Publications by authors named "Jean Paul Henry"

44 Publications

Mineralocorticoid receptor blockade with finerenone improves heart function and exercise capacity in ovariectomized mice.

ESC Heart Fail 2021 Mar 20. Epub 2021 Mar 20.

Inserm U1096 ENVI, Rouen Medical School, UNIROUEN, Normandy University, Rouen, France.

Aims: In post-menopausal women, incidence of heart failure with preserved ejection fraction is higher than in men. Hormonal replacement therapies did not demonstrate benefits. We tested whether the non-steroidal mineralocorticoid receptor antagonist finerenone limits the progression of heart failure in ovariectomized (OVX) mice with metabolic disorders.

Methods And Results: Ovariectomy was performed in 4-month-old mice, treated or not at 7 months old for 1 month with finerenone (Fine) 1 mg/kg/day. Left ventricular (LV) cardiac and coronary endothelial functions were assessed by echocardiography, catheterization, and myography. Blood pressure was measured by plethysmography. Insulin and glucose tolerance tests were performed. Exercise capacity and spontaneous activity were measured on treadmill and in combined indirect calorimetric cages equipped with voluntary running wheel. OVX mice presented LV diastolic dysfunction without modification of ejection fraction compared with controls (CTL), whereas finerenone improved LV filling pressure (LV end-diastolic pressure, mmHg: CTL 3.48 ± 0.41, OVX 6.17 ± 0.30**, OVX + Fine 3.65 ± 0.55 , **P < 0.01 vs. CTL, P < 0.05 vs. OVX) and compliance (LV end-diastolic pressure-volume relation, mmHg/RVU: CTL 1.65 ± 0.42, OVX 4.77 ± 0.37***, OVX + Fine 2.87 ± 0.26 , ***P < 0.001 vs. CTL, P < 0.01 vs. OVX). Acetylcholine-induced endothelial-dependent relaxation of coronary arteries was impaired in ovariectomized mice and improved by finerenone (relaxation, %: CTL 86 ± 8, OVX 38 ± 3**, OVX + Fine 83 ± 7 , **P < 0.01 vs. CTL, P < 0.01 vs. OVX). Finerenone improved decreased ATP production by subsarcolemmal mitochondria after ovariectomy. Weight gain, increased blood pressure, and decreased insulin and glucose tolerance in OVX mice were improved by finerenone. The exercise capacity at race was diminished in untreated OVX mice only. Spontaneous activity measurements in ovariectomized mice showed decreased horizontal movements, reduced time spent in a running wheel, and reduced VO and VCO , all parameters improved by finerenone.

Conclusions: Finerenone improved cardiovascular dysfunction and exercise capacity after ovariectomy-induced LV diastolic dysfunction with preserved ejection fraction.
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http://dx.doi.org/10.1002/ehf2.13219DOI Listing
March 2021

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

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

Myocardial Injury After Ischemia/Reperfusion Is Attenuated By Pharmacological Galectin-3 Inhibition.

Sci Rep 2019 07 3;9(1):9607. Epub 2019 Jul 3.

Cardiovascular Translational Research. Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.

Although optimal therapy for myocardial infarction includes reperfusion to restore blood flow to the ischemic region, ischemia/reperfusion (IR) also initiates an inflammatory response likely contributing to adverse left ventricular (LV) extracellular matrix (ECM) remodeling. Galectin-3 (Gal-3), a β-galactoside-binding-lectin, promotes cardiac remodeling and dysfunction. Our aim is to investigate whether Gal-3 pharmacological inhibition using modified citrus pectin (MCP) improves cardiac remodeling and functional changes associated with IR. Wistar rats were treated with MCP from 1 day before until 8 days after IR (coronary artery ligation) injury. Invasive hemodynamics revealed that both LV contractility and LV compliance were impaired in IR rats. LV compliance was improved by MCP treatment 8 days after IR. Cardiac magnetic resonance imaging showed decreased LV perfusion in IR rats, which was improved with MCP. There was no difference in LV hypertrophy in MCP-treated compared to untreated IR rats. However, MCP treatment decreased the ischemic area as well as Gal-3 expression. Gal-3 blockade paralleled lower myocardial inflammation and reduced fibrosis. These novel data showing the benefits of MCP in compliance and ECM remodeling in IR reinforces previously published data showing the therapeutic potential of Gal-3 inhibition.
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http://dx.doi.org/10.1038/s41598-019-46119-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610618PMC
July 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

Selective Vascular Endothelial Protection Reduces Cardiac Dysfunction in Chronic Heart Failure.

Circ Heart Fail 2016 Apr 8;9(4):e002895. Epub 2016 Apr 8.

From the Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Department of Pharmacology, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., O.B., L.N., P.M., J.M., V.R.); Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France (J.M., M.B., E.G., N.B., J.-P.H., L.N., P.M., V.R.); and Inserm (Institut National de la Santé et de la Recherche Médicale) U905, Department of Immunology, Rouen, France (O.B., J.M.).

Background: Chronic heart failure (CHF) induces endothelial dysfunction in part because of decreased nitric oxide (NO(·)) production, but the direct link between endothelial dysfunction and aggravation of CHF is not directly established. We previously reported that increased NO production via inhibition of protein tyrosine phosphatase 1B (PTP1B) is associated with reduced cardiac dysfunction in CHF. Investigation of the role of endothelial PTP1B in these effects may provide direct evidence of the link between endothelial dysfunction and CHF.

Methods And Results: Endothelial deletion of PTP1B was obtained by crossing LoxP-PTP1B with Tie2-Cre mice. CHF was assessed 4 months after myocardial infarction. In some experiments, to exclude gene extinction in hematopoietic cells, Tie2-Cre/LoxP-PTP1B mice were lethally irradiated and reconstituted with bone marrow from wild-type mice, to obtain mouse with endothelial-specific deletion of PTP1B. Vascular function evaluated ex vivo in mesenteric arteries showed that in wild-type mice, CHF markedly impaired NO-dependent flow-mediated dilatation. CHF-induced endothelial dysfunction was less marked in endoPTP1B(-/-) mice, suggesting restored NO production. Echocardiographic, hemodynamic, and histological evaluations demonstrated that the selectively improved endothelial function was associated with reduced left ventricular dysfunction and remodeling, as well as increased survival, in the absence of signs of stimulated angiogenesis or increased cardiac perfusion.

Conclusions: Prevention of endothelial dysfunction, by endothelial PTP1B deficiency, is sufficient to reduce cardiac dysfunction post myocardial infarction. Our results provide for the first time a direct demonstration that endothelial protection per se reduces CHF and further suggest a causal role for endothelial dysfunction in CHF development.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.115.002895DOI Listing
April 2016

Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction.

Circulation 2016 Apr 1;133(15):1484-97; discussion 1497. Epub 2016 Mar 1.

From Inserm (Institut National de la Santé et de la Recherche Médicale) U1096, Rouen, France (O.H., C.P., M.H., L.N., J.-P.H., A.D., I.B., S.B., C.T., V.R., P.M., E.B.); Normandy University & University of Rouen, Institute for Research and Innovation in Biomedicine, France (O.H., C.P., M.H., L.G., L.N., J.-P.H., A.D., I.B., S.B., D.S., C.T., V.R., P.M., E.B.); PRIMACEN, Cell Imaging Platform of Normandy, Inserm, Mont-Saint-Aignan, France (L.G., D.S.); PICTUR, In Vivo Imaging Platform, University of Rouen, Institute for Research and Innovation in Biomedicine, France (L.N., C.T., P.M.); Reims Institute of Molecular Chemistry, UMR 7312 CNRS-URCA, University of Reims Champagne Ardenne, France (F.E.-L,); and Rouen University Hospital, Department of Pharmacology, France (C.T.).

Background: The lymphatic system regulates interstitial tissue fluid balance, and lymphatic malfunction causes edema. The heart has an extensive lymphatic network displaying a dynamic range of lymph flow in physiology. Myocardial edema occurs in many cardiovascular diseases, eg, myocardial infarction (MI) and chronic heart failure, suggesting that cardiac lymphatic transport may be insufficient in pathology. Here, we investigate in rats the impact of MI and subsequent chronic heart failure on the cardiac lymphatic network. Further, we evaluate for the first time the functional effects of selective therapeutic stimulation of cardiac lymphangiogenesis post-MI.

Methods And Results: We investigated cardiac lymphatic structure and function in rats with MI induced by either temporary occlusion (n=160) or permanent ligation (n=100) of the left coronary artery. Although MI induced robust, intramyocardial capillary lymphangiogenesis, adverse remodeling of epicardial precollector and collector lymphatics occurred, leading to reduced cardiac lymphatic transport capacity. Consequently, myocardial edema persisted for several months post-MI, extending from the infarct to noninfarcted myocardium. Intramyocardial-targeted delivery of the vascular endothelial growth factor receptor 3-selective designer protein VEGF-CC152S, using albumin-alginate microparticles, accelerated cardiac lymphangiogenesis in a dose-dependent manner and limited precollector remodeling post-MI. As a result, myocardial fluid balance was improved, and cardiac inflammation, fibrosis, and dysfunction were attenuated.

Conclusions: We show that, despite the endogenous cardiac lymphangiogenic response post-MI, the remodeling and dysfunction of collecting ducts contribute to the development of chronic myocardial edema and inflammation-aggravating cardiac fibrosis and dysfunction. Moreover, our data reveal that therapeutic lymphangiogenesis may be a promising new approach for the treatment of cardiovascular diseases.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.020143DOI Listing
April 2016

Vascular Smooth Muscle Mineralocorticoid Receptor Contributes to Coronary and Left Ventricular Dysfunction After Myocardial Infarction.

Hypertension 2016 Apr 22;67(4):717-23. Epub 2016 Feb 22.

From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1096, Rouen, France (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.); Institute for Research and Innovative Biomedicine (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), UFR Médecine-Pharmacie (A.G., N.H., J.F., L.N., J.-P.H., M.B., C.T., V.R., P.M., A.O.-P.), and Plateau d'Imagerie Cardio-Thoracique de l'Université de Rouen (PICTUR) (L.N., C.T., P.M.), Normandy-University, Rouen, France; Inserm U1138, Cordeliers Institute, Paris VI-University, Paris, France (G.G., F.J.); and Cardiology Research, Bayer-Pharmaceuticals, Wuppertal, Germany (P.K.).

Mineralocorticoid receptor (MR) antagonists slow down the progression of heart failure after myocardial infarction (MI), but the cell-specific role of MR in these benefits is unclear. In this study, the role of MR expressed in vascular smooth muscle cells (VSMCs) was investigated. Two months after coronary artery ligation causing MI, mice with VSMC-specific MR deletion (MI-MR(SMKO)) and mice treated with the MR antagonist finerenone (MI-fine) had improved left ventricular compliance and elastance when compared with infarcted control mice (MI-CTL), as well as reduced interstitial fibrosis. Importantly, the coronary reserve assessed by magnetic resonance imaging was preserved (difference in myocardial perfusion before and after induction of vasodilatation, mL mg(-1) min(-1): MI-CTL: 1.1 ± 0.5, nonsignificant; MI-MR(SMKO): 4.6 ± 1.6 [P<0.05]; MI-fine: 3.6 ± 0.7 [P<0.01]). The endothelial function, tested on isolated septal coronary arteries by analyzing the acetylcholine-induced nitric oxide-dependent relaxation, was also improved by MR deletion in VSMCs or by finerenone treatment (relaxation %: MI-CTL: 36 ± 5, MI-MR(SMKO): 54 ± 3, and MI-fine: 76 ± 4; P<0.05). Such impairment of the coronary endothelial function on MI involved an oxidative stress that was reduced when MR was deleted in VSMCs or by finerenone treatment. Moreover, short-term incubation of coronary arteries isolated from noninfarcted animals with low-dose angiotensin-II (10(-9) mol/L) induced oxidative stress and impaired acetylcholine-induced relaxation in CTL but neither in MR(SMKO) nor in mice pretreated with finerenone. In conclusion, deletion of MR in VSMCs improved left ventricular dysfunction after MI, likely through maintenance of the coronary reserve and improvement of coronary endothelial function. MR blockage by finerenone had similar effects.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.06709DOI 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

Role of M2-like macrophage recruitment during angiogenic growth factor therapy.

Angiogenesis 2015 Apr 24;18(2):191-200. Epub 2014 Dec 24.

UFR Médecine-Pharmacie, Inserm (Institut National de la Santé et de la Recherche Médicale) UMR1096, 22 Boulevard Gambetta, 76183, Rouen Cedex, France.

Therapeutic angiogenesis has yet to fulfill its promise for the clinical treatment of ischemic diseases. Given the impact of macrophages during pathophysiological angiogenesis, we asked whether macrophages may similarly modulate vascular responses to targeted angiogenic therapies. Mouse matrigel plug assay and rat myocardial infarction (MI) model were used to assess angiogenic therapy with either VEGF-A or FGF-2 with HGF (F+H) delivered locally via albumin-alginate microcapsules. The infiltration of classical M1-type and alternative M2-like macrophages was assessed. Clodronate was used to prevent macrophage recruitment, and the VEGFR2 blocking antibody, DC101, to prevent VEGF-A signaling. At 3 weeks after matrigel implantation, the combination therapy (F+H) led to increased total, and specifically M2-like, macrophage infiltration versus control and VEGF-A plugs, correlating with the angiogenic response. In contrast, VEGF-A preferential recruited M1-type macrophages. In agreement with a direct role of M2-like macrophages in F+H-induced vessel growth, clodronate radically decreased angiogenesis. Further, DC101 reduced F+H-induced angiogenesis, without altering macrophage infiltration, revealing macrophage-derived VEGF-A as a crucial determinant of tissue responsiveness. Similarly, increased cardiac M2-like macrophage infiltration was found following F+H therapy post-MI, with strong correlation between macrophage levels and angiogenic and arteriogenic responses. In conclusion, M2-like macrophages play a decisive role, linked to VEGF-A production, in regulation of tissue responsiveness to angiogenic therapies including the combination of F+H. Our data suggest that future attempts at therapeutic revascularization in ischemic patients might benefit from coupling targeted growth factor delivery with either direct or indirect approaches to recruit pro-angiogenic macrophages in order to maximize therapeutic angiogenic/arteriogenic responses.
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http://dx.doi.org/10.1007/s10456-014-9456-zDOI Listing
April 2015

Enhanced angiogenesis and increased cardiac perfusion after myocardial infarction in protein tyrosine phosphatase 1B-deficient mice.

FASEB J 2014 Aug 23;28(8):3351-61. Epub 2014 Apr 23.

Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; Institute of Research and Innovations in Biomedicine (IRIB), University of Rouen, Rouen, France; and

The protein tyrosine phosphatase 1B (PTP1B) modulates tyrosine kinase receptors, among which is the vascular endothelial growth factor receptor type 2 (VEGFR2), a key component of angiogenesis. Because PTP1B deficiency in mice improves left ventricular (LV) function 2 mo after myocardial infarction (MI), we hypothesized that enhanced angiogenesis early after MI via activated VEGFR2 contributes to this improvement. At 3 d after MI, capillary density was increased at the infarct border of PTP1B(-/-) mice [+7±2% vs. wild-type (WT), P = 0.05]. This was associated with increased extracellular signal-regulated kinase 2 phosphorylation and VEGFR2 activation (i.e., phosphorylated-Src/Src/VEGFR2 and dissociation of endothelial VEGFR2/VE-cadherin), together with higher infiltration of proangiogenic M2 macrophages within unchanged overall infiltration. In vitro, we showed that PTP1B inhibition or silencing using RNA interference increased VEGF-induced migration and proliferation of mouse heart microvascular endothelial cells as well as fibroblast growth factor (FGF)-induced proliferation of rat aortic smooth muscle cells. At 8 d after MI in PTP1B(-/-) mice, increased LV capillary density (+21±3% vs. WT; P<0.05) and an increased number of small diameter arteries (15-50 μm) were likely to participate in increased LV perfusion assessed by magnetic resonance imaging and improved LV compliance, indicating reduced diastolic dysfunction. In conclusion, PTP1B deficiency reduces MI-induced heart failure promptly after ischemia by enhancing angiogenesis, myocardial perfusion, and diastolic function.
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http://dx.doi.org/10.1096/fj.13-245753DOI 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

Circulating plasma serine208-phosphorylated troponin T levels are indicator of cardiac dysfunction.

J Cell Mol Med 2013 Oct 2;17(10):1335-44. Epub 2013 Aug 2.

INSERM, U744, Lille, France; Institut Pasteur de Lille, Lille, France; University of Lille 2, IFR141, Lille, France.

Heart failure (HF) following myocardial infarction (MI) is characterized by progressive alterations of left ventricular (LV) structure and function, named LV remodelling. Although several risk factors such as infarct size have been identified, HF remains difficult to predict in clinical practice. Recently, using phosphoproteomic technology, we found that serine(208)-phosphorylated troponin T (P-Ser(208)-TnT) decreases in LV of HF rats. Our aim was to determine the performance of P-Ser(208)-TnT as plasma biomarker of HF compared to conventional cardiac biomarkers such as B-type natriuretic peptide (BNP), cardiac troponin I (cTnI), C-reactive protein (CRP) or tissue inhibitor of metalloproteinase I (TIMP-1) measured by x-MAP technology, as well as its capacity to reflect a pharmacological improvement of HF. We observed a significant increase of BNP, TnT and cTnI levels and a significant decrease of P-Ser(208)-TnT and TIMP-1 in the plasma of 2-month-MI rats compared with control rats with no modulation of CRP level. Circulating levels of P-Ser(208)-TnT were shown to be associated with most of the echocardiographic and haemodynamic parameters of cardiac function. We verified that the decrease of P-Ser(208)-TnT was not because of an excess of phosphatase activity in plasma of HF rats. Two-month-MI rats treated with the heart rate reducing agent ivabradine had improved LV function and increased plasma levels of P-Ser(208)-TnT. Thus, circulating phosphorylated troponin T is a highly sensitive biological indicator of cardiac dysfunction and has the potentiality of a new biomarker of HF post-MI, and of a surrogate marker for the efficacy of a successful treatment of HF.
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http://dx.doi.org/10.1111/jcmm.12112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159027PMC
October 2013

Immunological tolerance to muscle autoantigens involves peripheral deletion of autoreactive CD8+ T cells.

PLoS One 2012 3;7(5):e36444. Epub 2012 May 3.

Inserm, U905, Rouen, France.

Muscle potentially represents the most abundant source of autoantigens of the body and can be targeted by a variety of severe autoimmune diseases. Yet, the mechanisms of immunological tolerance toward muscle autoantigens remain mostly unknown. We investigated this issue in transgenic SM-Ova mice that express an ovalbumin (Ova) neo-autoantigen specifically in skeletal muscle. We previously reported that antigen specific CD4(+) T cell are immunologically ignorant to endogenous Ova in this model but can be stimulated upon immunization. In contrast, Ova-specific CD8(+) T cells were suspected to be either unresponsive to Ova challenge or functionally defective. We now extend our investigations on the mechanisms governing CD8(+) tolerance in SM-Ova mice. We show herein that Ova-specific CD8(+) T cells are not detected upon challenge with strongly immunogenic Ova vaccines even after depletion of regulatory T cells. Ova-specific CD8(+) T cells from OT-I mice adoptively transferred to SM-Ova mice started to proliferate in vivo, acquired CD69 and PD-1 but subsequently down-regulated Bcl-2 and disappeared from the periphery, suggesting a mechanism of peripheral deletion. Peripheral deletion of endogenous Ova-specific cells was formally demonstrated in chimeric SM-Ova mice engrafted with bone marrow cells containing T cell precursors from OT-I TCR-transgenic mice. Thus, the present findings demonstrate that immunological tolerance to muscle autoantigens involves peripheral deletion of autoreactive CD8(+) T cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0036444PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343038PMC
January 2013

Reduction of heart failure by pharmacological inhibition or gene deletion of protein tyrosine phosphatase 1B.

J Mol Cell Cardiol 2012 Jun 15;52(6):1257-64. Epub 2012 Mar 15.

INSERM U1096, Rouen, France.

Protein tyrosine phosphatase 1B (PTP1B) regulates tyrosine kinase receptor-mediated responses, and especially negatively influences insulin sensitivity, thus PTP1B inhibitors (PTP1Bi) are currently evaluated in the context of diabetes. We recently revealed another important target for PTP1Bi, consisting in endothelial protection. The present study was designed to test whether reduction of PTP1B activity may be beneficial in chronic heart failure (CHF). We evaluated the impact of either a 2 month pharmacological inhibition, or a gene deletion of PTP1B (PTP1B(-/-)) in CHF mice (2 months post-myocardial infarction). PTP1Bi and PTP1B deficiency reduced adverse LV remodeling, and improved LV function, as shown by the increased LV fractional shortening and cardiac output (measured by echocardiography), the increased LV end systolic pressure, and the decreased LV end diastolic pressure, at identical infarct sizes. This was accompanied by reduced cardiac fibrosis, myocyte hypertrophy and cardiac expression of ANP. In vitro vascular studies performed in small mesenteric artery segments showed a restored endothelial function (i.e. improved NO-dependent, flow-mediated dilatation, increased eNOS phosphorylation) after either pharmacological inhibition or gene deletion. PTP1B(-/-) CHF also displayed an improved insulin sensitivity (assessed by euglycemic-hyperinsulinemic clamp studies), when compared to wild-type CHF associated with an increased insulin mediated mesenteric artery dilation. Thus, chronic pharmacological inhibition or gene deletion of PTP1B improves cardiac dysfunction and cardiac remodeling in the absence of changes in infarct size. Thus this enzyme may be a new therapeutic target in CHF. Diabetic patients with cardiac complications may potentially benefit from PTP1B inhibition via two different mechanisms, reduced diabetic complications, and reduced heart failure.
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http://dx.doi.org/10.1016/j.yjmcc.2012.03.003DOI Listing
June 2012

Progenitor cell mobilizing treatments prevent experimental transplant arteriosclerosis.

J Surg Res 2012 Aug 22;176(2):657-65. Epub 2011 Dec 22.

Inserm U644, Institute for Biomedical Research, Rouen University, Rouen, France.

Objective: Vascular rejection after organ transplantation is characterized by an arterial occlusive lesion, resulting from intimal proliferation occurring in response to arterial wall immune aggression. Our hypothesis is that an early endothelial repair may prevent vascular graft rejection. The aim of the current study was to compare different pharmacologic progenitor cell mobilizing treatments for their protective effects against vascular rejection.

Methods And Results: Aortic transplants were made from balb/c donor to C57Bl/6 recipient mice. Three different mobilizing pharmacologic agents were used: low molecular weight fucoidan (LMWF), simvastatin, and AMD3100. The circulating levels of progenitor cells were found to be increased by all three treatments, as determined by flow cytometry. For each treatment, the design was: treated allografts, nontreated allografts, treated isografts, and nontreated isografts. After 21 d, morphometric and immunohistochemical analyses were performed. We found that the three treatments significantly reduced intimal proliferation, compared with nontreated allografts. This was associated with intimal re-endothelialization of the grafts. Further, in chimeric mice that had previously received GFP-transgenic bone marrow transplantation, GFP-positive cells were found in the vascular allograft intima, indicating that re-endothelialization was, at least partly, due to the recruitment of bone marrow-derived, presumably endothelial progenitor circulating cells.

Conclusions: In this aortic allograft model, three different mobilizing treatments were found to partially prevent vascular transplant rejection. Bone marrow-derived progenitor cells mobilized by the three treatments may play a direct role in the endothelial repair process and in the suppression of intimal proliferation.
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http://dx.doi.org/10.1016/j.jss.2011.11.1014DOI Listing
August 2012

Heart rate reduction induced by the if current inhibitor ivabradine improves diastolic function and attenuates cardiac tissue hypoxia.

J Cardiovasc Pharmacol 2012 Mar;59(3):260-7

INSERM U644, Institut Hospitalier Recherche BioMedicale Normandie, IFRMP n°23, UFR de Médecine et de Pharmacie, Rouen, France.

Aims: Enhanced heart rate (HR) is a compensatory mechanism in chronic heart failure (CHF), preserving cardiac output, but at the cost of increased left ventricular (LV) oxygen consumption and impaired diastolic function. The HR reduction (HRR) induced by the If current inhibitor ivabradine prevents LV systolic dysfunction in CHF, but whether HRR improves LV diastolic function is unknown.

Methods: LV diastolic function and remodeling were assessed in rats with CHF after coronary ligation after long-term (90 days, starting 7 days after ligation) and delayed short-term (4 days, starting 93 days after ligation) ivabradine treatment (10 mg·kg·d).

Results: Long- and short-term HRR reduced LV end-diastolic pressure, LV relaxation, and LV end-diastolic pressure-volume relation. Simultaneously, LV hypoxia-inducible factor-1α expression was reduced. Long-term and, to a more marked extent, short-term HRR increased endothelial cell proliferation, associated after long-term HRR with the prevention of CHF-related LV capillary rarefaction. Long-term and, to a lesser extent, short-term HRR increased endothelial nitric oxide synthase expression, associated after long-term HRR with improved nitric oxide-dependent coronary vasodilatation.

Conclusions: Long-term HRR induced by ivabradine improves diastolic LV function probably involving attenuated hypoxia, reduced remodeling, and/or preserved nitric oxide bioavailability, resulting from processes triggered early after HRR initiation: angiogenesis and/or preservation of endothelial nitric oxide synthase expression.
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http://dx.doi.org/10.1097/FJC.0b013e31823e5e01DOI Listing
March 2012

Arteriogenic therapy by intramyocardial sustained delivery of a novel growth factor combination prevents chronic heart failure.

Circulation 2011 Aug 8;124(9):1059-69. Epub 2011 Aug 8.

Inserm U644, Institute for Biomedical Research, Rouen University, 22 Blvd Gambetta, 76183 Rouen, France.

Background: Therapeutic angiogenesis is a promising approach for the treatment of cardiovascular diseases, including myocardial infarction and chronic heart failure. We aimed to improve proangiogenic therapies by identifying novel arteriogenic growth factor combinations, developing injectable delivery systems for spatiotemporally controlled growth factor release, and evaluating functional consequences of targeted intramyocardial growth factor delivery in chronic heart failure.

Methods And Results: First, we observed that fibroblast growth factor and hepatocyte growth factor synergistically stimulate vascular cell migration and proliferation in vitro. Using 2 in vivo angiogenesis assays (n=5 mice per group), we found that the growth factor combination results in a more potent and durable angiogenic response than either growth factor used alone. Furthermore, we determined that the molecular mechanisms involve potentiation of Akt and mitogen-activated protein kinase signal transduction pathways, as well as upregulation of angiogenic growth factor receptors. Next, we developed crosslinked albumin-alginate microcapsules that sequentially release fibroblast growth factor-2 and hepatocyte growth factor. Finally, in a rat model of chronic heart failure induced by coronary ligation (n=14 to 15 rats per group), we found that intramyocardial slow release of fibroblast growth factor-2 with hepatocyte growth factor potently stimulates angiogenesis and arteriogenesis and prevents cardiac hypertrophy and fibrosis, as determined by immunohistochemistry, leading to improved cardiac perfusion after 3 months, as shown by magnetic resonance imaging. These multiple beneficial effects resulted in reduced adverse cardiac remodeling and improved left ventricular function, as revealed by echocardiography.

Conclusion: Our data showing the selective advantage of using fibroblast growth factor-2 together with hepatocyte growth factor suggest that this growth factor combination may constitute an efficient novel treatment for chronic heart failure.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.110.010264DOI Listing
August 2011

In vitro and ex vivo evaluation of smart infra-red fluorescent caspase-3 probes for molecular imaging of cardiovascular apoptosis.

Int J Mol Imaging 2011 5;2011:413290. Epub 2011 May 5.

Inserm U644 and Rouen University Hospital, Institute for Biomedical Research and IRFMP23, University of Rouen, 76183 Rouen, France.

Purpose. The aim of this paper is to develop new optical bioprobes for the imaging of apoptosis. Procedure. We developed quenched near-infrared probes which become fluorescent upon cleavage by caspase-3, the key regulatory enzyme of apoptosis. Results. Probes were shown to be selectively cleaved by recombinant caspase-3. Apoptosis of cultured endothelial cells was associated with an increased fluorescent signal for the cleaved probes, which colocalized with caspase-3 and was reduced by the addition of a caspase-3 inhibitor. Flow cytometry demonstrated a similar profile between the cleaved probes and annexin V. Ex vivo experiments showed that sections of hearts obtained from mice treated with the proapoptotic drug doxorubicin displayed an increase in the fluorescent signal for the cleaved probes, which was reduced by a caspase-3 inhibitor. Conclusion. We demonstrated the capacity of these novel probes to detect apoptosis by optical imaging in vitro and ex vivo.
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http://dx.doi.org/10.1155/2011/413290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3099191PMC
July 2011

Soluble epoxide hydrolase inhibition prevents coronary endothelial dysfunction in mice with renovascular hypertension.

J Hypertens 2011 Jun;29(6):1128-35

From the INSERM U644, France.

Objectives: The study addresses the hypothesis that endothelial dysfunction in experimental arterial hypertension can be related to an alteration in epoxyeicosatrienoic acids (EETs) pathway and can be prevented by the inhibition of EETs degradation by soluble epoxide hydrolase (sEH).

Methods And Results: Arterial hypertension was induced in FVB/N mice by renal artery stenosis ('two-kidney-one-clip', 2K1C). Seven weeks after surgery, increased aortic pressures (Millar tonometer; Millar Instruments, Houston, Texas, USA) and cardiac hypertrophy (echocardiography) were present in 2K1C mice as compared with control mice. Left coronary artery endothelium-dependent relaxations to acetylcholine were decreased in 2K1C mice without modification in the relaxing responses to NS309 and NS1619, the openers of calcium-activated potassium channels mediating the hyperpolarizing effect of EETs. The inhibitors of the EET-synthesizing enzymes cytochrome P450 epoxygenases, fluconazole and N-methylsulfonyl-6-(2-propargyloxyphenyl)-hexanamide (MSPPOH), reduced the coronary relaxations to acetylcholine in control but not in 2K1C mice. The sEH expression was increased in 2K1C mice. The sEH inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid administered for 2 weeks starting 5 weeks after surgery in 2K1C mice (25 mg/l in drinking water) reduced aortic pressures and cardiac hypertrophy, improved the coronary relaxations to acetylcholine and restored the inhibitory effect of fluconazole and MSPPOH on acetylcholine-induced relaxations, without modifying the relaxations to NS309 and NS1619.

Conclusion: These results demonstrate that a reduced EET-mediated relaxations related to an increased degradation by sEH contributes to coronary endothelial dysfunction in 2K1C hypertensive mice. Inhibiting sEH prevents endothelial dysfunction by restoring EET-mediated relaxations and thus, could represent a promising pharmacological intervention to limit cardiovascular morbidity and mortality in arterial hypertension.
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http://dx.doi.org/10.1097/HJH.0b013e328345ef7bDOI Listing
June 2011

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

Brain death provokes very acute alteration in myocardial morphology detected by echocardiography: preventive effect of beta-blockers.

Transpl Int 2011 Mar 16;24(3):300-6. Epub 2010 Nov 16.

Inserm, U886, Université de Lyon, Université Lyon 1, Lyon, France.

Our objective was to evaluate immediate acute changes in myocardial function during the autonomic storm of brain death (BD). Wistar rats were divided into four groups (n = 8/group): controls without any treatment, β-blocker (Esmolol®, 10 mg/kg), calcium channel blocker (Diltiazem®, 10 mg/kg), or alpha-blocker (Prazosin®, 0.3 mg/kg). Treatments were administered intravenously 5 min before BD induction. Echocardiography (ATL-5000, 8 MHz) was performed to measure left ventricular (LV) dimensions and fractional shortening at baseline, during BD induction and 5 min and 15 min after BD. In controls, BD was immediately associated with an increase in wall thickness and a decrease in LV cavity dimension. This myocardial wall hypertrophy was completely prevented by β-blockers, but not with calcium- and alpha-blockers. Extensive myocardial interstitial edema was found in all groups, except in the β-blocker group. Myocardial wall hypertrophy was also prevented during a longer follow-up of 180 min after BD in β-blocker group as opposed to controls. In conclusion, BD is associated with an immediate and severe myocardial damage related to an important interstitial edema which is prevented by β-blockers.
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http://dx.doi.org/10.1111/j.1432-2277.2010.01184.xDOI Listing
March 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

Decreased serine207 phosphorylation of troponin T as a biomarker for left ventricular remodelling after myocardial infarction.

Eur Heart J 2011 Jan 25;32(1):115-23. Epub 2010 Apr 25.

INSERM U744, Lille, France.

Aims: Chronic heart failure following myocardial infarction (MI) is characterized by progressive left ventricular remodelling (LVR). Despite significant improvements in MI management, LVR remains a frequent complication. Although several risk factors have been identified, such as infarct size, LVR is difficult to predict in clinical practice.

Methods And Results: Using a rat model of MI and phosphoproteomic technology, we discovered that remodelling is associated with decreased levels of myocardial and plasma serine(208)-phosphorylated troponin T (TnT). To confirm the association in human plasma, we developed new specific polyclonal antibodies against human/rat serine(207/208)-phosphorylated TnT and tested plasma obtained in the first week after MI from patients with low, intermediate, and high remodelling a year later. We observed a significant decrease of serine(207)-phosphorylated TnT and of the serine(207)-phosphorylated TnT/total TnT ratio in those with intermediate or high LVR. These differences remained statistically significant when adjusted for other determinants of LVR. In contrast, baseline B-type natriuretic peptide levels were not associated with LVR.

Conclusion: The level of circulating phosphorylated TnT could be a new biomarker of LVR.
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http://dx.doi.org/10.1093/eurheartj/ehq108DOI Listing
January 2011

Role of endogenous endothelin in endothelial dysfunction in murine model of systemic sclerosis: tight skin mice 1.

Fundam Clin Pharmacol 2008 Dec;22(6):649-55

Inserm U644 & Rouen University Hospital, Institute for Biomedical Research and IFRMP 23, University of Rouen, Rouen, France.

Systemic sclerosis (SSc) is a systemic inflammatory disorder, resulting in severe vascular dysfunction. The endothelin (ET) system has vasoconstrictor and profibrotic properties and has been shown to be activated in SSc. ET antagonists are currently used in SSc-related pulmonary arterial hypertension, but the endothelial impact of ET antagonists remains less known in SSc. We thus assessed the effects of the dual ET(A)-ET(B) antagonist, bosentan, on endothelial dysfunction in a murine model of SSc, the heterozygous tight-skin mice 1 (TSK1(+)). Six-week-old TSK1(+) were either untreated or treated for 6 weeks with bosentan (100 mg/kg/day), and compared with controls. Endothelial function was evaluated in isolated mesenteric resistance arteries, using a small vessel myograph. TSK1(+) displayed endothelial dysfunction, as shown by a decreased response of mesenteric arteries to acetylcholine, especially in the presence of L-nitro-arginine methyl ester (L-NAME), corresponding to NO-independent, prostaglandin-mediated relaxation. The NO-independent relaxation was partially restored in bosentan-treated TSK1(+), and this was abolished by a cyclo-oxygenase inhibitor. Therefore, the murine model of SSc, TSK1(+) exhibits severe endothelial dysfunction of peripheral resistance arteries. The ET antagonist bosentan prevents endothelial alterations, suggesting a major role of ET in the adverse vascular effects of SSc.
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http://dx.doi.org/10.1111/j.1472-8206.2008.00634.xDOI Listing
December 2008

Proteomic analysis of left ventricular remodeling in an experimental model of heart failure.

J Proteome Res 2008 Nov 16;7(11):5004-16. Epub 2008 Oct 16.

INSERM, U744, Lille, France.

The development of chronic heart failure (CHF) following myocardial infarction is characterized by progressive alterations of left ventricle (LV) structure and function called left ventricular remodeling (LVR), but the mechanism of LVR remains still unclear. Moreover, information concerning the global alteration protein pattern during the LVR will be helpful for a better understanding of the process. We performed differential proteomic analysis of whole LV proteins using an experimental model of CHF in which myocardial infarction was induced in adult male rats by left coronary ligation. Among 1000 protein spots detected in 2D-gels, 49 were differentially expressed in LV of 2-month-old CHF-rats, corresponding to 27 different identified proteins (8 spots remained unidentified), classified in different functional groups as being heat shock proteins, reticulum endoplasmic stress proteins, oxidative stress proteins, glycolytic enzymes, fatty acid metabolism enzymes, tricarboxylic acid cycle proteins and respiratory chain proteins. We validated modulation of selected proteins using Western blot analysis. Our data showed that proteins involved in cardiac metabolism and oxidative stress are modulated during LVR. Interestingly, proteins of stress response showed different adaptation pathways in the early and late phase of LVR. Expression of four proteins, glyceraldehyde-3-phosphate dehydrogenase, alphaB-crystallin, peroxiredoxin 2, and isocitrate dehydrogenase, was linked to echographic parameters according to heart failure severity.
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http://dx.doi.org/10.1021/pr800409uDOI Listing
November 2008

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

Low molecular weight fucoidan prevents neointimal hyperplasia after aortic allografting.

Transplantation 2007 May;83(9):1234-41

Inserm U644, IFRMP 23, Rouen University Hospital-Charles Nicolle, Rouen, France.

Background: Fucoidan, a new low molecular weight sulfated polysaccharide (LMWF), has previously been shown to mobilize bone marrow-derived progenitors cells via stimulation of stromal derived factor (SDF)-1 release. Mobilized progenitor cells have been suggested to repair intimal lesions after immune-mediated endothelial injury and thus prevent intimal proliferation. The aim of this study was to evaluate the effect of LMWF treatment in a rat aortic allograft model of transplant arteriosclerosis (TA).

Methods: Aortic grafts were performed in Brown Norway (BN, donor) and Lewis (Lew, recipient) rats. The recipient rats were treated with LMWF (5 mg/kg/day) and sacrificed at 30 days. To determine the role of SDF-1 in mediating the effects of LMWF, a specific inhibitor of the SDF-1 receptor CXCR4, AMD 3100 (20 microg/kg/day), was used. The grafted segments were evaluated by morphometric (histochemical) analyses.

Results: Untreated aortic allografts exhibited severe intimal proliferation, indicative of TA. In contrast, LMWF treatment significantly prevented allograft intimal proliferation as compared with controls (5.7+/-3 vs. 66.2+/-6 microm, P<0.01) and permitted a normalization of the intima/media ratio (0.1+/-0.1 vs. 1.7+/-0.3, P<0.01). Further, LMWF treatment stimulated allograft reendothelialization, as evidenced by strong intimal endothelial nitric oxide synthase antibody and CD31 signals. Unexpectedly, AMD treatment failed to prevent the protective effect of LMWF on intimal thickening and AMD treatment alone was found to reduced intimal proliferation in allografts.

Conclusions: We found that LMWF treatment reduced intimal thickness and induced the presence of an endothelial cell lining in the vascular graft at 30 days. Our findings may suggest a novel therapeutic strategy in the prevention of TA.
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http://dx.doi.org/10.1097/01.tp.0000261109.97928.9cDOI Listing
May 2007

Transient recurrent ascites.

Acta Gastroenterol Belg 2006 Oct-Dec;69(4):381-3

Department of Gastroenterology and Hepaticopancreatology, Erasme Hospital, University Clinics of Brussels, Free University of Brussels, Brussels, Belgium.

Angiotensin-converting enzyme (ACE) inhibitors are widely used in heart diseases. We describe a case of a young woman treated with fosinopril. She started experiencing abdominal pain, vomiting and diarrhoea with peritoneal signs on physical examination three years after her treatment has been initiated. She presented ascites and signs of ileitis on imaging studies. She even underwent surgery. The diagnosis of ACE inhibitor-induced angiooedema of the small bowel was made after the fourth episode. Fosinopril was stopped and the symptoms never recurred. The case we describe illustrates clinical presentation, radiological findings and difficulty of making an accurate diagnosis in such a patient.
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May 2007

Toll-like receptors 2-deficient mice are protected against postischemic coronary endothelial dysfunction.

Arterioscler Thromb Vasc Biol 2007 May 1;27(5):1064-71. Epub 2007 Mar 1.

Inserm U644 & Rouen University Hospital, Institute for Biomedical Research and IFRMP 23, University of Rouen, France.

Objectives: Toll-like receptors (TLR) 2 are expressed in cardiac and inflammatory cells, and regulate leukocyte function. Because leukocyte adhesion is a critical event in endothelial injury induced by ischemia/reperfusion (I/R), we assessed whether TLR2 were involved in I/R-induced coronary endothelial injury.

Methods And Results: Ischemia-reperfusion markedly decreased NO-mediated coronary relaxations to acetylcholine assessed ex vivo. In contrast, in TLR2 deficient mice, I/R paradoxically improved the NO-mediated responses to acetylcholine. To precise the cellular compartment expressing TLR2 which is involved in endothelial injury, we developed bone-marrow chimeric mice by transplanting TLR2-/- bone marrow to WT mice or WT bone marrow to TLR2-/- mice and submitted them to I/R 5 weeks after transplant. Both chimeric mice displayed similar protection as TLR2-/- mice against I/R-induced endothelial dysfunction, suggesting a role of TLR2 expressed on both non-bone marrow cells (in our case presumably endothelial cells and/or cardiomyocytes) and cells of bone marrow origin (presumably neutrophils). TLR2 deficiency was also associated with a smaller infarct size, and reduced reperfusion-induced production of reactive oxygen species and leukocyte infiltration.

Conclusions: TLR2 contribute to coronary endothelial dysfunction after I/R, possibly through stimulation of neutrophil- (and free radical-) mediated endothelial injury.
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http://dx.doi.org/10.1161/ATVBAHA.107.140723DOI Listing
May 2007