Publications by authors named "Sylvanie Renet"

28 Publications

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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

Cardiopulmonary bypass increases endothelial dysfunction after pulmonary ischaemia-reperfusion in an animal model.

Eur J Cardiothorac Surg 2020 Dec 4. Epub 2020 Dec 4.

Normandie Univ, UNIVROUEN, INSERM U1096, Rouen, France.

Objectives: Endothelial dysfunction during ischaemia-reperfusion (IR) is a major cause of primary graft dysfunction during lung transplantation. The routine use of cardiopulmonary bypass (CPB) during lung transplantation remains controversial. However, the contribution of CPB to pulmonary endothelial dysfunction remains unclear. The objective was to investigate the impact of CPB on endothelial dysfunction in a lung IR rat model.

Methods: Rats were allocated to 4 groups: (i) Sham, (ii) IR, (iii) CPB and (iv) IR-CPB. The primary outcome was the study of pulmonary vascular reactivity by wire myograph. We also assessed glycocalyx degradation by enzyme-linked immunosorbent assay and electron microscopy and both systemic and pulmonary inflammation by enzyme-linked immunosorbent assay and immunohistochemistry. Rats were exposed to 45 min of CPB and IR. We used a CPB model allowing femoro-femoral support with left pulmonary hilum ischaemia for IR.

Results: Pulmonary endothelium-dependent relaxation to acetylcholine was markedly reduced in the IR-CPB group (10.7 ± 9.1%) compared to the IR group (50.5 ± 5.2%, P < 0.001), the CPB group (54.1 ± 4.7%, P < 0.001) and the sham group (80.8 ± 6.7%, P < 0.001), suggesting that the association of pulmonary IR and CPB increases endothelial dysfunction. In IR-CPB, IR and CPB groups, vasorelaxation was completely abolished when inhibiting nitric oxide synthase, suggesting that this relaxation process was mainly mediated by nitric oxide. We observed higher syndecan-1 plasma levels in the IR-CPB group in comparison with the other groups, reflecting an increased degradation of glycocalyx. We also observed higher systemic inflammation in the IR-CPB group as shown by the increased plasma levels of IL-1β, IL-10.

Conclusions: CPB significantly increased the IR-mediated effects on pulmonary endothelial dysfunction. Therefore, the use of CPB during lung transplantation could be deleterious, by increasing endothelial dysfunction.
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http://dx.doi.org/10.1093/ejcts/ezaa412DOI Listing
December 2020

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

Lymphatic and Immune Cell Cross-Talk Regulates Cardiac Recovery After Experimental Myocardial Infarction.

Arterioscler Thromb Vasc Biol 2020 07 14;40(7):1722-1737. Epub 2020 May 14.

From the Normandy University, UniRouen, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096 (EnVI Laboratory), FHU REMOD-VHF, Rouen, France (H.M., A.D., V.T., I.B., J.P.H., S.R., J.R., S.F., V.R., P.M.).

Objective: Lymphatics play an essential pathophysiological role in promoting fluid and immune cell tissue clearance. Conversely, immune cells may influence lymphatic function and remodeling. Recently, cardiac lymphangiogenesis has been proposed as a therapeutic target to prevent heart failure after myocardial infarction (MI). We investigated the effects of gene therapy to modulate cardiac lymphangiogenesis post-MI in rodents. Second, we determined the impact of cardiac-infiltrating T cells on lymphatic remodeling in the heart. Approach and Results: Comparing adenoviral versus adeno-associated viral gene delivery in mice, we found that only sustained VEGF (vascular endothelial growth factor)-C therapy, achieved by adeno-associated viral vectors, increased cardiac lymphangiogenesis, and led to reduced cardiac inflammation and dysfunction by 3 weeks post-MI. Conversely, inhibition of VEGF-C/-D signaling, through adeno-associated viral delivery of soluble VEGFR3 (vascular endothelial growth factor receptor 3), limited infarct lymphangiogenesis. Unexpectedly, this treatment improved cardiac function post-MI in both mice and rats, linked to reduced infarct thinning due to acute suppression of T-cell infiltration. Finally, using pharmacological, genetic, and antibody-mediated prevention of cardiac T-cell recruitment in mice, we discovered that both CD4 and CD8 T cells potently suppress, in part through interferon-γ, cardiac lymphangiogenesis post-MI.

Conclusions: We show that resolution of cardiac inflammation after MI may be accelerated by therapeutic lymphangiogenesis based on adeno-associated viral gene delivery of VEGF-C. Conversely, our work uncovers a major negative role of cardiac-recruited T cells on lymphatic remodeling. Our results give new insight into the interconnection between immune cells and lymphatics in orchestration of cardiac repair after injury.
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http://dx.doi.org/10.1161/ATVBAHA.120.314370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310303PMC
July 2020

Gene Expression of Protein Tyrosine Phosphatase 1B and Endoplasmic Reticulum Stress During Septic Shock.

Front Med (Lausanne) 2019 1;6:240. Epub 2019 Nov 1.

Normandie Univ, UNIROUEN, INSERM U1096, FHU REMOD-VHF, Rouen, France.

Protein Tyrosine Phosphatase 1B (PTP1B) and endoplasmic reticulum stress (ERS) are involved in the septic inflammatory response. Their inhibition is associated with improved survival in murine models of sepsis. The objective was to describe PTP1B and ERS expression during septic shock in human. Prospective study including patients admitted to intensive care unit (ICU) for septic shock. Blood samples were collected on days 1 (D1), 3 and 5 (D5). Quantitative PCR (performed from whole blood) evaluated the expression of genes coding for PTP1B () and key elements of ERS (GRP78, ATF6, CHOP) or for endothelial dysfunction-related markers (ICAM1 and ET1). We analyzed gene variation between D5 and D1, collected glycemic parameters, insulin resistance and organ failure was evaluated by Sequential Organ Failure Assessment (SOFA) score. We included 44 patients with a mean SAPS II 50 ± 16 and a mortality rate of 13.6%. Between D1 and D5, there was a significant decrease of ( < 0.001) and ( < 0.001) expressions. Their variations of expression were correlated with SOFA variation ( = 0.35, CI 95% [0.05; 0.54], = 0.03 and = 0.45 CI 95% [0.20; 0.65], < 0.001). We did not find any correlation between expression and insulin resistance or glycemic parameters. Between D1 and D5, and expressions were correlated with that of . Our study has evaluated for the first time the expression of PTP1B and ERS in patients with septic shock, revealing that gene expression variation of and are partly correlated with the evolution of septic organ failure and with endothelial dysfunction markers expression.
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http://dx.doi.org/10.3389/fmed.2019.00240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839276PMC
November 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

Protein tyrosine phosphatase 1B regulates endothelial endoplasmic reticulum stress; role in endothelial dysfunction.

Vascul Pharmacol 2018 10 9;109:36-44. Epub 2018 Jun 9.

Normandie Univ, UNIROUEN, INSERM U1096 EnVI, 76000 Rouen, France. Electronic address:

Protein tyrosine phosphatase 1B (PTP1B) impairs nitric oxide (NO) production and induces endothelial dysfunction in various diseases, including diabetes, septic shock and heart failure. In non-cardiovascular tissues, PTP1B modulates endoplasmic reticulum stress (ERS) however this role has never been assessed in endothelial cells. We evaluated the link between PTP1B, ERS and endothelial dysfunction in mice. Induction of ERS (Tunicamycin) in vivo in mice or ex vivo in mouse arteries led to severe arterial endothelial dysfunction (i.e. reduced flow-dependent, NO mediated dilatation in isolated small mesenteric arteries), and this was prevented by the PTP1B inhibitor trodusquemine and absent in PTP1B-/- mice. Trodusquemine also prevented the Tunicamycin -induced increased arterial levels of the molecular ERS actors 78 kDa glucose-regulated protein (GRP78) and Activating Transcription Factor 6 (ATF6α). Tunicamycin strongly increased the interactions of PTP1B with GRP78 and the activated forms of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and IRE1α (proximity Ligation Assay). Thus, PTP1B plays a central role in the regulation of ERS in the endothelium, and the endothelial protective effect of PTP1B inhibition appears likely due at least in part to reduction of endothelial ERS, notably by promoting PERK protective pathway. Modulation of ER stress via PTP1B inhibitors may be a promising approach to protect the endothelium in cardiovascular diseases.
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http://dx.doi.org/10.1016/j.vph.2018.05.011DOI Listing
October 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

A 30-Minute Supraceliac Aortic Clamping in the Rat Causes Death Due to an Inflammatory Response and Pulmonary Lesions.

Ann Vasc Surg 2018 Oct 16;52:192-200. Epub 2018 Apr 16.

Service de chirurgie vasculaire, CHU de Rouen, Rouen, France. Electronic address:

Background: The treatment of thoracoabdominal aortic aneurysms through an open approach has general and pulmonary consequences of multiple etiologies. Our assumption was that the supraceliac aortic clamping needed for this operation causes a systemic inflammatory response associated with a pulmonary attack.

Methods: We developed a model of 30-min supraceliac aortic clamping in Wistar rats weighing 300 g. After 90 min of reperfusion, the rats were sacrificed. The effects on the digestive tract wall were analyzed by measurement of the mucosal thickness/total thickness ratio. The effects on the mesenteric endothelial function were determined by an ex situ measurement of the arterial pressure/volume curves (third branch). The systemic consequences of the procedure were analyzed by dosing tumor necrosis factor alpha (TNFα), interleukin (IL)1β, and IL10 in the blood. The pulmonary consequences were analyzed by the measurement of macrophages, polymorphonuclear neutrophils (PNs), T lymphocyte infiltration, pulmonary apoptosis (TUNEL) and active caspase 3. The experimental scheme included 20 rats with ischemia-reperfusion (IR) and 20 control rats. An analysis of survival was carried out on 20 other rats (10 IR and 10 controls).

Results: The results were expressed as average ± standard error of the mean. The statistical tests were Student's t-test and Mann-Whitney test. This visceral IR model decreased the ratio of the thickness of the intestinal mucosa compared with that of the control rats (0.77 ± 0.008 vs. 0.82 ± 0.009 [P < 0.001]). This local effect was not accompanied by any mesenteric endothelial dysfunction (P = 0.91). On a systemic level, IR increased TNFα (37.9 ± 1.5 vs. 28.2 ± 0.6 pg/mL; P < 0.0001), IL1β (67.1 ± 9.8 vs. 22.5 ± 5.6 pg/mL; P < 0.001), and IL10 (753.3 ± 96 vs. 3.7 ± 1.7 pg/mL; P < 0.0001). As regards the lungs, IR increased the parenchymal cellular infiltration by macrophages (6.8 ± 0.8 vs. 4.5 ± 0.4 cells per field; P < 0.05) and PNs (7.4 ± 0.5 vs. 6.2 ± 03 cells per field; P < 0.05). There was no increase in the pulmonary cellular apoptosis measured by TUNEL (P = 0.77) or in the caspase 3 activity (P = 0.59). The mortality of the visceral IR rats was 100% at 36 hr vs. 0% in the animals without IR.

Conclusions: This work showed that the inflammatory response to visceral IR had systemic and pulmonary effects which always results in the death in the rat.
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http://dx.doi.org/10.1016/j.avsg.2017.12.027DOI Listing
October 2018

Reduced Insulin Resistance Contributes to the Beneficial Effect of Protein Tyrosine Phosphatase-1B Deletion in a Mouse Model of Sepsis.

Shock 2017 09;48(3):355-363

*Normandie Univ, UNIROUEN, Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Rouen, France †Lille University, LIRIC INSERM U995/Team "Glycation: From Inflammation to Aging," Lille, France ‡Inserm (Institut National de la Santé et de la Recherche Médicale) U1060, Lyon, France §Rouen University Hospital Department of Intensive Care, Rouen, France.

Hyperglycemia is a common feature of septic patients and has been associated with poor outcome and high mortality. In contrast, insulin has been shown to decrease mortality and to prevent the incidence of multiorgan failure but is often associated with deleterious hypoglycemia. Protein Tyrosine Phosphatase 1B (PTP1B) is a negative regulator of both insulin signaling and NO production, and has been shown to be an aggravating factor in septic shock. To evaluate the potential therapeutic effect of PTP1B blockade on glucose metabolism and insulin resistance in an experimental model of sepsis, we assessed the effect of PTP1B gene deletion in a cecal ligation and puncture (CLP) model of sepsis. PTP1B gene deletion significantly limited CLP-induced insulin resistance, improved AMP-activated protein kinase signaling pathway and Glucose Transporter 4 translocation, and decreased inflammation. These effects were associated with a reduction of sepsis-induced endothelial dysfunction/impaired NO production and especially of insulin-mediated dilatation. This modulation of insulin resistance may contribute to the beneficial effect of PTP1B blockade in septic shock, especially in terms of inflammation and cardiac metabolism.
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http://dx.doi.org/10.1097/SHK.0000000000000853DOI Listing
September 2017

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

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

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

Omega-3 polyunsaturated fatty acids delay the progression of endotoxic shock-induced myocardial dysfunction.

Inflammation 2013 Aug;36(4):932-40

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

Septic shock has a high mortality rate, partially related to myocardial dysfunction. Polyunsaturated fatty acids (omega-3 PUFAs) possess anti-inflammatory and antioxidant properties, but whether omega-3 PUFAs exert beneficial effects on myocardial function is unknown. We investigated, in a rat model of endotoxic shock, the effects of omega-3 PUFAs pretreatment on cardiac hemodynamics, function, and oxidative stress as well as intestinal barrier. Endotoxic shock was induced by lipopolysaccharide (LPS; 20 mg/kg IP) administered to rats pretreated or not with omega-3 PUFAs (Omegaven®; 0.5 g/kg IP, 90 min before injection of LPS). Two or 5 h after LPS, left ventricular function and arterial pressure were measured, followed by assessment left ventricular total glutathione as well as tumor necrosis factor alpha expression, occuldin expression, and proteasome activities. LPS reduced mean arterial blood pressure to the same extent 2 and 5 h after its administration, but cardiac output was more markedly decreased after 5 h. Omega-3 PUFAs pretreatment did not significantly modify the effect of LPS on mean arterial pressure and total peripheral resistance, but prevented the decrease in cardiac output 2 h after LPS. LPS increased oxidized glutathione after 2 h, and this increase was significantly attenuated by omega-3 PUFAs. Simultaneously, omega-3 PUFAs increased myocardial hemeoxygenase-1 (HO-1) mRNA expression. Finally, omega-3 PUFAs prevented the reduction of intestinal occludin expression. Omega-3 PUFAs pre-treatment improves myocardial dysfunction during endotoxemia and increases myocardial HO-1 expression. Moreover, the preservation of the intestinal occludin induced by omega-3 PUFAs precedes myocardial protection, suggesting the involvement of the intestinal barrier in the myocardial improvement observed with omega-3 PUFAs parenteral supplementation.
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http://dx.doi.org/10.1007/s10753-013-9622-2DOI Listing
August 2013

Myocardial dysfunction in early state of endotoxemia role of heme-oxygenase-1.

J Surg Res 2010 Jan;158(1):94-103

Inserm (Institut National de la Santé et de la Recherche Médicale) Rouen University Medical School, Rouen, France.

Background: The triggers and cellular mechanisms of cardiac dysfunction have not been clearly established during the early period following challenge with lipopolysaccharides (LPS) (<1 h post-LPS). The aim of the study was to evaluate the myocardial depression during early stage of endotoxemia, the relationship between oxidative stress production and cardiac dysfunction in a rat model of endotoxic shock, and its inhibition by heme-oxygenase-1 (HO-1) overexpression.

Materials And Methods: LPS-induced myocardial deformation was assessed by tissue Doppler imaging and invasive hemodynamic measurements in rats 2 h after LPS challenge. Myocardial samples were processed for the measurements of tumor necrosis factor alpha (TNFalpha), nitric oxidase synthase II (NOSII), HO-1 gene expression, reactive oxygen species (ROS) production, and reduced glutathione/oxidized glutathione (GSH/GSSH) ratio.

Results: Myocardial systolic and diastolic deformation was evident as determined by tissue Doppler imaging but left ventricular conventional echocardiographic parameters did not show significant alterations. Myocardial deformation was significantly associated with reactive oxygen species and TNFalpha overproduction. Pretreatment with hemin to induce HO-1 resulted in decreased oxidative stress and TNFalpha production, and prevented LPS-induced alterations in myocardium.

Conclusions: These preliminary results suggest myocardial alteration at a very early stage after LPS challenge associated with oxidative stress response. Manipulation of the HO-1 pathway may represent a future therapeutic strategy to counteract oxidative stress of endotoxemia and perhaps may limit future myocardial deformation.
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http://dx.doi.org/10.1016/j.jss.2008.09.023DOI Listing
January 2010

Toll-like receptors 4 contribute to endothelial injury and inflammation in hemorrhagic shock in mice.

Crit Care Med 2009 May;37(5):1724-8

Inserm U644, Institute for Biomedical Research and IFRMP 23, Rouen University Medical School, Rouen, France.

Objective: Hemorrhagic shock followed by resuscitation (HS/R) promotes organ injury by priming cells of the innate immune system for inflammatory response. Toll-like receptors (TLRs) play an important role in signal transduction in shock/resuscitation conditions. Because proinflammatory mediators are a critical event in mesenteric endothelial injury induced by HS/R, we assessed the role of TLR4 or TLR2 in this setting.

Design: Laboratory investigation.

Setting: Research laboratory at Rouen University Medical School.

Subjects: Male wild-type, TLR4(-/-) and TLR2(-/-) mice with the same C57BL/6 background.

Interventions: Mice were submitted to 30 minutes hemorrhagic shock followed by 1 hour resuscitation, after which mesenteric endothelial dysfunction, microvascular injury, and TNF[alpha] production were assessed.

Measurements And Main Results: HS/R markedly decreased nitric oxide-mediated mesenteric relaxations induced by acetylcholine, assessed ex vivo on a myograph. By contrast, in TLR4-deficient mice, HS/R did not impair the nitric oxide-mediated responses to acetylcholine. No protection was observed in TLR2-deficient mice. TLR4-deficient mice also displayed a significant reduction in fluid resuscitation and TNF[alpha] systemic production.

Conclusions: TLR4 contributes to mesenteric endothelial dysfunction after hemorrhagic shock. This early TLR4-induced vascular injury may be an important trigger of the systemic inflammatory response occurring in this disease.
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http://dx.doi.org/10.1097/CCM.0b013e31819da805DOI Listing
May 2009

Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: a comparison with spironolactone.

Eur Heart J 2008 Sep 27;29(17):2171-9. Epub 2008 Jun 27.

Faculté de Médecine et Pharmacie, INSERM U644, 22 Boulevard Gambetta, 76183 Rouen Cedex, France.

Aims: Inhibition of aldosterone synthase, the key enzyme in aldosterone formation, could be an alternative strategy for mineralocorticoid-receptor antagonists in congestive heart failure (CHF), but its effect in CHF is unknown.

Methods And Results: We compared, in rats with CHF, the effects of a 7 day and a 12 week treatment with the aldosterone synthase inhibitor FAD286 (4 mg kg(-1) day(-1)) with those induced by spironolactone (80 mg kg(-1) day(-1)). FAD286/spironolactone increased cardiac output without modifying arterial pressure. Long-term FAD286 and spironolactone reduced left ventricular (LV) end-diastolic pressure, LV relaxation constant, and LV dilatation, and these effects were more marked with FAD286, whereas both drugs reduced LV hypertrophy and collagen accumulation to the same extent. Long-term FAD286/spironolactone prevented CHF-related enhancement in LV ACE and reduction in LV ACE-2, but only FAD286 prevented the reduction in LV AT(2) receptors. FAD286, but not long-term spironolactone, reduced the CHF-related enhancements in LV reactive oxygen species, reduced-oxidized glutathione ratio, and aortic nicotinamide adenine dinucleotide phosphate oxidase activity. FAD286 normalized the CHF-induced impairment of endothelium-dependent vasodilatation.

Conclusion: In experimental CHF, FAD286 and spironolactone improve LV haemodynamics, remodelling, and function, but only FAD286 persistently normalizes LV 'redox status'. These results suggest that aldosterone synthase inhibition is a potential therapeutic strategy for the treatment of CHF.
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http://dx.doi.org/10.1093/eurheartj/ehn277DOI Listing
September 2008

Intestinal preconditioning prevents inflammatory response by modulating heme oxygenase-1 expression in endotoxic shock model.

Am J Physiol Gastrointest Liver Physiol 2007 Dec 6;293(6):G1308-14. Epub 2007 Sep 6.

Institut National de la Santé et de la Recherche Médicale U644, Rouen University Medical School, Rouen, France.

Gut mucosal injury observed during ischemia-reperfusion is believed to trigger a systemic inflammatory response leading to multiple organ failure. It should be interesting to demonstrate this relationship between gut and multiple organ failure in a sepsis model. Intestinal preconditioning (PC) can be used as a tool to assess the effect of intestinal ischemia in inflammatory response after LPS challenge. The aim of this study was to investigate the protective effect of PC against LPS-induced systemic inflammatory and intestinal heme oxygenase-1 (HO-1) expression. ES was performed with LPS (10 mg/kg iv) with or without PC, which was done before LPS. Rats were first subjected to sham surgery or PC with four cycles of 1 min ischemia and 4 min of reperfusion 24 h before LPS challenge or saline administration. PC significantly reduced fluid requirements, lung edema, intestinal lactate production, and intestinal injury. Inflammatory mRNA expressions for intestine and lung ICAM and TNF were significantly reduced after PC, and these effects were significantly abolished by zinc-protoporphyrin (a specific HO-1 activity inhibitor) and mimicked by bilirubin administration. Intestinal PC selectively increased HO-1 mRNA expression in intestine, but we have observed no expression in lungs. These findings demonstrate that intestinal injury is a important event for inflammatory response and multiple organ injury after LPS challenge. Intestinal HO-1 expression attenuates LPS-induced multiple organ failure by modulating intestine injury and its consequences on inflammatory response. Identification of the exact mechanisms responsible for intestine HO-1 induction may lead to the development of new pharmacological interventions.
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http://dx.doi.org/10.1152/ajpgi.00154.2007DOI Listing
December 2007

Protective effects of heme-oxygenase expression against endotoxic shock: inhibition of tumor necrosis factor-alpha and augmentation of interleukin-10.

J Trauma 2006 Nov;61(5):1078-84

Institut National de la Santé et de la Recherche Médicale, Rouen University Hospital, Rouen, France.

Background: Heme-oxygenase (HO)-1 acts as an inducible defense against oxidative stress and could play an important role in inflammation models, providing protection against oxidative stress and systemic inflammatory response. The objective of this study was to improve the role of HO-1 on systemic inflammatory response in an endotoxic shock model.

Methods: Five groups of animals were used: control group; lipopolysaccharide (LPS) group, animals received LPS 5 mg/kg; hemin + LPS group, animals received pretreatment with hemin, used to induce HO-1 expression; Zn-PP group, animals received Zn-PP, a specific inhibitor of HO-1 activity and hemin group. At the end of the experiment, tissue and blood samples were isolated for the measurement of HO-1 mRNA expression, biochemical measurements, and cytokine measurements.

Results: HO-1 messenger RNA expression and protein were induced to a larger extent in LPS group in distal organs. Hemin pretreatment induced a significant decrease oxidative stress and tumor necrosis factor-alpha plasma levels with a significant increase of interleukin-10 plasma levels. Pulmonary injury was markedly limited after hemin. Onset of lethality in LPS group occurred at H6, and was delayed until H10 with hemin. Inhibition of HO-1 activity by Zn-PP administration abolished the beneficial effect of hemin-pretreatment.

Conclusions: Early HO-1 expression may modulate systemic inflammatory response and limit end-organ injury in endotoxic shock model.
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http://dx.doi.org/10.1097/01.ta.0000239359.41464.efDOI Listing
November 2006

Triple ACE-ECE-NEP inhibition in heart failure: a comparison with ACE and dual ECE-NEP inhibition.

J Cardiovasc Pharmacol 2005 Sep;46(3):390-7

INSERM U644, IFRMP no. 23, Rouen University Medical School, Rouen, France and Novarhis Institutes for BioMedical Research, East Hanover, New Jersey, USA.

Mortality remains high in chronic heart failure (CHF) because under ACE inhibitor treatment other neurohumoral systems remain/become (de)activated, such as the endothelin and atrial natriuretic peptide pathways. Dual endothelin-converting enzyme-neutral endopeptidase (ECE-NEP) inhibition exerts beneficial effects in experimental CHF, but whether "triple" ACE-ECE-NEP inhibition is superior to ACE or ECE-NEP inhibition is unknown. We compared, in rats with CHF, ACE-ECE-NEP to ACE or ECE-NEP inhibition in terms of left ventricular (LV) hemodynamics and remodeling. Benazepril (2 mg/kg/d) or the ECE-NEP inhibitor CGS26303 (10 mg/kg/d) were administered alone or in combination (subcutaneously for 28 days starting 7 days after coronary ligation). ACE-ECE-NEP inhibition reduced blood pressure more markedly than ACE or ECE-NEP inhibition. All treatments increased cardiac output to the same extent, but ACE-ECE-NEP inhibition reduced LV diameter and LV end-diastolic pressure more markedly than ACE or ECE-NEP inhibition. The reduction of LV weight and collagen accumulation in the "viable" myocardium was most pronounced after ACE-ECE-NEP inhibition. These results, obtained in experimental CHF, illustrate a further improvement of LV hemodynamics and structure after ACE-ECE-NEP inhibition compared with either ACE or ECE-NEP inhibition, but whether this is associated with a further improvement of exercise tolerance and/or survival remains to be determined.
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http://dx.doi.org/10.1097/01.fjc.0000175457.48031.8bDOI Listing
September 2005

Sustained improvement of cardiac function and prevention of cardiac remodeling after long-term dual ECE-NEP inhibition in rats with congestive heart failure.

J Cardiovasc Pharmacol 2004 Apr;43(4):489-94

Rouen University Medical School, France.

Acute inhibition of endothelin converting enzyme (ECE) and neutral endopeptidase (NEP) exerts beneficial hemodynamic effects in chronic heart failure (CHF). However, the long-term effects of dual ECE-NEP inhibition are unknown. We evaluated, in rats with CHF, the long-term effects of the dual ECE-NEP inhibitor CGS 26303 (10 mg.kg(-1).day(-1)) on systemic and left ventricular (LV) hemodynamics and LV remodeling, and compared them to those induced by the selective NEP inhibitor CGS 24592 (10 mg.kg(-1).day(-1)), both administered subcutaneously by mini-pump for 30 days starting 7 days after left coronary artery ligation. After 30 days, CGS 26303, but not CGS 24592, reduced systolic blood pressure, while both drugs never affected heart rate. Echocardiographic studies showed that only CGS 26303 diminished LV end-diastolic and systolic diameters and increased LV fractional shortening and cardiac output. Moreover, CGS 26303, but not CGS 24592, reduced LV end-diastolic pressure, while LV dP/dtmax/min was not affected. Both drugs reduced collagen accumulation in the 'viable' part of the LV, but only CGS 26303 reduced LV weight. Thus, long-term treatment with CGS 26303 decreases both preload and afterload, increases cardiac output, and diminishes LV hypertrophy, dilatation, and cardiac fibrosis, suggesting that dual ECE-NEP inhibition might be beneficial in human CHF.
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http://dx.doi.org/10.1097/00005344-200404000-00003DOI Listing
April 2004

Long-term heart rate reduction induced by the selective I(f) current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure.

Circulation 2004 Apr 23;109(13):1674-9. Epub 2004 Feb 23.

INSERM U644, UFR de Médecine et de Pharmacie, Rouen, France.

Background: Heart rate reduction (HRR) improves left ventricular (LV) filling, increases myocardial O2 supply, and reduces myocardial O2 consumption, which are all beneficial in congestive heart failure (CHF). However, the long-term effects of HRR on cardiac function and remodeling are unknown.

Methods And Results: We assessed, in rats with CHF, the effects of long-term HRR induced by the selective I(f) current inhibitor ivabradine (as food admix for 90 days starting 7 days after coronary artery ligation). To assess intrinsic modifications of LV tissue induced by long-term HRR, all parameters were reassessed 3 days after interruption of treatment. Ivabradine decreased heart rate over the 90-day treatment period (-18% versus untreated at 10 mg x kg(-1) x d(-1)), without modifying blood pressure, LV end-diastolic pressure, or dP/dt(max/min). Ivabradine significantly reduced LV end-systolic but not end-diastolic diameter, which resulted in preserved cardiac output due to increased stroke volume. In the Langendorff preparation, ivabradine shifted LV systolic but not end-diastolic pressure-volume relations to the left. Ivabradine decreased LV collagen density and increased LV capillary density without modifying LV weight. Three days after interruption of treatment, the effects of ivabradine on LV geometry, shortening, and stroke volume persisted despite normalization of heart rate.

Conclusions: In rats with CHF, long-term HRR induced by the selective I(f) inhibitor ivabradine improves LV function and increases stroke volume, preserving cardiac output despite the HRR. The improvement of cardiac function is related not only to the HRR per se but also to modifications in the extracellular matrix and/or function of myocytes as a consequence of long-term HRR.
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http://dx.doi.org/10.1161/01.CIR.0000118464.48959.1CDOI Listing
April 2004

Prolonged cardiac dysfunction after withdrawal of chronic cocaine exposure in rats.

J Cardiovasc Pharmacol 2003 Nov;42(5):642-7

INSERM E 9920, IFRMP no. 23, University Medical School, Rouen, France.

Cocaine abuse causes myocardial dysfunction and induces oxidative stress. However, the reversibility of these effects is unknown. We evaluated myocardial function and oxidative stress after cocaine withdrawal, in a rat model of chronic cocaine exposure. Standard echocardiography and Doppler tissue imaging were performed after 4 weeks (W4) of cocaine administration (2 x 7.5 mg/kg/d, i.p.) and 4 weeks after interruption (W8). At these time points, redox state (reduced glutathione GSH, oxidized glutathione GSH, and GSH/GSSG) as well as activities of GSH peroxidase (GPX), superoxide dismutase (SOD), and catalase were determined in the left ventricle (LV). At W4, LV fractional shortening, posterior wall thickening, systolic myocardial ventricular gradient (SMVG), dP/dt(max), and dp/dt(min) were decreased, compared with control values while LV myocardial thickness was increased. At W8, even though dP/dtmax and dp/dt(min) were restored, myocardial function was still impaired as demonstrated by the decrease in posterior wall thickening, and systolic myocardial velocity gradient. At W4, CAT and GPX activities as well as GSH/GSSG ratio were reduced while SOD activity was increased. Antioxidant markers and redox ratio remained altered 4 weeks after the last injection. Thus, these data demonstrate the persistence of LV dysfunction after cocaine withdrawal, which occurs in a context of a deficit in antioxidant defenses.
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http://dx.doi.org/10.1097/00005344-200311000-00010DOI Listing
November 2003

Role of reactive oxygen species in cocaine-induced cardiac dysfunction.

Cardiovasc Res 2003 Oct;59(4):834-43

INSERM E9920, Faculté de médecine-Pharmacie de Rouen, IFRMP n degrees 23, University Medical School, 22 boulevard Gambetta, 76183 Rouen, France.

Objective: Contractility alterations and LV hypertrophy after chronic cocaine administration have been shown to be accompanied by an increase in oxidative stress. This study was carried out to investigate whether the production of reactive oxygen species is an early event of primary importance in cocaine-induced myocardial injury or simply occurs as a consequence of the ventricular dysfunction itself.

Methods And Results: After 2 days of cocaine administration to rats, no differences were observed in echocardiographic parameters between the cocaine-treated group and the control group. However, an increase in oxidative stress in the myocardium was indicated by an increase in lipid peroxidation (+35%, cocaine vs. control), an increase in antioxidant enzymes (catalase +110%, glutathione peroxidase +40% and superoxide dismutase +38%) and of NADPH-driven superoxide production (assessed by chemiluminescence). Furthermore, higher gp91phox and p22phox mRNA expression, measured by quantitative real-time RT-PCR, was found in the cocaine group. On day 8, cocaine administration induced a cardiac dysfunction, characterized by a decrease in cardiac index (-30%, cocaine vs. controls) and left ventricular (LV) fractional shortening (-23%, cocaine vs. controls). This LV dysfunction was prevented by antioxidant treatment (100 mg/kg/day vitamin C and 100 U/kg/day vitamin E). Moreover, in these animals, antioxidant treatment decreased lipid peroxides and decreased the activity of NADPH oxidase, associated with the downregulation of gp91phox.

Conclusion: These data indicate that cocaine administration induces early NADPH-driven O2-. release which may play an important role in the development and progression of the LV dysfunction observed after chronic cocaine abuse.
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http://dx.doi.org/10.1016/s0008-6363(03)00499-1DOI Listing
October 2003

Long-term survival and hemodynamics after endothelin-a receptor antagonism and angiotensin-converting enzyme inhibition in rats with chronic heart failure: monotherapy versus combination therapy.

Circulation 2002 Aug;106(9):1159-64

Rouen University Medical School, Rouen, France.

Background: In patients with congestive heart failure (CHF) receiving ACE inhibitors, acute administration of selective endothelin (ET) antagonists additionally improves systemic and cardiac hemodynamics. We investigated, in a rat model of CHF, whether such acute synergistic effects are sustained and accompanied, in the long term, by an additional limitation of left ventricular remodeling or an increase in survival.

Methods And Results: Rats were subjected to coronary artery ligation and treated for 3 or 9 months with vehicle or with the ACE inhibitor trandolapril (Tr) (0.3 mg/kg(-1) per day(-1)), the ET(A) antagonist LU 135252 (LU, 30 mg/kg(-1) per day(-1)), or their combination starting 7 days after ligation. After 3 months, the combination decreased LV systolic- and end-diastolic pressures (-32% and -80%, respectively) more markedly than Tr (-21% and -61%, respectively) or LU alone (-14% and -48%, respectively). Echocardiographic studies revealed that all treatments limited LV dilatation and increased LV fractional shortening and cardiac index. All treatments equally reduced left ventricular collagen density, whereas only Tr or the combination reduced LV weight. Finally, although LU did not modify long-term survival, Tr and the combination of Tr with LU induced a similar improvement of survival.

Conclusions: In this rat model, long-term combined administration of an ET(A) antagonist and an ACE inhibitor induces additional effects in terms of systemic and cardiac hemodynamics; however, this is not associated with an additional increase in long-term survival.
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http://dx.doi.org/10.1161/01.cir.0000027138.07524.38DOI Listing
August 2002