Publications by authors named "Lionel Nicol"

21 Publications

  • Page 1 of 1

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

A polymeric diet rich in transforming growth factor beta 2 does not reduce inflammation in chronic 2,4,6-trinitrobenzene sulfonic acid colitis in pre-pubertal rats.

BMC Gastroenterol 2020 Dec 10;20(1):416. Epub 2020 Dec 10.

INSERM UMR 1073, Institute for Biomedical Research, Rouen University, Rouen, France.

Background: Pediatric Crohn's disease is characterized by a higher incidence of complicated phenotypes. Murine models help to better understand the dynamic process of intestinal fibrosis and test therapeutic interventions. Pre-pubertal models are lacking. We aimed to adapt a model of chronic colitis to pre-pubertal rats and test if a polymeric diet rich in TGF-β2 could reduce TNBS-induced intestinal inflammation and fibrosis.

Methods: Colitis was induced in 20 five-week-old Sprague-Dawley male rats by weekly rectal injections of increasing doses of TNBS (90 mg/kg, 140 mg/kg and 180 mg/kg) for 3 weeks, while 10 controls received phosphate-buffered saline. Rats were anesthetized using ketamine and chlorpromazine. After first administration of TNBS, 10 rats were fed exclusively MODULEN IBD® powder, while remaining rats were fed breeding chow. Colitis was assessed one week after last dose of TNBS by histopathology and magnetic resonance colonography (MRC).

Results: Histological inflammation and fibrosis scores were higher in TNBS group than controls (p < 0.05 for both). MRC showed increased colon wall thickness in TNBS group compared to controls (p < 0.01), and increased prevalence of strictures and target sign (p < 0.05). Colon expression of COL1A1, CTGF, α-SMA and COX-2 did not differ between TNBS rats and controls. TNBS colitis was not associated with growth failure. Treatment with MODULEN IBD® was associated with growth failure, increased colon weight/length ratio (p < 0.01), but did not affect histological scores or MRI characteristics. Colon expression of α-SMA was significantly lower in the MODULEN group versus controls (p = 0.005).

Conclusion: Features of chronic colitis were confirmed in this model, based on MRC and histopathology. Treatment with MODULEN did not reverse inflammation or fibrosis.
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http://dx.doi.org/10.1186/s12876-020-01574-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731574PMC
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

Major hepatectomy decreased tumor growth in an experimental model of bilobar liver metastasis.

HPB (Oxford) 2020 Oct 7;22(10):1480-1489. Epub 2020 Mar 7.

Department of Hepatobiliary and Liver Transplantation - Paul Brousse University Hospital, France.

Background/purpose: Two-stage hepatectomy (TSH), is associated with a risk of drop-out due to tumoral progression following portal vein occlusion (PVO). We explored the impact of majorhepatectomy on tumor growth by objective radiological measures comparing to PVO and minor hepatectomy, using a model of bilobar colorectal liver metastasis (CLM).

Methods: CLM were induced in 48 BDIX rats by injection of DHDK12-cells. 7 days after cells injection, animals were distributed into 4 groups of equal number (n = 12): portal vein ligation (PVL), sham laparotomy (sham), minor (30%Phx) and major (70%Phx) hepatectomy. MR imaging was used for in vivo analysis of tumor implantation, growth and volumes.

Results: At POD10, tumour volumes were homogeneously distributed among the 4 groups. Lower TV were significantly observed after 70%Phx comparing to PVL at POD17 (0.63 ± 0.14cm3 vs 0.9 ± 0.16cm3, p = 0.008) and to the 3 others groups at POD24: 1.78 ± 0.38cm3 vs 3.2 ± 0.62cm3 (PVL, p = 0.019), 2.41 ± 0.74cm3 (Sham, p = 0.024) and 2.32 ± 0.59cm3 (30%PHx, p = 0.019).

Conclusion: We confirmed in a reproducible model that contrary to PVO, a major hepatectomy decreases the growth of CLM in the remnant liver. This result leads to questioning the usual TSH and justifies exploring alternative strategies. The "major hepatectomy first-approach" should be an option to be evaluated.
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http://dx.doi.org/10.1016/j.hpb.2020.02.008DOI Listing
October 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

Contribution of genotoxic anticancer treatments to the development of multiple primary tumours in the context of germline TP53 mutations.

Eur J Cancer 2018 09 30;101:254-262. Epub 2018 Jul 30.

Normandie Univ, UNIROUEN, Inserm U1245, Rouen University Hospital, Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.

Introduction: Li-Fraumeni syndrome (LFS), due to TP53 germline mutations, is characterised by a remarkably high incidence of multiple primary cancers (MPCs), and the key role of p53 in response to DNA damage questions the contribution of anticancer treatments to MPCs development.

Materials And Methods: We first evaluated genotoxicity of X-rays and different classes of conventional chemotherapies, thanks to genotoxicity assays, based on the measurement of transcriptional response to DNA damage and performed in murine splenocytes, either exposed ex vivo or extracted from exposed mice. We then exposed a total of 208 Trp53Δ/Δ, wt/Δ or wt/wt mice to clinical doses of X-rays or genotoxic or non-genotoxic chemotherapies. Tumour development was monitored using whole-body magnetic resonance imaging and pathological examination at death.

Results: X-rays and conventional chemotherapies, except mitotic spindle poisons, were found to be genotoxic in both p53 genotoxicity assays. Exposition to X-rays and the topoisomerase inhibitor etoposide, analysed as genotoxic anticancer treatment, drastically increase the tumour development risk in Trp53Δ/Δ and wt/Δ mice (hazard ration [HR] = 4.4, 95% confidence interval [CI] [2.2-8.8], p < 0.001*** and HR = 4.7, 95% CI [2.4-9.3], p < 0.001***, respectively). In contrast, exposure to the non-genotoxic mitotic spindle poison, docetaxel, had no impact on tumour development.

Conclusions: This study shows that radiotherapy and genotoxic chemotherapies significantly increase the risk of tumour development in a LFS mice model. These results strongly support the contribution of genotoxic anticancer treatments to MPC development in LFS patients. Therefore, to reduce the risk of MPCs in germline TP53 mutation carriers, radiotherapy should be avoided whenever possible, surgical treatment prioritised, and non-genotoxic treatments considered.
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http://dx.doi.org/10.1016/j.ejca.2018.06.011DOI Listing
September 2018

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

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

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

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

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

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

This study addressed the hypothesis that inhibiting the soluble epoxide hydrolase (sEH)-mediated degradation of epoxy-fatty acids, notably epoxyeicosatrienoic acids, has an additional impact against cardiovascular damage in insulin resistance, beyond its previously demonstrated beneficial effect on glucose homeostasis. The cardiovascular and metabolic effects of the sEH inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB; 10 mg/l in drinking water) were compared with those of the sulfonylurea glibenclamide (80 mg/l), both administered for 8 wk in FVB mice subjected to a high-fat diet (HFD; 60% fat) for 16 wk. Mice on control chow diet (10% fat) and nontreated HFD mice served as controls. Glibenclamide and t-AUCB similarly prevented the increased fasting glycemia in HFD mice, but only t-AUCB improved glucose tolerance and decreased gluconeogenesis, without modifying weight gain. Moreover, t-AUCB reduced adipose tissue inflammation, plasma free fatty acids, and LDL cholesterol and prevented hepatic steatosis. Furthermore, only the sEH inhibitor improved endothelium-dependent relaxations to acetylcholine, assessed by myography in isolated coronary arteries. This improvement was related to a restoration of epoxyeicosatrienoic acid and nitric oxide pathways, as shown by the increased inhibitory effects of the nitric oxide synthase and cytochrome P-450 epoxygenase inhibitors l-NA and MSPPOH on these relaxations. Moreover, t-AUCB decreased cardiac hypertrophy, fibrosis, and inflammation and improved diastolic function, as demonstrated by the increased E/A ratio (echocardiography) and decreased slope of the end-diastolic pressure-volume relation (invasive hemodynamics). These results demonstrate that sEH inhibition improves coronary endothelial function and prevents cardiac remodeling and diastolic dysfunction in obese insulin-resistant mice.
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http://dx.doi.org/10.1152/ajpheart.00465.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551118PMC
May 2015

Magnetic resonance colonography for fibrosis assessment in rats with chronic colitis.

PLoS One 2014 7;9(7):e100921. Epub 2014 Jul 7.

Radiology Department, Rouen University Hospital, Rouen, France; QUANTIF-LITIS EA 4108, Rouen University, Rouen, France.

Background: Magnetic resonance colonography (MRC) has been developed to assess inflammatory bowel diseases. We aimed to assess the feasibility of MRC in rats with TNBS-induced chronic colitis and to confront imaging results with fibrosis and stenosing features of the model.

Materials And Methods: Chronic colitis was induced in 12 rats by weekly intra-rectal injection of increasing doses of TNBS for 6 weeks, while 8 control rats received the vehicle. At week 7, MRC was performed. Fibrosis scores were assessed and fibrosis mediators measured.

Results: Chronic colitis was associated with significant body weight loss (p<0.0001) and higher colon weight/length compared to controls (p = 0.0004). Fibrosis mediators and histological scores were significantly higher in rats with TNBS than in controls: α-SMA expression (0.9 versus 0.61, p = 0.0311) and fibrosis score (p = 0.0308). Colon wall thickness was higher in rats with TNBS than in controls: maximal thickness (2.38 versus 0.74 mm, p<0.0001) and minimal thickness (1.33 versus 0.48 mm, p<0.0001). Wall signal intensity on T2w images was higher in rats with TNBS than in controls (9040 versus 6192, p = 0.0101) and correlated with fibrosis score (r = 0.5214; p = 0.04). Luminal narrowing was higher in rats with TNBS (50.08 versus 10.33%, p<0.0001) and correlated with α-SMA expression (r = 0.5618; p = 0.01). Stenosis was observed in 7/9 rats with TNBS and in no controls (p = 0.0053).

Conclusions: MRC is feasible and easily distinguishes rats with colitis from controls. MRC signs correlated with fibrosis parameters. MRC evaluation may be part of a new anti-fibrosis drug assessment in experimental models of chronic colitis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100921PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085031PMC
February 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

MR relaxometry and perfusion of the myocardium in spontaneously hypertensive rat: correlation with histopathology and effect of anti-hypertensive therapy.

Eur Radiol 2013 Jul 17;23(7):1871-81. Epub 2013 Apr 17.

Inserm U1096, Rouen, France.

Objectives: To investigate myocardial relaxation times and perfusion values in spontaneously hypertensive rats (SHRs) at various stages of the disease, with or without anti-fibrotic therapy, and to correlate magnetic resonance imaging (MRI) findings with histopathological myocardial fibrosis and capillary density.

Methods: Five groups of rats underwent MRI at 4.7 T. They were either untreated or treated with an aldosterone-synthase inhibitor. T1, T2 and T2 relaxation times were determined and myocardial perfusion was quantified from an arterial spin labelling sequence. MR relaxation times and perfusion values were compared with the fibrotic content and capillary density of the myocardium obtained at histology after euthanasia.

Results: T1 values significantly increased during the course of hypertensive disease, and correlated with myocardial fibrosis (R = 0.71, P < 0.001); T2 values also increased but were weakly correlated with myocardial fibrosis (R = 0.27,P = 0.047). Myocardial perfusion and capillary density significantly decreased with hypertensive disease but they did not correlate. Following prolonged treatment, we observed a trend associating T1 decrease and improved perfusion compared with untreated SHRs.

Conclusions: Myocardial T1 and T2 values increase with hypertensive disease, whereas myocardial perfusion decreases. The correlation between T1 values and collagen density suggests that the former could be considered as a non-invasive marker of myocardial fibrosis.

Key Points: • MR is increasingly used to assess alteration in myocardial tissue content. • MR relaxometry and perfusion can be assessed in rats without exogenous contrast agents. • Myocardial T1 and T2 values significantly increase during the course of hypertensive heart disease. • T1 values correlate significantly with myocardial collagen content. • Myocardial perfusion values decrease with hypertensive disease.
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http://dx.doi.org/10.1007/s00330-013-2801-6DOI Listing
July 2013

Magnetic resonance colonography in rats with TNBS-induced colitis: a feasibility and validation study.

Inflamm Bowel Dis 2012 Oct 19;18(10):1940-9. Epub 2012 Jan 19.

INSERM Unit U1073, Institute for Biomedical Research, Rouen University, Rouen, France.

Background: Magnetic resonance colonography (MRC) has been recently developed to assess bowel inflammation in inflammatory bowel disease (IBD) patients. Evaluating animal models of inflammation with MRC may be important in new drug-screening processes. The aim of this study was to assess the feasibility of MRC in colitic rats and confront it with model characteristics.

Methods: Colitis was induced by rectal injection of trinitrobenzene-sulfonic acid (TNBS) in 13 rats while six rats received the vehicle. MRC was performed at day 2. Colon inflammation and production of inflammatory mediators were evaluated. Image quality was assessed by wall and motion artifacts. MRC criteria were bowel wall thickness, wall signal intensity on T2-weighted (T2w) and T1w images, the appearance of a target sign pattern, and irregular patterns of mucosal surface.

Results: MRC quality was good or excellent in 16/21 examinations with no difference between groups. Colitis rats were significantly different from controls in terms of wall thickness (P = 0.004), the appearance of a target sign pattern (P = 0.02), irregular patterns of mucosal surface (P = 0.01), and hyperintensity on T1w images (P = 0.03). All MRC criteria except maximal bowel wall thickness were associated with colon weight:length ratio and inflammatory biomarkers (all P < 0.05). Minimal bowel wall thickness and wall signal intensity on T2w images were associated with histological score (P < 0.05).

Conclusions: MRC is feasible and reliable in rats with TNBS-induced colitis. MRC criteria including colon wall thickness, wall signal intensity on T2w images, hyperintensity in T1w sequence, and the appearance of a target sign pattern may be potential targets for new IBD drugs.
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http://dx.doi.org/10.1002/ibd.22897DOI Listing
October 2012

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

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

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

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

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

Improvement of left ventricular diastolic function induced by β-blockade: a comparison between nebivolol and metoprolol.

J Mol Cell Cardiol 2011 Aug 24;51(2):168-76. Epub 2011 May 24.

INSERM U644, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides n°23 Institut de Recherche et d'Innovation Biomédicale de Haute Normandie, UFR de Médecine et de Pharmacie, Rouen, France.

Objectives: Enhanced adrenergic drive is involved in the development of left ventricular (LV) diastolic dysfunction observed in metabolic syndrome (MS). Thus, β-blockers might improve LV dysfunction observed in MS, but whether this occurs is unknown.

Methods: We assessed in Zucker fa/fa rats the effects of short- (5 days) and long-term (90 days) metoprolol ('pure' β-blockade; 80 mg/kg/day) or nebivolol (β-blocker with vasodilating properties; 5mg/kg/day) treatment on LV hemodynamics and remodeling, as well as the long-term effects on coronary and peripheral endothelial dysfunction.

Results: At identical degree of β(1)-receptor blockade, metoprolol and nebivolol decreased heart rate to the same extent and preserved cardiac output via increased stroke volume. None of the β-blockers, either after long- or short-term administration, modified LV end-systolic pressure-volume relation. Both β-blockers reduced, after long-term administration, LV end-diastolic pressure, Tau and end-diastolic pressure-volume relation, and this was associated with reduced LV collagen density, but not heart weight. Similar hemodynamic effects were also observed after short-term nebivolol, but not short-term metoprolol. These short-term effects of nebivolol were abolished by NO synthase inhibition. At the vascular level, nebivolol, and to a lesser extend metoprolol, improved NO dependent coronary vasorelaxation, which was abolished by NO synthase inhibition.

Conclusions: In a model of MS, the β-blockers metoprolol and nebivolol improve to the same extent LV hemodynamics, remodeling and diastolic function, but nebivolol prevent more markedly endothelium dependent vasorelaxation involving a more marked enhancement of NO bio-availability.
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http://dx.doi.org/10.1016/j.yjmcc.2011.05.012DOI Listing
August 2011