Publications by authors named "David Coquerel"

17 Publications

  • Page 1 of 1

Soluble Epoxide Hydrolase Inhibition Prevents Experimental Type 4 Cardiorenal Syndrome.

Front Mol Biosci 2020 11;7:604042. Epub 2021 Mar 11.

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

Cardiovascular diseases (CVD) remain the leading cause of morbimortality in patients with chronic kidney disease (CKD). The aim of this study was to assess the cardiovascular impact of the pharmacological inhibition of soluble epoxide hydrolase (sEH), which metabolizes the endothelium-derived vasodilatory and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acid (DHETs), in the 5/6 nephrectomy (Nx) mouse model. Compared to sham-operated mice, there was decrease in EET-to-DHET ratio 3 months after surgery in vehicle-treated Nx mice but not in mice treated with the sEH inhibitor -AUCB. Nx induced an increase in plasma creatinine and in urine albumin-to-creatinine ratio as well as the development of kidney histological lesions, all of which were not modified by -AUCB. In addition, -AUCB did not oppose Nx-induced blood pressure increase. However, AUCB prevented the development of cardiac hypertrophy and fibrosis induced by Nx, as well as normalized the echocardiographic indices of diastolic and systolic function. Moreover, the reduction in endothelium-dependent flow-mediated dilatation of isolated mesenteric arteries induced by Nx was blunted by -AUCB without change in endothelium-independent dilatation to sodium nitroprusside. Inhibition of sEH reduces the cardiac remodelling, and the diastolic and systolic dysfunctions associated with CKD. These beneficial effects may be mediated by the prevention of endothelial dysfunction, independent from kidney preservation and antihypertensor effect. Thus, inhibition of sEH holds a therapeutic potential in preventing type 4 cardiorenal syndrome.
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http://dx.doi.org/10.3389/fmolb.2020.604042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991096PMC
March 2021

Gαi-biased apelin analog protects against isoproterenol-induced myocardial dysfunction in rats.

Am J Physiol Heart Circ Physiol 2021 04 26;320(4):H1646-H1656. Epub 2021 Feb 26.

Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Institut de Pharmacologie de Sherbrooke, Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, Québec, Canada.

Apelin receptor (APJ) activation by apelin-13 (APLN-13) engages both Gαi proteins and β-arrestins, stimulating distinct intracellular pathways and triggering physiological responses like enhanced cardiac contractility. Substituting the C-terminal phenylalanine of APLN-13 with α-methyl-l-phenylalanine [(l-α-Me)Phe] or p-benzoyl-l-phenylalanine (Bpa) generates biased analogs inducing APJ functional selectivity toward Gαi proteins. Using these original analogs, we proposed to investigate how the canonical Gαi signaling of APJ regulates the cardiac function and to assess their therapeutic impact in a rat model of isoproterenol-induced myocardial dysfunction. In vivo and ex vivo infusions of either Bpa or (l-α-Me)Phe analogs failed to enhance rats' left ventricular (LV) contractility compared with APLN-13. Inhibition of Gαi with pertussis toxin injection optimized the cardiotropic effect of APLN-13 and revealed the inotropic impact of Bpa. Moreover, both APLN-13 and Bpa efficiently limited the forskolin-induced and PKA-dependent phosphorylation of phospholamban at the Ser16 in neonatal rat ventricular myocytes. However, only Bpa significantly reduced the inotropic effect of forskolin infusion in isolated-perfused heart, highlighting its efficient bias toward Gαi. Compared with APLN-13, Bpa also markedly improved isoproterenol-induced myocardial systolic and diastolic dysfunctions. Bpa prevented cardiac weight increase, normalized both ANP and BNP mRNA expressions, and decreased LV fibrosis in isoproterenol-treated rats. Our results show that APJ-driven Gαi/adenylyl cyclase signaling is functional in cardiomyocytes and acts as negative feedback of the APLN-APJ-dependent inotropic response. Biased APJ signaling toward Gαi over the β-arrestin pathway offers a promising strategy in the treatment of cardiovascular diseases related to myocardial hypertrophy and high catecholamine levels. By using more potent Gαi-biased APJ agonists that strongly inhibit cAMP production, these data point to the negative inotropic effect of APJ-mediated Gαi signaling in the heart and highlight the potential protective impact of APJ-dependent Gαi signaling in cardiovascular diseases associated with left ventricular hypertrophy.
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http://dx.doi.org/10.1152/ajpheart.00688.2020DOI Listing
April 2021

Preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients.

Sci Rep 2021 Feb 12;11(1):3739. Epub 2021 Feb 12.

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

This study addressed the hypothesis that epoxyeicosatrienoic acids (EETs) synthesized by CYP450 and catabolized by soluble epoxide hydrolase (sEH) are involved in the maintenance of renal allograft function, either directly or through modulation of cardiovascular function. The impact of single nucleotide polymorphisms (SNPs) in the sEH gene EPHX2 and CYP450 on renal and vascular function, plasma levels of EETs and peripheral blood monuclear cell sEH activity was assessed in 79 kidney transplant recipients explored at least one year after transplantation. Additional experiments in a mouse model mimicking the ischemia-reperfusion (I/R) injury suffered by the transplanted kidney evaluated the cardiovascular and renal effects of the sEH inhibitor t-AUCB administered in drinking water (10 mg/l) during 28 days after surgery. There was a long-term protective effect of the sEH SNP rs6558004, which increased EET plasma levels, on renal allograft function and a deleterious effect of K55R, which increased sEH activity. Surprisingly, the loss-of-function CYP2C9*3 was associated with a better renal function without affecting EET levels. R287Q SNP, which decreased sEH activity, was protective against vascular dysfunction while CYP2C8*3 and 2C9*2 loss-of-function SNP, altered endothelial function by reducing flow-induced EET release. In I/R mice, sEH inhibition reduced kidney lesions, prevented cardiac fibrosis and dysfunction as well as preserved endothelial function. The preservation of EET bioavailability may prevent allograft dysfunction and improve cardiovascular disease in kidney transplant recipients. Inhibition of sEH appears thus as a novel therapeutic option but its impact on other epoxyfatty acids should be carefully evaluated.
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http://dx.doi.org/10.1038/s41598-021-83274-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881112PMC
February 2021

Structure-Activity Relationship and Bioactivity of Short Analogues of ELABELA as Agonists of the Apelin Receptor.

J Med Chem 2021 01 22;64(1):602-615. Epub 2020 Dec 22.

Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.

ELABELA (ELA) is the second endogenous ligand of the apelin receptor (APJ). Although apelin-13 and ELA both target APJ, there is limited information on structure-activity relationship (SAR) of ELA. In the present work, we identified the shortest bioactive C-terminal fragment ELA23-32, which possesses high affinity for APJ ( 4.6 nM) and produces cardiorenal effects similar to those of ELA. SAR studies on conserved residues (Leu25, His26, Val29, Pro30, Phe31, Pro32) show that ELA and apelin-13 may interact differently with APJ. His26 and Val29 emerge as important for ELA binding. Docking and binding experiments suggest that Phe31 of ELA may bind to a tight groove distinct from that of Phe13 of Ape13, while the Phe13 pocket may be occupied by Pro32 of ELA. Further characterization of signaling profiles on the Gα, Gα, and β-arrestin2 pathways reveals the importance of aromatic residue at the Phe31 or Pro32 position for receptor activation.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01547DOI Listing
January 2021

Hypertonic sodium lactate improves microcirculation, cardiac function, and inflammation in a rat model of sepsis.

Crit Care 2020 06 16;24(1):354. Epub 2020 Jun 16.

Normandie Université, UNIROUEN, Inserm U1096, FHU-REMOD-VHF, 76000, Rouen, France.

Background: Hypertonic sodium lactate (HSL) may be of interest during inflammation. We aimed to evaluate its effects during experimental sepsis in rats (cecal ligation and puncture (CLP)).

Methods: Three groups were analyzed (n = 10/group): sham, CLP-NaCl 0.9%, and CLP-HSL (2.5 mL/kg/h of fluids for 18 h after CLP). Mesenteric microcirculation, echocardiography, cytokines, and biochemical parameters were evaluated. Two additional experiments were performed for capillary leakage (Evans blue, n = 5/group) and cardiac hemodynamics (n = 7/group).

Results: HSL improved mesenteric microcirculation (CLP-HSL 736 [407-879] vs. CLP-NaCl 241 [209-391] UI/pixel, p = 0.0006), cardiac output (0.34 [0.28-0.43] vs. 0.14 [0.10-0.18] mL/min/g, p < 0.0001), and left ventricular fractional shortening (55 [46-73] vs. 39 [33-52] %, p = 0.009). HSL also raised dP/dt slope (6.3 [3.3-12.1] vs. 2.7 [2.0-3.9] 10 mmHg/s, p = 0.04), lowered left ventricular end-diastolic pressure-volume relation (1.9 [1.1-2.3] vs. 3.0 [2.2-3.7] RVU/mmHg, p = 0.005), and reduced Evans blue diffusion in the gut (37 [31-43] vs. 113 [63-142], p = 0.03), the lung (108 [82-174] vs. 273 [222-445], p = 0.006), and the liver (24 [14-37] vs. 70 [50-89] ng EB/mg, p = 0.04). Lactate and 3-hydroxybutyrate were higher in CLP-HSL (6.03 [3.08-10.30] vs. 3.19 [2.42-5.11] mmol/L, p = 0.04; 400 [174-626] vs. 189 [130-301] μmol/L, p = 0.03). Plasma cytokines were reduced in HSL (IL-1β, 172 [119-446] vs. 928 [245-1470] pg/mL, p = 0.004; TNFα, 17.9 [12.5-50.3] vs. 53.9 [30.8-85.6] pg/mL, p = 0.005; IL-10, 352 [267-912] vs. 905 [723-1243] pg/mL) as well as plasma VEGF-A (198 [185-250] vs. 261 [250-269] pg/mL, p = 0.009).

Conclusions: Hypertonic sodium lactate fluid protects against cardiac dysfunction, mesenteric microcirculation alteration, and capillary leakage during sepsis and simultaneously reduces inflammation and enhances ketone bodies.
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http://dx.doi.org/10.1186/s13054-020-03083-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298868PMC
June 2020

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

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

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

Protein tyrosine phosphatase 1B (PTP1B) impairs nitric oxide (NO) production and induces endothelial dysfunction in various diseases, including diabetes, septic shock and heart failure. In non-cardiovascular tissues, PTP1B modulates endoplasmic reticulum stress (ERS) however this role has never been assessed in endothelial cells. We evaluated the link between PTP1B, ERS and endothelial dysfunction in mice. Induction of ERS (Tunicamycin) in vivo in mice or ex vivo in mouse arteries led to severe arterial endothelial dysfunction (i.e. reduced flow-dependent, NO mediated dilatation in isolated small mesenteric arteries), and this was prevented by the PTP1B inhibitor trodusquemine and absent in PTP1B-/- mice. Trodusquemine also prevented the Tunicamycin -induced increased arterial levels of the molecular ERS actors 78 kDa glucose-regulated protein (GRP78) and Activating Transcription Factor 6 (ATF6α). Tunicamycin strongly increased the interactions of PTP1B with GRP78 and the activated forms of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and IRE1α (proximity Ligation Assay). Thus, PTP1B plays a central role in the regulation of ERS in the endothelium, and the endothelial protective effect of PTP1B inhibition appears likely due at least in part to reduction of endothelial ERS, notably by promoting PERK protective pathway. Modulation of ER stress via PTP1B inhibitors may be a promising approach to protect the endothelium in cardiovascular diseases.
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http://dx.doi.org/10.1016/j.vph.2018.05.011DOI Listing
October 2018

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

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

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

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

A Systematic Exploration of Macrocyclization in Apelin-13: Impact on Binding, Signaling, Stability, and Cardiovascular Effects.

J Med Chem 2018 03 26;61(6):2266-2277. Epub 2018 Feb 26.

Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé , Université de Sherbrooke , Sherbrooke J1H 5N4 , Québec , Canada.

The apelin receptor generates increasing interest as a potential target across several cardiovascular indications. However, the short half-life of its cognate ligands, the apelin peptides, is a limiting factor for pharmacological use. In this study, we systematically explored each position of apelin-13 to find the best position to cyclize the peptide, with the goal to improve its stability while optimizing its binding affinity and signaling profile. Macrocyclic analogues showed a remarkably higher stability in rat plasma (half-life >3 h versus 24 min for Pyr-apelin-13), accompanied by improved affinity (analogue 15, K 0.15 nM and t 6.8 h). Several compounds displayed higher inotropic effects ex vivo in the Langendorff isolated heart model in rats (analogues 13 and 15, maximum response at 0.003 nM versus 0.03 nM of apelin-13). In conclusion, this study provides stable and active compounds to better characterize the pharmacology of the apelinergic system.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01353DOI Listing
March 2018

The apelinergic system as an alternative to catecholamines in low-output septic shock.

Crit Care 2018 01 19;22(1):10. Epub 2018 Jan 19.

Division of Intensive Care Units, Department of Medicine, Université de Sherbrooke, 3001 - 12e Avenue Nord, Sherbrooke, QC, J1H 5 N4, Canada.

Catecholamines, in concert with fluid resuscitation, have long been recommended in the management of septic shock. However, not all patients respond positively and controversy surrounding the efficacy-to-safety profile of catecholamines has emerged, trending toward decatecholaminization. Contextually, it is time to re-examine the "maintaining blood pressure" paradigm by identifying safer and life-saving alternatives. We put in perspective the emerging and growing knowledge on a promising alternative avenue: the apelinergic system. This target exhibits invaluable pleiotropic properties, including inodilator activity, cardio-renal protection, and control of fluid homeostasis. Taken together, its effects are expected to be greatly beneficial for patients in septic shock.
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http://dx.doi.org/10.1186/s13054-018-1942-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774146PMC
January 2018

ELABELA Improves Cardio-Renal Outcome in Fatal Experimental Septic Shock.

Crit Care Med 2017 Nov;45(11):e1139-e1148

1Centre de Recherche du CHUS (CRCHUS) et Unité des Soins Intensifs Médicaux, Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC, Canada. 2Institut de Pharmacologie de Sherbrooke (IPS) and Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC, Canada. 3IPS Thérapeutique, Sherbrooke, QC, Canada.

Objectives: Apelin-13 was recently proposed as an alternative to the recommended β-adrenergic drugs for supporting endotoxin-induced myocardial dysfunction. Since Apelin-13 signals through its receptor (Apelin peptide jejunum) to exert singular inotropic/vasotropic actions and to optimize body fluid balance, this candidate pathway might benefit septic shock management. Whether the newly discovered ELABELA (ELA), a second endogenous ligand of the Apelin peptide jejunum receptor highly expressed in the kidney, further improves cardio-renal impairment remains unknown.

Design, Setting, And Subjects: Interventional study in a rat model of septic shock (128 adult males) to assess the effects of ELA and Apelin-13 on vascular and cardio-renal function. Experiments were performed in a tertiary care University-based research institute.

Interventions: Polymicrobial sepsis-induced cardiac dysfunction was produced by cecal ligation puncture to assess hemodynamic efficacy, cardioprotection, and biomechanics under acute or continuous infusions of the apelinergic agonists ELA or Apelin-13 (39 and 15 µg/kg/hr, respectively) versus normal saline.

Measurements And Main Results: Apelinergic agonists improved 72-hour survival after sepsis induction, with ELA providing the best clinical outcome after 24 hours. Apelinergic agonist infusion counteracted cecal ligation puncture-induced myocardial dysfunction by improving left ventricular pressure-volume relationship. ELA-treated cecal ligation puncture rats were the only group to 1) display a significant improvement in left ventricular filling as shown by increased E-wave velocity and left ventricular end-diastolic volume, 2) exhibit a higher plasma volume, and 3) limit kidney injury and free-water clearance. These beneficial renal effects were superior to Apelin-13, likely because full-length ELA enabled a distinctive regulation of pituitary vasopressin release.

Conclusions: Activation of the apelinergic system by exogenous ELA or Apelin-13 infusion improves cardiovascular function and survival after cecal ligation puncture-induced sepsis. However, ELA proved better than Apelin-13 by improving fluid homeostasis, cardiovascular hemodynamics recovery, and limiting kidney dysfunction in a vasopressinergic-dependent manner.
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http://dx.doi.org/10.1097/CCM.0000000000002639DOI Listing
November 2017

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

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

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

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

Apelin Compared With Dobutamine Exerts Cardioprotection and Extends Survival in a Rat Model of Endotoxin-Induced Myocardial Dysfunction.

Crit Care Med 2017 Apr;45(4):e391-e398

1Soins Intensifs Médicaux et Service de Cardiologie, Université de Sherbrooke, Sherbrooke, QC, Canada.2Centre de Recherche du CHUS (CR-CHUS), Sherbrooke, QC, Canada.3IPS Therapeutique Inc., Sherbrooke, QC, Canada4Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC, Canada.5Institut de Pharmacologie de Sherbrooke (IPS), Université de Sherbrooke, Sherbrooke, QC, Canada.6Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC, Canada.

Objective: Dobutamine is the currently recommended β-adrenergic inotropic drug for supporting sepsis-induced myocardial dysfunction when cardiac output index remains low after preload correction. Better and safer therapies are nonetheless mandatory because responsiveness to dobutamine is limited with numerous side effects. Apelin-13 is a powerful inotropic candidate that could be considered as an alternative noncatecholaminergic support in the setting of inflammatory cardiovascular dysfunction.

Design: Interventional controlled experimental animal study.

Setting: Tertiary care university-based research institute.

Subjects: One hundred ninety-eight adult male rats.

Interventions: Using a rat model of "systemic inflammation-induced cardiac dysfunction" induced by intraperitoneal lipopolysaccharide injection (10 mg/kg), hemodynamic efficacy, cardioprotection, and biomechanics were assessed under IV osmotic pump infusions of apelin-13 (0.25 μg/kg/min) or dobutamine (7.5 μg/kg/min).

Measurements And Main Results: In this model and in both in vivo and ex vivo studies, apelin-13 compared with dobutamine provoked distinctive effects on cardiac function: 1) optimized cardiac energy-dependent workload with improved cardiac index and lower vascular resistance, 2) upgraded hearts' apelinergic responsiveness, and 3) consecutive downstream advantages, including increased urine output, enhanced plasma volume, reduced weight loss, and substantially improved overall outcomes. In vitro studies confirmed that these apelin-13-driven processes encompassed a significant and rapid reduction in systemic cytokine release with dampening of myocardial inflammation, injury, and apoptosis and resolution of associated molecular pathways.

Conclusions: In this inflammatory cardiovascular dysfunction, apelin-13 infusion delivers distinct and optimized hemodynamic support (including positive fluid balance), along with cardioprotective effects, modulation of circulatory inflammation and extended survival.
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http://dx.doi.org/10.1097/CCM.0000000000002097DOI Listing
April 2017

Discovery and Structure-Activity Relationship of a Bioactive Fragment of ELABELA that Modulates Vascular and Cardiac Functions.

J Med Chem 2016 Apr 30;59(7):2962-72. Epub 2016 Mar 30.

Département de Pharmacologie et Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke , Sherbrooke, J1H 5N4 Québec, Canada.

ELABELA (ELA) was recently discovered as a novel endogenous ligand of the apelin receptor (APJ), a G protein-coupled receptor. ELA signaling was demonstrated to be crucial for normal heart and vasculature development during embryogenesis. We delineate here ELA's structure-activity relationships and report the identification of analogue 3 (ELA(19-32)), a fragment of ELA that binds to APJ, activates the Gαi1 and β-arrestin-2 signaling pathways, and induces receptor internalization similarly to its parent endogenous peptide. An alanine scan performed on 3 revealed that the C-terminal residues are critical for binding to APJ and signaling. Finally, using isolated-perfused hearts and in vivo hemodynamic and echocardiographic measurements, we demonstrate that ELA and 3 both reduce arterial pressure and exert positive inotropic effects on the heart. Altogether, these results present ELA and 3 as potential therapeutic options in managing cardiovascular diseases.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01549DOI Listing
April 2016

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

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

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

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

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

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