activity, DNA fragmentation, interleukin-1β levels, and reactive astrogliosis. At P7, the sizes of the ibotenate-induced lesions were significantly reduced by remifentanil treatment. Performance on negative geotaxis (P6-8) and grasping reflex (P10-12) tests was improved in the remifentanil group. At P18, a sex specificity was noticed; remifentanil-treated females spent more time in the open field center than did the controls, suggesting less anxiety in young female mice. exposure to remifentanil exerts a beneficial effect against excitotoxicity on the developing mouse brain, which is associated with a reduction in the size of ibotenate-induced brain lesion as well as prevention of some behavioral deficits in young mice. The long-term effect of neonatal exposure to remifentanil should be investigated.
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http://dx.doi.org/10.3389/fneur.2019.00407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491788PMC
April 2019

Altered bioavailability of epoxyeicosatrienoic acids is associated with conduit artery endothelial dysfunction in type 2 diabetic patients.

Cardiovasc Diabetol 2019 03 18;18(1):35. Epub 2019 Mar 18.

Department of Pharmacology, Rouen University Hospital, 76000, Rouen Cedex, France.

Background: This pathophysiological study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes the vasodilator and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), contributes to conduit artery endothelial dysfunction in type 2 diabetes.

Methods And Results: Radial artery endothelium-dependent flow-mediated dilatation in response to hand skin heating was reduced in essential hypertensive patients (n = 9) and type 2 diabetic subjects with (n = 19) or without hypertension (n = 10) compared to healthy subjects (n = 36), taking into consideration cardiovascular risk factors, flow stimulus and endothelium-independent dilatation to glyceryl trinitrate. Diabetic patients but not non-diabetic hypertensive subjects displayed elevated whole blood reactive oxygen species levels and loss of NO release during heating, assessed by measuring local plasma nitrite variation. Moreover, plasma levels of EET regioisomers increased during heating in healthy subjects, did not change in hypertensive patients and decreased in diabetic patients. Correlation analysis showed in the overall population that the less NO and EETs bioavailability increases during heating, the more flow-mediated dilatation is reduced. The expression and activity of sEH, measured in isolated peripheral blood mononuclear cells, was elevated in diabetic but not hypertensive patients, leading to increased EETs conversion to DHETs. Finally, hyperglycemic and hyperinsulinemic euglycemic clamps induced a decrease in flow-mediated dilatation in healthy subjects and this was associated with an altered EETs release during heating.

Conclusions: These results demonstrate that an increased EETs degradation by sEH and altered NO bioavailability are associated with conduit artery endothelial dysfunction in type 2 diabetic patients independently from their hypertensive status. The hyperinsulinemic and hyperglycemic state in these patients may contribute to these alterations. Trial registration NCT02311075. Registered December 8, 2014.
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http://dx.doi.org/10.1186/s12933-019-0843-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423843PMC
March 2019

The IL-1β Antibody Gevokizumab Limits Cardiac Remodeling and Coronary Dysfunction in Rats With Heart Failure.

JACC Basic Transl Sci 2017 Aug 28;2(4):418-430. Epub 2017 Aug 28.

INSERM U1096, Rouen, France.

This study reports preclinical data showing that the interleukin (IL)-1β modulation is a new promising target in the pathophysiological context of heart failure. Indeed, in nondiabetic Wistar and diabetic Goto-Kakizaki rats with chronic heart failure induced by myocardial infarction, administration of the IL-1β antibody gevokizumab improves 'surrogate' markers of survival (i.e., left ventricular remodeling, hemodynamics, and function as well as coronary function). However, whether IL-1β modulation per se or in combination with standard treatments of heart failure improves long-term outcome in human heart failure remains to be determined.
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http://dx.doi.org/10.1016/j.jacbts.2017.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034492PMC
August 2017

Alteration in the availability of epoxyeicosatrienoic acids contributes with NO to the development of endothelial dysfunction in conduit arteries during aging.

Atherosclerosis 2018 08 19;275:239-245. Epub 2018 Jun 19.

Department of Pharmacology, CHU de Rouen, 76000, Rouen, France; INSERM U1096, Normandie University, UNIROUEN, 76000, Rouen, France; Centre d'Investigation Clinique (CIC)-INSERM 1404, CHU de Rouen, 76000, Rouen, France. Electronic address:

Background And Aims: The mechanisms involved in endothelial dysfunction in humans during aging are largely unknown at the level of conduit arteries. We aimed to asses the role of NO and CYP450 epoxygenases-derived epoxyeicosatrienoic acids (EETs) in the regulation of endothelium-dependent flow-mediated dilatation of conduit arteries during aging.

Methods: Radial artery diameter and mean wall shear stress were determined by echotracking coupled with Doppler in 83 subjects (19-71 years old) during a sustained flow increase induced by hand skin heating, with the brachial infusion of saline or NO-synthase and cytochrome P450 epoxygenase inhibitors (L-NNMA and fluconazole respectively). Local blood sampling was performed for the quantification of NO metabolite nitrite and EETs.

Results: The magnitude of flow-mediated dilatation was independently and negatively correlated with age, baseline artery diameter and systolic blood pressure, and positively correlated with the increase in shear stress induced by heating. There was an increase in nitrite level during heating until the age of 35-40 years, which declined thereafter. However, the inhibitory effect of L-NMMA on flow-mediated dilatation progressively decreased during aging, demonstrating a decrease in functional NO availability. Moreover, aging progressively reduced the increase in EET level during heating as well as the inhibitory effect of fluconazole on flow-mediated dilatation.

Conclusions: These results show that aging impairs the availability of EETs and NO and epoxyeicosatrienoic acids in peripheral conduit arteries, contributing to the development of endothelial dysfunction.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.06.865DOI Listing
August 2018

Short- and long-term administration of the non-steroidal mineralocorticoid receptor antagonist finerenone opposes metabolic syndrome-related cardio-renal dysfunction.

Diabetes Obes Metab 2018 10 27;20(10):2399-2407. Epub 2018 Jun 27.

Normandie Univ, UNIROUEN, Institut National de la Santé et de la Recherche Médicale U1096, FHU- REMOD-VHF, 76000 Rouen, France.

Aim: To determine whether non-steroidal mineralocorticoid receptor (MR) antagonists oppose metabolic syndrome-related end-organ, i.e. cardiac, damage.

Materials And Methods: In Zucker fa/fa rats, a rat model of metabolic syndrome, we assessed the effects of the non-steroidal MR antagonist finerenone (oral 2 mg/kg/day) on left ventricular (LV) function, haemodynamics and remodelling (using echocardiography, magnetic resonance imaging and biochemical methods).

Results: Long-term (90 days) finerenone modified neither systolic blood pressure nor heart rate, but reduced LV end-diastolic pressure and LV end-diastolic pressure-volume relationship, without modifying LV end-systolic pressure and LV end-systolic pressure-volume relationship. Simultaneously, long-term finerenone reduced both LV systolic and diastolic diameters, associated with reductions in LV weight and LV collagen density, while proteinuria and renal nGAL expression were reduced. Short-term (7 days) finerenone improved LV haemodynamics and reduced LV systolic diameter, without modifying LV diastolic diameter. Moreover, short-term finerenone increased myocardial tissue perfusion and reduced myocardial reactive oxygen species, while plasma nitrite levels, an indicator of nitric oxide (NO) bio-availability, were increased.

Conclusions: In rats with metabolic syndrome, the non-steroidal MR antagonist finerenone opposed metabolic syndrome-related diastolic cardiac dysfunction and nephropathy. This involved acute effects, such as improved myocardial perfusion, reduced oxidative stress/increased NO bioavailability, as well as long-term effects, such as modifications in the myocardial structure.
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http://dx.doi.org/10.1111/dom.13393DOI Listing
October 2018

Protein tyrosine phosphatase 1B inactivation limits aging-associated heart failure in mice.

Am J Physiol Heart Circ Physiol 2018 06 23;314(6):H1279-H1288. Epub 2018 Mar 23.

Normandie University UNIROUEN, Institut National de la Santé et de la Recherche Médicale U1096 , Rouen , France.

We have previously shown that protein tyrosine phosphatase 1B (PTP1B) inactivation in mice [PTP1B-deficient (PTP1B) mice] improves left ventricular (LV) angiogenesis, perfusion, remodeling, and function and limits endothelial dysfunction after myocardial infarction. However, whether PTP1B inactivation slows aging-associated cardiovascular dysfunction remains unknown. Wild-type (WT) and PTP1B mice were allowed to age until 18 mo. Compared with old WT mice, in which aging increased the LV mRNA expression of PTP1B, old PTP1B mice had 1) reduced cardiac hypertrophy with decreased LV mRNA levels of hypertrophic markers and atrial and brain natriuretic peptides, 2) lower LV fibrosis (collagen: 16 ± 3% in WT mice and 5 ± 3% in PTP1B mice, P < 0.001) with decreased mRNA levels of transforming growth-factor-β and matrix metalloproteinase-2, and 3) higher LV capillary density and lower LV mRNA level of hypoxic inducible factor-1α, which was associated over time with a higher rate of proangiogenic M2 type macrophages and a stable LV mRNA level of VEGF receptor-2. Echocardiography revealed an age-dependent LV increase in end-diastolic volume in WT mice together with alterations of fractional shortening and diastole (transmitral Doppler E-to-A wave ratio). Invasive hemodynamics showed better LV systolic contractility and better diastolic compliance in old PTP1B mice (LV end-systolic pressure-volume relation: 13.9 ± 0.9 in WT mice and 18.4 ± 1.6 in PTP1B mice; LV end-diastolic pressure-volume relation: 5.1 ± 0.8 mmHg/relative volume unit in WT mice and 1.2 ± 0.3 mmHg/relative volume unit in PTP1B mice, P < 0.05). In addition, old PTP1B mice displayed a reduced amount of LV reactive oxygen species. Finally, in isolated resistance mesenteric arteries, PTP1B inactivation reduced aging-associated endothelial dysfunction (flow-mediated dilatation: -0.4 ± 2.1% in WT mice and 8.2 ± 2.8% in PTP1B mice, P < 0.05). We conclude that PTP1B inactivation slows aging-associated LV remodeling and dysfunction and reduces endothelial dysfunction in mesenteric arteries. NEW & NOTEWORTHY The present study shows that protein tyrosine phosphatase 1B inactivation in aged mice improves left ventricular systolic and diastolic function associated with reduced adverse cardiac remodeling (hypertrophy, fibrosis, and capillary rarefaction) and limits vascular endothelial dysfunction. This suggests that protein tyrosine phosphatase 1B inhibition could be an interesting treatment approach in age-related cardiovascular dysfunction.
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http://dx.doi.org/10.1152/ajpheart.00049.2017DOI Listing
June 2018

Evidence for a Role of Vascular Endothelium in the Control of Arterial Wall Viscosity in Humans.

Hypertension 2018 01 20;71(1):143-150. Epub 2017 Nov 20.

From the Department of Pharmacology, Rouen University Hospital, France (F.R., M.I., J.B., R.J.); Inserm U1096, Normandie Univ, UNIROUEN, France (F.R., M.I., I.R.-J., J.B., R.J.); Institute for Research and Innovation in Biomedicine, University of Rouen, France (F.R., I.R.-J., J.B., R.J.); and Clinical Investigation Center CIC-CRB 1404, Rouen University Hospital, France (F.R., J.B., R.J.).

Arterial wall viscosity (AWV) is a major cause of energy dissipation along the arterial tree. Its determinants remain controversial but an active endothelial regulation has been suggested. Our objective was to assess in humans the physiological role of endothelium-derived nitric oxide (NO), epoxyeicosatrienoic acids and the effect of modulating smooth muscle tone in the regulation of AWV. We simultaneously measured radial artery diameter, wall thickness, and arterial pressure in healthy volunteers during the local infusion of inhibitors of NO-synthase (-monomethyl-l-arginine), epoxyeicosatrienoic acids synthesis by cytochrome P450 (fluconazole), the epoxyeicosatrienoic acids cellular targets calcium-activated potassium channels (tetraethylammonium), alone and in combination. AWV was estimated from the relative viscosity expressed as the ratio of the area of the hysteresis loop of the pressure-diameter relationship to the area under the loading phase. Arterial tone was assessed by measuring change in wall stiffness and midwall stress. -monomethyl-l-arginine paradoxically reduced relative viscosity (34.9±8.9%-28.9±8.6%). Conversely, relative viscosity was not modified by fluconazole (33.5±15.5%-32.0±13.6%) but increased by tetraethylammonium (31.7±6.6%-35.7±8.0%). This increase was more marked with -monomethyl-l-arginine+fluconazole (31.1±10.7%-43.3±13.2%) and -monomethyl-l-arginine+tetraethylammonium (29.5±2.3%-41.5±11.1%) compared with inhibitors alone. Sodium nitroprusside decreased AWV (35.4±2.9%-28.7±2.0%). These effects were associated with parallel change in tone but of different magnitude for similar variations in viscosity, suggesting tone-dependent and independent mechanisms. In conclusion, this is the first demonstration that the endothelial factors, NO and epoxyeicosatrienoic acids, regulate AWV in humans and support the role of arterial tone in this regulation.

Clinical Trial Registration: URL: https://eudract.ema.europa.eu. Unique identifier: RCB2007-A001-10-53.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.09870DOI Listing
January 2018

Heterologous expression of the N-acetylglucosaminyltransferase I dictates a reinvestigation of the N-glycosylation pathway in Chlamydomonas reinhardtii.

Sci Rep 2017 08 31;7(1):10156. Epub 2017 Aug 31.

Normandie Univ, UNIROUEN, Laboratoire Glycobiologie et Matrice Extracellulaire végétale, EA 4358, 76000, Rouen, France.

Eukaryotic N-glycosylation pathways are dependent of N-acetylglucosaminyltransferase I (GnTI), a key glycosyltransferase opening the door to the formation of complex-type N-glycans by transferring a N-acetylglucosamine residue onto the ManGlcNAc intermediate. In contrast, glycans N-linked to Chlamydomonas reinhardtii proteins arise from a GnTI-independent Golgi processing of oligomannosides giving rise to ManGlcNAc substituted eventually with one or two xylose(s). Here, complementation of C. reinhardtii with heterologous GnTI was investigated by expression of GnTI cDNAs originated from Arabidopsis and the diatom Phaeodactylum tricornutum. No modification of the N-glycans was observed in the GnTI transformed cells. Consequently, the structure of the ManGlcNAc synthesized by C. reinhardtii was reinvestigated. Mass spectrometry analyses combined with enzyme sequencing showed that C. reinhardtii proteins carry linear ManGlcNAc instead of the branched structure usually found in eukaryotes. Moreover, characterization of the lipid-linked oligosaccharide precursor demonstrated that C. reinhardtii exhibit a GlcManGlcNAc dolichol pyrophosphate precursor. We propose that this precursor is then trimmed into a linear ManGlcNAc that is not substrate for GnTI. Furthermore, cells expressing GnTI exhibited an altered phenotype with large vacuoles, increase of ROS production and accumulation of starch granules, suggesting the activation of stress responses likely due to the perturbation of the Golgi apparatus.
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http://dx.doi.org/10.1038/s41598-017-10698-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578997PMC
August 2017

Holaphyllamine, a steroid, is able to induce defense responses in Arabidopsis thaliana and increases resistance against bacterial infection.

Planta 2017 Dec 16;246(6):1109-1124. Epub 2017 Aug 16.

Normandie Univ, UniRouen, Laboratoire Glycobiologie et Matrice Extracellulaire végétale, SFR Normandie Végétal, 76000, Rouen, France.

Main Conclusion: A chemical screen of plant-derived compounds identified holaphyllamine, a steroid, able to trigger defense responses in Arabidopsis thaliana and improve resistance against the pathogenic bacterium Pseudomonas syringae pv tomato DC3000. A chemical screen of 1600 plant-derived compounds was conducted and allowed the identification of a steroid able to activate defense responses in A. thaliana at a concentration of 1 µM without altering growth. The identified compound is holaphyllamine (HPA) whose chemical structure is similar to steroid pregnanes of mammals. Our data show that HPA, which is not constitutively present in A. thaliana, is able to trigger the formation of reactive oxygen species, deposition of callose and expression of several pathogenesis-related genes of the salicylic and jasmonic acid pathways. In addition, the results show that pre-treatment of A. thaliana seedlings with HPA before infection with the pathogenic bacterium Pseudomonas syringae pv tomato DC3000 results in a significant reduction of symptoms (i.e., reduction of bacterial colonies). Using A. thaliana mutants, we have found that the activation of defense responses by HPA does not depend on BRI1/BAK1 receptor kinases. Finally, a structure/function study reveals that the minimal structure required for activity is a 5-pregnen-20-one steroid with an equatorial nucleophilic group in C-3. Together, these findings demonstrate that HPA can activate defense responses that lead to improved resistance against bacterial infection in A. thaliana.
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http://dx.doi.org/10.1007/s00425-017-2755-zDOI Listing
December 2017

Physiological role of endothelin-1 in flow-mediated vasodilatation in humans and impact of cardiovascular risk factors.

J Hypertens 2017 06;35(6):1204-1212

aDepartment of Pharmacology, Rouen University HospitalbInstitut National de la Santé et de la Recherche Médicale (INSERM) U1096cInstitute for Research and Innovation in Biomedicine, Normandy University, University of RouendCentre d'Investigation Clinique (CIC)-INSERM 1404, Rouen University HospitaleEquipe d'Accueil (EA) 4651, Rouen, France.

Objectives: The current study addressed the hypothesis that the local decrease in endothelin-1 (ET-1) bioavailability during sustained flow increases contributes to endothelium-dependent, flow-mediated dilatation (FMD) of conduit arteries and is altered in presence of cardiovascular risk factors.

Methods And Results: In nine young healthy individuals, the decrease in local ET-1 plasma levels and radial artery FMD in response to hand skin heating (from 34 to 44 °C) was not affected by endothelin type A (ETA) receptor blockade, achieved using the brachial infusion of BQ-123 (100 nmol/min per l of forearm), as compared with physiological saline (0.9% NaCl) infusion. In contrast, endothelin type B (ETB) receptor blockade with BQ-788 (10 nmol/min per l) suppressed the decrease in plasma ET-1 during heating and reduced FMD, without altering nitric oxide release. The coinfusion of BQ-123 did not affect the inhibitory effect of ETB receptor blockade on the decrease in ET-1 plasma levels during heating but prevented the reduction in FMD. Basal radial artery parameters, systemic hemodynamics, and endothelium-independent dilatation to glyceryl trinitrate were not modified by ETA and/or ETB blockade. In a general population of 40 participants without treatment or major cardiovascular diseases, including the nine healthy individuals, the reduction in endothelin-1 level during heating was correlated with FMD (r = -0.55, P < 0.001) and decreased with increased age (r = 0.49, P = 0.001), mean arterial blood pressure (r = 0.48, P = 0.002), and total cholesterol level (r = 0.37, P = 0.024).

Conclusion: The uptake of endothelin-1 by ETB receptors contributes to conduit artery FMD, preventing its vasoconstrictor action mediated by ETA receptors. The alteration of this mechanism by cardiovascular risk factors may contribute to endothelial dysfunction.
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http://dx.doi.org/10.1097/HJH.0000000000001307DOI Listing
June 2017

Endotoxemia Engages the RhoA Kinase Pathway to Impair Cardiac Function By Altering Cytoskeleton, Mitochondrial Fission, and Autophagy.

Antioxid Redox Signal 2016 Apr 7;24(10):529-42. Epub 2016 Jan 7.

1 Department of Physiology, School of Medicine , Lille, France .

Aims: The RhoA/ROCK pathway controls crucial biological processes involved in cardiovascular pathophysiology, such as cytoskeleton dynamics, vascular smooth muscle contraction, and inflammation. In this work, we tested whether Rho kinase inhibition would beneficially impact cardiac cytoskeleton organization, bioenergetics, and autophagy in experimental endotoxemia induced by lipopolysaccharides (LPSs) in mice.

Results: Fasudil, a potent ROCK inhibitor, prevented LPS-induced cardiac inflammation, oxidative stress, cytoskeleton disarray, and mitochondrial injury. ROCK inhibition prevented phosphorylation of cofilin and dynamin-related protein-1, which promotes stabilization-polymerization of F-actin and mediates mitochondrial fission, respectively. Pyr1, which exclusively alters actin dynamics, prevented LPS-induced myocardial dysfunction, suggesting that beneficial impact of ROCK inhibition was not mainly related to pleiotropic effects of fasudil on cardiac inflammation and oxidative stress. Fasudil reduced mitochondrial fragmentation, stimulated initiation of autophagy, and elicited cardioprotection in LPS heart. Mdivi-1, a potent mitochondria fission inhibitor, converted cardioprotective autophagy to an inefficient form due to cargo loading failure in which autophagic vacuoles fail to trap cytosolic cargo, despite their formation at enhanced rates and lysosomal elimination.

Innovation: In experimental endotoxemia, cardioprotection by RhoA/ROCK inhibition may be related to changes in actin cytoskeleton reorganization and mitochondrial homeostasis. Improvement of LPS-induced mitochondrial dysfunction by fasudil was attributed to inhibition of ROCK-dependent Drp1 phosphorylation and activation of autophagic processes that can limit mitochondrial fragmentation and enhance degradation of damaged mitochondria, respectively.

Conclusion: Fasudil prevented LPS-induced heart oxidative stress, abnormal F-actin distribution, and oxidative phosphorylation, which concur to improve cardiac contractile and bioenergetic function. We suggest that fasudil may represent a valuable therapy for patients with sepsis.
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http://dx.doi.org/10.1089/ars.2015.6421DOI Listing
April 2016

Selective Heart Rate Reduction Improves Metabolic Syndrome-related Left Ventricular Diastolic Dysfunction.

J Cardiovasc Pharmacol 2015 Oct;66(4):399-408

*Institut National de la Santé et de la Recherche Médicale U1096, Rouen, France; †Institute for Research and Innovation in Biomedicine, Rouen, France; ‡UFR de Médecine et Pharmacie, Rouen University, Rouen, France; §Plateau d'Imagerie CardioThoracique de l'Universite de Rouen, Rouen, France; ¶Equipe d'Acceuil 4651, Aliment Bioprocedes Toxicologie Environnement, Rouen, France; ‖Bruker Biospin MRI GMBH, Ettlingen, Germany; and **Servier, Suresnes, France.

Background: Enhanced heart rate observed in metabolic syndrome (MS) contributes to the deterioration of left ventricular (LV) function via impaired LV filling and relaxation, increased myocardial O2 consumption, and reduced coronary perfusion. However, whether heart rate reduction (HRR) opposes LV dysfunction observed in MS is unknown.

Methods: We assessed in Zucker fa/fa rats, a rat model of MS, the cardiovascular effects of HRR induced by the If current inhibitor S38844 (3 mg · kg(-1) · d(-1)).

Results: Delayed short-term (4 days) and long-term (90 days) HRR induced by S38844 reduced LV end-diastolic pressure and LV end-diastolic pressure-volume relation, increased myocardial tissue perfusion, decreased myocardial oxidized glutathione levels, and preserved cardiac output, without modifying LV end-systolic pressure and LV end-systolic pressure-volume relation, although only long-term S38844 opposed LV collagen accumulation. Long-term S38844 improved flow-induced endothelium-dependent dilatation of mesenteric arteries, while metabolic parameters, such as plasma glucose levels, and Hb1c, were never modified.

Conclusions: In rats with MS, HRR induced by the If inhibitor S38844 improved LV diastolic function and endothelium-dependent vascular dilatation, independent from modifications in metabolic status. Moreover, this improvement in cardiac function involves not only immediate effects such as improved myocardial perfusion and reduced oxidative stress but also long-term effects such as modifications in the myocardial structure.
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http://dx.doi.org/10.1097/FJC.0000000000000294DOI Listing
October 2015

Hypothermic Total Liquid Ventilation Is Highly Protective Through Cerebral Hemodynamic Preservation and Sepsis-Like Mitigation After Asphyxial Cardiac Arrest.

Crit Care Med 2015 Oct;43(10):e420-30

1Inserm, U955, Equipe 03, Créteil, France. 2Université Paris Est, UMR_S955, DHU A-TVB, UPEC, Créteil, France. 3Université Paris Est, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France. 4Inserm, U1096, Rouen, France. 5Assistance Publique, Hôpitaux de Paris, Hôpital du Kremlin-Bicêtre, Service d'Anatomie Pathologique, Le Kremlin-Bicêtre, France. 6Inserm, U970, Paris, France. 7Inserm, U955, Equipe 16, Créteil, France. 8Vaccine Research Institute, Créteil, France. 9SAMU de Paris, Département d'Anesthésie Réanimation, Hôpital Universitaire Necker-Enfants Malades, Université Paris Descartes-Paris V, Paris, France. 10Inserm, IAME, 1137, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France. 11Assistance Publique-Hôpitaux de Paris, Hôpital Louis Mourier, Service de Réanimation Médico-chirurgicale, Colombes, France. 12Department of Mechanical Engineering, University of Sherbrooke, QC, Canada. 13Department of Physiology, University of Sherbrooke, QC, Canada. 14Institut Langevin, CNRS UMR 7587, INSERM U979, ESPCI ParisTech, Paris, France.

Objectives: Total liquid ventilation provides ultrafast and potently neuro- and cardioprotective cooling after shockable cardiac arrest and myocardial infarction in animals. Our goal was to decipher the effect of hypothermic total liquid ventilation on the systemic and cerebral response to asphyxial cardiac arrest using an original pressure- and volume-controlled ventilation strategy in rabbits.

Design: Randomized animal study.

Setting: Academic research laboratory.

Subjects: New Zealand Rabbits.

Interventions: Thirty-six rabbits were submitted to 13 minutes of asphyxia, leading to cardiac arrest. After resumption of spontaneous circulation, they underwent either normothermic life support (control group, n = 12) or hypothermia induced by either 30 minutes of total liquid ventilation (total liquid ventilation group, n = 12) or IV cold saline (conventional cooling group, n = 12).

Measurements And Main Results: Ultrafast cooling with total liquid ventilation (32 °C within 5 min in the esophagus) dramatically attenuated the post-cardiac arrest syndrome regarding survival, neurologic dysfunction, and histologic lesions (brain, heart, kidneys, liver, and lungs). Final survival rate achieved 58% versus 0% and 8% in total liquid ventilation, control, and conventional cooling groups (p < 0.05), respectively. This was accompanied by an early preservation of the blood-brain barrier integrity and cerebral hemodynamics as well as reduction in the immediate reactive oxygen species production in the brain, heart, and kidneys after cardiac arrest. Later on, total liquid ventilation also mitigated the systemic inflammatory response through alteration of monocyte chemoattractant protein-1, interleukin-1β, and interleukin-8 transcripts levels compared with control. In the conventional cooling group, cooling was achieved more slowly (32 °C within 90-120 min in the esophagus), providing none of the above-mentioned systemic or organ protection.

Conclusions: Ultrafast cooling by total liquid ventilation limits the post-cardiac arrest syndrome after asphyxial cardiac arrest in rabbits. This protection involves an early limitation in reactive oxidative species production, blood-brain barrier disruption, and delayed preservation against the systemic inflammatory response.
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http://dx.doi.org/10.1097/CCM.0000000000001160DOI Listing
October 2015

Impact of soluble epoxide hydrolase inhibition on early kidney damage in hyperglycemic overweight mice.

Prostaglandins Other Lipid Mediat 2015 Jul 27;120:148-54. Epub 2015 May 27.

Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France; Department of Pharmacology, Rouen University Hospital, Rouen, France. Electronic address:

This study addressed the hypothesis that inhibition of the EETs degrading enzyme soluble epoxide hydrolase affords renal protection in the early stage of diabetic nephropathy. The renal effects of the sEH inhibitor t-AUCB (10mg/l in drinking water) were compared to those of the sulfonylurea glibenclamide (80mg/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. Compared with non-treated HFD mice, HFD mice treated with t-AUCB had a decreased EET degradation, as shown by their higher plasma EETs-to-DHETs ratio, and an increased EET production, as shown by the increase in EETs+DHETs levels, which was associated with induction of CYP450 epoxygenase expression. Both agents similarly reduced fasting glycemia but only t-AUCB prevented the increase in the urinary albumine-to-creatinine ratio in HFD mice. Histopathological analysis showed that t-AUCB reduced renal inflammation, which was associated with an increased mRNA expression of the NFκB inhibitor Iκ≡ and related decrease in MCP-1, COX2 and VCAM-1 expressions. Finally, there was a marginally significant increase in reactive oxygen species production in HFD mice, together with an enhanced NOX2 expression. Both agents did not modify these parameters but t-AUCB increased the expression of the antioxidant enzyme superoxide dismutase 1. These results demonstrate that, independently from its glucose-lowering effect, sEH inhibition prevents microalbuminuria and renal inflammation in overweight hyperglycemic mice, suggesting that this pharmacological strategy could be useful in the management of diabetic nephropathy.
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http://dx.doi.org/10.1016/j.prostaglandins.2015.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575616PMC
July 2015

Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice.

Am J Physiol Heart Circ Physiol 2015 May 27;308(9):H1020-9. Epub 2015 Feb 27.

Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France; Department of Pharmacology, Rouen University Hospital, Rouen, France

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 trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB; 10 mg/l in drinking water) were compared with those of the sulfonylurea glibenclamide (80 mg/l), both administered for 8 wk in FVB mice subjected to a high-fat diet (HFD; 60% fat) for 16 wk. Mice on control chow diet (10% fat) and nontreated 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 nitric oxide synthase and cytochrome P-450 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.
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http://dx.doi.org/10.1152/ajpheart.00465.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551118PMC
May 2015

Role of Toll-like receptors 2 and 4 in mediating endothelial dysfunction and arterial remodeling in primary arterial antiphospholipid syndrome.

Arthritis Rheumatol 2014 Nov;66(11):3210-20

Rouen University Hospital, INSERM U1096, University of Rouen, and Centre d'Investigation Clinique, INSERM 1404, Rouen, France.

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.

Results: APS 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.
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http://dx.doi.org/10.1002/art.38785DOI Listing
November 2014

Polycystin deficiency induces dopamine-reversible alterations in flow-mediated dilatation and vascular nitric oxide release in humans.

Kidney Int 2015 Feb 16;87(2):465-72. Epub 2014 Jul 16.

1] Department of Pharmacology, Rouen University Hospital, Rouen, France [2] Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France [3] Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France [4] Centre d'Investigation Clinique (CIC)-INSERM 1404, Rouen University Hospital, Rouen, France.

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.
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http://dx.doi.org/10.1038/ki.2014.241DOI Listing
February 2015

Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients.

Circulation 2014 Aug 13;130(7):554-64. Epub 2014 Jun 13.

From the Department of Physiology, Faculty of Medicine Lille, Lille, France (D.M., X.M., A.C., N.D., C.P., S.M., S.P., R.N.); Service d'Explorations Fonctionnelles CardioVasculaires (D.M., A.C., S.M.), Department of Cardiovascular Surgery (T.M., G.F., J.-M.E.A., M.K.), and Biochemistry Division, Pathology and Biology Center (F.Z.), University Hospital of Lille, Lille, France; Université Lille 2, Inserm, U1011, and Institut Pasteur de Lille, Lille, France (D.M., X.M., Y.S., H.D., P.L., B.S.); University Hospital of Lille, Lille, France; INSERM U1096, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (I.R.-J., V.R.); and EA4483-Département de Médecine du Travail, Faculty of Medicine; University Lille 2, Lille, France (J.-L.E.).

Background: Obesity and diabetes mellitus are independently associated with the development of heart failure. In this study, we determined the respective effects of obesity, insulin resistance, and diabetes mellitus on the intrinsic contraction and mitochondrial function of the human myocardium before the onset of cardiomyopathy.

Methods And Results: Right atrial myocardium was obtained from 141 consecutive patients presenting no sign of cardiomyopathy. We investigated ex vivo isometric contraction, mitochondrial respiration and calcium retention capacity, and respiratory chain complex activities and oxidative stress status. Diabetes mellitus was associated with a pronounced impairment of intrinsic contraction, mitochondrial dysfunction, and increased myocardial oxidative stress, regardless of weight status. In contrast, obesity was associated with less pronounced contractile dysfunction without any significant perturbation of mitochondrial function or oxidative stress status. Tested as continuous variables, glycated hemoglobin A1C, but neither body mass index nor the insulin resistance index (homeostasis model assessment-insulin resistance), was independently associated with cardiac mitochondrial function. Furthermore, diabetes mellitus was associated with cardiac mitochondrial network fragmentation and significantly decreased expression of the mitochondrial fusion related protein MFN1. Myocardial MFN1 content was inversely proportional to hemoglobin A1C.

Conclusion: Worsening of intrinsic myocardial contraction in the transition from obesity to diabetes mellitus is likely related to worsening of cardiac mitochondrial function because impaired mitochondrial function and dynamics and contractile dysfunction are observed in diabetic patients but not in "metabolically healthy" obese patients at early stage in insulin resistance.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.113.008476DOI Listing
August 2014

Gene deletion of protein tyrosine phosphatase 1B protects against sepsis-induced cardiovascular dysfunction and mortality.

Arterioscler Thromb Vasc Biol 2014 May 27;34(5):1032-44. Epub 2014 Feb 27.

From the Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Rouen, France (D.C., E.D., P.M., S.R., I.R.-J., E.G., J.-P.H., V.R., F.T.); University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France (D.C., E.D., P.M., S.R., I.R.-J., E.G., J.-P.H., J.-C.d.R., V.R., F.T.); EA 4484 and Department of Physiology, Faculty of Medicine, University of Lille, Lille, France (R.N., X.M., D.M.); Intensive Care Unit, University Hospital, Rouen, France (F.T.); and Platform of Behavioural Analysis (SCAC), Faculty of Medicine, Rouen, France (J.-C.d.R.).

Objective: Cardiovascular dysfunction is a major cause of mortality in patients with sepsis. Recently, we showed that gene deletion or pharmacological inhibition of protein tyrosine phosphatase 1B (PTP1B) improves endothelial dysfunction and reduces the severity of experimental heart failure. However, the cardiovascular effect of PTP1B invalidation in sepsis is unknown. Thus, we explored the beneficial therapeutic effect of PTP1B gene deletion on lipopolysaccharide (LPS)-induced cardiovascular dysfunction, inflammation, and mortality.

Approach And Results: PTP1B(-/-) or wild-type mice received LPS (15 mg/kg) or vehicle followed by subcutaneous fluid resuscitation (saline, 30 mL/kg). α-1-dependent constriction and endothelium-dependent dilatation, assessed on isolated perfused mesenteric arteries, were impaired 8 hours after LPS and significantly improved in PTP1B(-/-) mice. This was associated with reduced vascular expression of interleukin1-β, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, cyclooxygenase-2, and inducible nitric oxide synthase mRNA. PTP1B gene deletion also limited LPS-induced cardiac dysfunction assessed by echocardiography, left ventricular pressure-volume curves, and in isolated perfused hearts. PTP1B(-/-) mice also displayed reduced LPS-induced cardiac expression of tumor necrosis factor-α, interleukin1-β, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and Gp91phox, as well as of several markers of cellular infiltration. PTP1B deficiency also reduced cardiac P38 and extracellular signal-regulated protein kinase 1 and 2 phosphorylation and increased phospholamban phosphorylation. Finally, PTP1B(-/-) mice displayed a markedly reduced LPS-induced mortality, an effect also observed using a pharmacological PTP1B inhibitor. PTP1B deletion also improved survival in a cecal ligation puncture model of sepsis.

Conclusions: PTP1B gene deletion protects against septic shock-induced cardiovascular dysfunction and mortality, and this may be the result of the profound reduction of cardiovascular inflammation. PTP1B is an attractive target for the treatment of sepsis.
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http://dx.doi.org/10.1161/ATVBAHA.114.303450DOI Listing
May 2014

High-efficiency on-line haemodiafiltration improves conduit artery endothelial function compared with high-flux haemodialysis in end-stage renal disease patients.

Nephrol Dial Transplant 2014 Feb 13;29(2):414-22. Epub 2013 Nov 13.

Department of Pharmacology, Rouen University Hospital, Rouen, France.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1093/ndt/gft448DOI Listing
February 2014

Mitochondrial dysfunction as an arrhythmogenic substrate: a translational proof-of-concept study in patients with metabolic syndrome in whom post-operative atrial fibrillation develops.

J Am Coll Cardiol 2013 Oct 1;62(16):1466-73. Epub 2013 May 1.

Equipe d'Accueil 4484, Department of Physiology, Faculty of Medicine Lille, University Lille 2, Lille, France; Service d'Explorations Fonctionnelles CardioVasculaires, University Hospital of Lille, Lille, France. Electronic address:

Objectives: This study sought to provide bedside evidence of the potential link between cardiac mitochondrial dysfunction and arrhythmia as reported in bench studies.

Background: Atrial fibrillation (AF) is a frequent complication of cardiac surgery. Underlying mechanisms of post-operative atrial fibrillation (POAF) remain largely unknown. Because cardiac mitochondrial dysfunction has been reported in clinical conditions with a high risk of POAF, we investigated whether a causal link exists between POAF onset and pre-operative function of cardiac mitochondria.

Methods: Pre-operative mitochondrial respiration and calcium retention capacity, respiratory complex activity, and myocardial oxidative stress were quantified in right atrial tissue from 104 consecutive patients with metabolic syndrome, in sinus rhythm, and undergoing coronary artery bypass graft surgery.

Results: In this high-risk population, POAF occurred in 44% of patients. Decreased pre-operative mitochondrial respiration and increased sensitivity to calcium-induced mitochondrial permeability transition pore opening were significantly associated with POAF. Adenosine diphosphate-stimulated mitochondrial respiration supported by palmitoyl-l-carnitine was significantly lower in POAF patients and remained independently associated with AF onset after adjustment for age, body mass index, heart rate, beta-blocker use, and statin medication (multivariate logistic regression coefficient per unit = -0.314 ± 0.144; p = 0.028). Gene expression profile analysis identified a general downregulation of the mitochondria/oxidative phosphorylation gene cluster in pre-operative atrial tissue of patients in whom AF developed.

Conclusions: Our prospective study identifies an association between pre-operative mitochondrial dysfunction of the atrial myocardium and AF occurrence after cardiac surgery in patients with metabolic disease, providing novel insights into the link between mitochondria and arrhythmias in patients.
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http://dx.doi.org/10.1016/j.jacc.2013.03.061DOI Listing
October 2013

Impaired role of epoxyeicosatrienoic acids in the regulation of basal conduit artery diameter during essential hypertension.

Hypertension 2012 Dec 22;60(6):1415-21. Epub 2012 Oct 22.

Departments of Pharmacology, Rouen University Hospital, Rouen, France.

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.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.112.201087DOI Listing
December 2012

Epoxyeicosatrienoic acids contribute with altered nitric oxide and endothelin-1 pathways to conduit artery endothelial dysfunction in essential hypertension.

Circulation 2012 Mar;125(10):1266-75

Department of Pharmacology, Rouen University Hospital, France.

Background: 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.

Methods And Results: 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.

Conclusions: 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.

Clinical Trial Registration: https://www.eudract.ema.europa.eu. Unique identifier: RCB2007-A001-10-53.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.111.070680DOI Listing
March 2012

NO-dependent protective effect of VEGF against excitotoxicity on layer VI of the developing cerebral cortex.

Neurobiol Dis 2012 Mar 13;45(3):871-86. Epub 2011 Dec 13.

EA NeoVasc 4309, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Rouen Institute for Biomedical Research, European Institute for Peptide Research (IFR 23), University of Rouen, Rouen, France.

In industrialized countries, cerebral palsy affects 2.5‰ of preterm and term infants. At a neurochemical level, the massive release of glutamate constitutes a major process leading to excitotoxicity and neonatal brain lesions. Previous studies, conducted in the laboratory, revealed that, in (δ/δ)VEGF(A) transgenic mice, glutamate-induced brain lesions are exacerbated suggesting that VEGF(A) could play a protective action against excitotoxicity. Using a model of cultured cortical brain slices, the aim of the study was to characterize the central effects of VEGF against glutamate-induced excitotoxicity in neonates. Exposure of brain slices to glutamate induced a strong increase of necrotic cell death in the deep cortical layer VI and a decrease of apoptotic death in superficial layers II-IV. When administered alone, a 6-h treatment with VEGF(A) had no effect on both apoptotic and necrotic deaths. In contrast, VEGF(A) abolished the glutamate-induced necrosis observed in layer VI. While MEK and PI3-K inhibitors had no effect on the protective action of VEGF(A), L-NAME, a pan inhibitor of NOS, abrogated the effect of VEGF(A) and exacerbated the excitotoxic action of glutamate. Calcimetry experiments performed on brain slices revealed that VEGF(A) reduced the massive calcium influx induced by glutamate in layer VI and this effect was blocked by L-NAME. Neuroprotective effect of VEGF(A) was also blocked by LNIO and NPLA, two inhibitors of constitutive NOS, while AGH, an iNOS inhibitor, had no effect. Nitrite measurements, electron paramagnetic resonance spectroscopy and immunohistochemistry indicated that glutamate was a potent inducer of NO production via activation of nNOS in the cortical layer VI. In vivo administration of nNOS siRNA promoted excitotoxicity and mimicked the effects of L-NAME, LNIO and NPLA. A short-term glutamate treatment increased nNOS Ser1412 phosphorylation, while a long-term exposure inhibited nNOS/NR2B protein-protein interactions. Altogether, these findings indicate that, in deep cortical layers of mice neonates, glutamate stimulates nNOS activity. Contrasting with mature brain, NO production induced by high concentrations of glutamate is neuroprotective and is required for the anti-necrotic effect of VEGF(A).
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http://dx.doi.org/10.1016/j.nbd.2011.12.003DOI Listing
March 2012

Soluble epoxide hydrolase inhibition improves myocardial perfusion and function in experimental heart failure.

J Mol Cell Cardiol 2012 Mar 6;52(3):660-6. Epub 2011 Dec 6.

Institut National de la Sante et de la Recherche Medicale U644, University of Rouen, Rouen, France.

The study addressed the hypothesis that soluble epoxide hydrolase (sEH) inhibition, which increases cardiovascular protective epoxyeicosatrienoic acids (EETs), exerts beneficial effects in an established chronic heart failure (CHF) model. In CHF rats, left ventricular (LV) function, perfusion and remodeling were assessed using MRI and invasive hemodynamics after 42-day (starting 8 days after coronary ligation) and delayed 3-day (starting 47 days after coronary ligation) treatments with the sEH inhibitor AUDA (twice 0.25 mg/day). Delayed 3-day and 42-day AUDA increased plasma EETs demonstrating the effective inhibition of sEH. Delayed 3-day and 42-day AUDA enhanced cardiac output without change in arterial pressure, thus reducing total peripheral resistance. Both treatment periods increased the slope of the LV end-systolic pressure-volume relation, but only 42-day AUDA decreased LV end-diastolic pressure, relaxation constant Tau and the slope of the LV end-diastolic pressure-volume relation, associated with a reduced LV diastolic volume and collagen density. Delayed 3-day and, to a larger extent, 42-day AUDA increased LV perfusion associated with a decreased LV hypoxia-inducible factor-1alpha. Both treatment periods decreased reactive oxygen species level and increased reduced-oxidized glutathione ratio. Finally, MSPPOH, an inhibitor of the EET-synthesizing enzyme cytochrome epoxygenases, abolished the beneficial effects of 3-day AUDA on LV function and perfusion. Augmentation of EET availability by pharmacological inhibition of sEH increases LV diastolic and systolic functions in established CHF. This notably results from short-term processes, i.e. increased LV perfusion, reduced LV oxidative stress and peripheral vasodilatation, but also from long-term effects, i.e. reduced LV remodeling.
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http://dx.doi.org/10.1016/j.yjmcc.2011.11.015DOI Listing
March 2012

Protective effect of mycophenolate mofetil on endothelial function in an aortic allograft model.

Transplantation 2011 Jan;91(1):35-41

Department of Nephrology and Hemodialysis, Rouen University Hospital, Rouen, France.

Background: Whether mycophenolate mofetil (MMF) can prevent the vascular endothelial dysfunction related to the administration of calcineurin inhibitor after organ transplantation remains unknown.

Methods: Four groups of Lewis rats, grafted with Brown Norway donor aortic abdominal allograft, received since the transplantation cyclosporine A (CsA, 5 mg/kg/day), MMF (40 mg/kg/day), CsA+MMF, or vehicle (control) for 2 weeks.

Results: Fifteen days after transplantation, all immunosuppressive regimens were equally effective in preventing graft rejection. When compared with control rats, the endothelium-dependent relaxation to acetylcholine was reduced, and the vasoconstrictor effect of phenylephrine was enhanced in thoracic aorta of CsA-treated rats but not in rats treated with MMF alone or combined with CsA without difference for the endothelium-independent relaxation to sodium nitroprusside. The relaxation to acetylcholine was abolished by the nitric oxide (NO)-synthase inhibitor N-nitro-l-arginine in all groups. Moreover, the endothelial NO-synthase protein dimer:monomer ratio in the thoracic aorta and the plasma nitrites concentrations, an indicator of NO availability, were decreased in CsA-treated rats but not in rats treated with MMF alone or combined with CsA.

Conclusions: This study demonstrates that MMF prevents systemic endothelial dysfunction and the enhanced sensitivity to vasoconstrictors related to CsA administration in a rat allograft aortic model through an increase in NO availability related to the improvement of endothelial NO-synthase functionality.
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http://dx.doi.org/10.1097/TP.0b013e3181fe12d6DOI Listing
January 2011

Coronary endothelial dysfunction after cardiomyocyte-specific mineralocorticoid receptor overexpression.

Am J Physiol Heart Circ Physiol 2011 Jun 25;300(6):H2035-43. Epub 2011 Mar 25.

Inserm U644, UFR Médecine-Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex, France.

The deleterious effects of aldosterone excess demonstrated in cardiovascular diseases might be linked in part to coronary vascular dysfunction. However, whether such vascular dysfunction is a cause or a consequence of the changes occurring in the cardiomyocytes is unclear. Moreover, the possible link between mineralocorticoid receptor (MR)-mediated effects on the cardiomyocyte and the coronary arteries is unknown. Thus we used a mouse model with conditional, cardiomyocyte-specific overexpression of human MR (hMR) and observed the effects on endothelial function in isolated coronary segments. hMR overexpression decreased the nitric oxide (NO)-mediated relaxing responses to acetylcholine in coronary arteries (but not in peripheral arteries), and this was prevented by a 1-mo treatment either with an MR antagonist, vitamin E/vitamin C, or a NADPH oxidase inhibitor. hMR overexpression did not affect coronary endothelial NO synthase content nor its level of phosphorylation on serine 1177, but increased cardiac levels of reactive oxygen species, cardiac NADPH oxidase (NOX) activity, and expression of the NOX subunit gp91phox, which was limited to endothelial cells. Thus an increase in hMR activation, restricted to cardiomyocytes, is sufficient to induce a severe coronary endothelial dysfunction. We suggest a new paracrine mechanism by which cardiomyocytes trigger a NOX-dependent, reactive oxygen species-mediated coronary endothelial dysfunction.
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http://dx.doi.org/10.1152/ajpheart.00552.2010DOI Listing
June 2011

Endothelial estrogen receptor {alpha} plays an essential role in the coronary and myocardial protective effects of estradiol in ischemia/reperfusion.

Arterioscler Thromb Vasc Biol 2010 Dec 16;30(12):2562-7. Epub 2010 Sep 16.

Department of Pharmacology, Institut National de la Santé et de la Recherche Médicale U644 and Rouen University Hospital, Institute for Biomedical Research Institut Fédératif de Recherches, University of Rouen, France.

Objective: To assess the coronary endothelial protective effects of 17β-estradiol (E2) and the role of estrogen receptor (ER) α in ischemia/reperfusion (I/R).

Methods And Results: E2 exerts protective effects in cardiac I/R. However, the implication in vivo of the endothelium and the cellular targets of the anti-ischemic effects of E2 are unknown. Mice were subjected to I/R (30 minutes of I and 1 hour of R) in vivo, after which acetylcholine-induced relaxation of isolated coronary segments was assessed ex vivo. I/R induced a coronary endothelial dysfunction in untreated ovariectomized mice that was prevented by long-term treatment with E2 in wild-type, but not in ERα(-/-), mice. Chimeric mice inactivated for ERα in the hematopoietic compartment remained protected by E2. Further inactivation of endothelial ERα abolished the protective action of E2 on coronary endothelial function in Tie2-Cre(+) ERα(f/f) mice. More importantly, E2 significantly limited infarct size in wild-type mice but not in mice deficient in endothelial ERα, even in the presence of hematopoietic ERα.

Conclusions: Endothelial ERα plays a crucial role in the E2-induced prevention of endothelial dysfunction after I/R. To our knowledge, we demonstrate for the first time, by using unique genetically modified mice, that targeting endothelial protection per se can confer cardiomyocyte protection in I/R.
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http://dx.doi.org/10.1161/ATVBAHA.110.213637DOI Listing
December 2010