Physiopathologie de la dysfonction bêta-adrénergique et rôle de la protéine MRP4 au cours du vieillissement, du diabète et du syndrome métabolique

The studies presented in this report looked for a better understanding of the altered response to stimulation of the β-adrenergic receptors in several physiopathological contexts. The first study confirms the alteration of the β-adrenergic response at the cardiomyocyte level in the senescent cardiomyopathy. The role of MRP4 (multidrug resistance associated protein 4) in the reduced inotropic response to isoproterenol is emphasized. The second study evaluates the response to β-adrenoceptors stimulation in the metabolic syndrome and shows mild dysfunction in this context even in obesity associate with diabetes. These functional results are explained by a reduced expression of β1- and β2-adrenergic receptors but no overexpression of β3-adrenoceptor as observed in type 1 diabetes. The third study analyzes the role of atorvastatin on the β-adrenergic response in the diabetic cardiomyopathy and the mechanisms involved by study of the cardiac transcriptome. The inhibition of nitrite oxide production improves the response to β-adrenoceptors stimulation in diabetic heart. The fourth study explained part of the β-adrenergic dysfunction in the diabetic cardiomyopathy by the overexpression of MRP4. The inhibition of this protein restored the response to isoproterenol during diabetic cardiomyopathy. All together the present results carry on with description of the mechanisms involved in the β-adrenergic dysfunction in aging and diabetes and underline the role of MRP4.Les travaux présentés dans ce mémoire ont pour objectif d’approfondir la compréhension de l’altération de la réponse à la stimulation des récepteurs β-adrénergiques dans plusieurs contextes physiopathologiques. La première étude confirme l’existence d’une dysfonction β-adrénergique à l’échelle du cardiomyocyte au cours de la sénescence. Elle met en lumière le rôle de la protéine MRP4 (multidrug resistance associated protein 4) dans cette diminution de réponse inotrope positive à l’isoprotérénol. La deuxième étude évalue la réponse à la stimulation des récepteurs β-adrénergiques dans le syndrome métabolique et montre que la dysfonction est modérée dans ce contexte même en cas de diabète associé à l’obésité. Ces résultats fonctionnels sont expliqués par la diminution d’expression des récepteurs β1- et β2-adrénergiques mais l’absence de surexpression du récepteur β3-adrénergique comme observée dans le diabète de type 1. La troisième étude analyse le rôle de l’atorvastatine sur la réponse β-adrénergique chez les diabétiques et les mécanismes de modulation de cette réponse par une étude du transcriptome cardiaque. Elle montre également que l’inhibition de la production d’oxyde nitrite améliore la réponse β-adrénergique. La quatrième étude a expliqué une part de la dysfonction β-adrénergique chez les diabétiques par la surexpression de MRP4. L’inhibition de MRP4 a permis de restaurer la réponse à l’isoprotérénol au cours de la cardiopathie diabétique. Au total, l’ensemble de nos travaux poursuit la description des mécanismes de la dysfonction β-adrénergique dans la sénescence et le diabète et souligne le rôle de MRP4

Physiopathology of beta-adrenergic dysfunction and role of MRP4 during aging, diabetes mellitus and metabolic syndrom

Les travaux présentés dans ce mémoire ont pour objectif d’approfondir la compréhension de l’altération de la réponse à la stimulation des récepteurs β-adrénergiques dans plusieurs contextes physiopathologiques. La première étude confirme l’existence d’une dysfonction β-adrénergique à l’échelle du cardiomyocyte au cours de la sénescence. Elle met en lumière le rôle de la protéine MRP4 (multidrug resistance associated protein 4) dans cette diminution de réponse inotrope positive à l’isoprotérénol. La deuxième étude évalue la réponse à la stimulation des récepteurs β-adrénergiques dans le syndrome métabolique et montre que la dysfonction est modérée dans ce contexte même en cas de diabète associé à l’obésité. Ces résultats fonctionnels sont expliqués par la diminution d’expression des récepteurs β1- et β2-adrénergiques mais l’absence de surexpression du récepteur β3-adrénergique comme observée dans le diabète de type 1. La troisième étude analyse le rôle de l’atorvastatine sur la réponse β-adrénergique chez les diabétiques et les mécanismes de modulation de cette réponse par une étude du transcriptome cardiaque. Elle montre également que l’inhibition de la production d’oxyde nitrite améliore la réponse β-adrénergique. La quatrième étude a expliqué une part de la dysfonction β-adrénergique chez les diabétiques par la surexpression de MRP4. L’inhibition de MRP4 a permis de restaurer la réponse à l’isoprotérénol au cours de la cardiopathie diabétique. Au total, l’ensemble de nos travaux poursuit la description des mécanismes de la dysfonction β-adrénergique dans la sénescence et le diabète et souligne le rôle de MRP4.The studies presented in this report looked for a better understanding of the altered response to stimulation of the β-adrenergic receptors in several physiopathological contexts. The first study confirms the alteration of the β-adrenergic response at the cardiomyocyte level in the senescent cardiomyopathy. The role of MRP4 (multidrug resistance associated protein 4) in the reduced inotropic response to isoproterenol is emphasized. The second study evaluates the response to β-adrenoceptors stimulation in the metabolic syndrome and shows mild dysfunction in this context even in obesity associate with diabetes. These functional results are explained by a reduced expression of β1- and β2-adrenergic receptors but no overexpression of β3-adrenoceptor as observed in type 1 diabetes. The third study analyzes the role of atorvastatin on the β-adrenergic response in the diabetic cardiomyopathy and the mechanisms involved by study of the cardiac transcriptome. The inhibition of nitrite oxide production improves the response to β-adrenoceptors stimulation in diabetic heart. The fourth study explained part of the β-adrenergic dysfunction in the diabetic cardiomyopathy by the overexpression of MRP4. The inhibition of this protein restored the response to isoproterenol during diabetic cardiomyopathy. All together the present results carry on with description of the mechanisms involved in the β-adrenergic dysfunction in aging and diabetes and underline the role of MRP4

Enhanced recovery after cardiac surgery under CPB or off pump

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Interaction of metabolic and respiratory acidosis with α and β-adrenoceptor stimulation in rat myocardium.

International audienceBACKGROUND: The effects of acute respiratory versus metabolic acidosis on the myocardium and their consequences on adrenoceptor stimulation remain poorly described. We compared the effects of metabolic and respiratory acidosis on inotropy and lusitropy in rat myocardium and their effects on the responses to α- and β-adrenoceptor stimulations. METHODS: The effects of acute respiratory and metabolic acidosis (pH 7.10) and their interactions with α and β-adrenoceptor stimulations were studied in isolated rat left ventricular papillary muscle (n=8 per group). Intracellular pH was measured using confocal microscopy and a pH-sensitive fluorophore in isolated rat cardiomyocytes. Data are mean percentages of baseline±SD. RESULTS: Respiratory acidosis induced more pronounced negative inotropic effects than metabolic acidosis did both in isotonic (45±3 versus 63±6%, P<0.001) and isometric (44±5 versus 64±3%, P<0.001) conditions concomitant with a greater decrease in intracellular pH (6.85±0.07 versus 7.12±0.07, P<0.001). The response to α-adrenergic stimulation was not modified by respiratory or metabolic acidosis. The inotropic response to β-adrenergic stimulation was impaired only in metabolic acidosis (137±12 versus 200±33%, P<0.001), but this effect was not observed with administration of forskolin or dibutiryl-cyclic adenosine monophosphate. This effect might be explained by a change in transmembrane pH gradient only observed with metabolic acidosis. The lusitropic response to β-adrenergic stimulation was not modified by respiratory or metabolic acidosis. CONCLUSION: Acute metabolic and respiratory acidosis induce different myocardial effects related to different decreases in intracellular pH. Only metabolic acidosis impairs the positive inotropic effect of β-adrenergic stimulation

Postoperative serum levels of Endocan are associated with the duration of norepinephrine support after coronary artery bypass surgery

International audienceBACKGROUND : Cardiopulmonary bypass (CPB) is associated with a systemic inflammatory response and an endothelial dysfunction, whose qualitative assessment appears to be a major issue. Endocan (ESM-1, endothelial cell specific molecule-1) is a protein preferentially expressed by the endothelium and previously associated with prognosis of septic shock or acute respiratory distress syndrome. In this pilot study, we investigated the kinetic of Endocan in planned coronary artery bypass grafting (CABG) surgery with CPB.PATIENTS AND METHODS : We conducted an observational, prospective, mono centre study. All adult patients with left systolic ejection fraction>50%, undergoing planned on-pump CABG, were screened for inclusion. A written informed consent was obtained. Measurements and main results Serum Endocan concentrations were respectively 2.4 [2.1-3.0] ng. mL-1, 10.4 [7.4-13.9] ng.mL-1, 5.7 [4.4-8.2] ng.mL-1, and 5.4 [4.1-7.5] ng.mL-1 at day 0, day 1, day 3 and day 5. Endocan concentrations increased at day 1, day 3, and day 5 in comparison with preoperative concentration (P<0.001). In the multivariate analysis, age (P=0.002), history of acute coronary syndrome (P=0.024) and the catecholamine-free days at day 28 (P=0.007) were associated to the increase of perioperative Endocan concentrations.CONCLUSION : Serum Endocan concentration increases after CABG surgery with CPB until day 1. The norepinephrine support increases the risk of Endocan release, suggesting a relationship between the kinetic of Endocan and the vasoplegic syndrome. At day 3, Endocan concentration decreases slowly but is not normalised at day 5. Further studies should investigate the prognostic value of the magnitude of postoperative Endocan concentration after cardiac surgery

Atorvastatin reduces β-Adrenergic dysfunction in rats with diabetic cardiomyopathy.

In the diabetic heart the β-adrenergic response is altered partly by down-regulation of the β1-adrenoceptor, reducing its positive inotropic effect and up-regulation of the β3-adrenoceptor, increasing its negative inotropic effect. Statins have clinical benefits on morbidity and mortality in diabetic patients which are attributed to their "pleiotropic" effects. The objective of our study was to investigate the role of statin treatment on β-adrenergic dysfunction in diabetic rat cardiomyocytes.β-adrenergic responses were investigated in vivo (echocardiography) and ex vivo (left ventricular papillary muscles) in healthy and streptozotocin-induced diabetic rats, who were pre-treated or not by oral atorvastatin over 15 days (50 mg.kg-1.day-1). Micro-array analysis and immunoblotting were performed in left ventricular homogenates. Data are presented as mean percentage of baseline ± SD.Atorvastatin restored the impaired positive inotropic effect of β-adrenergic stimulation in diabetic hearts compared with healthy hearts both in vivo and ex vivo but did not suppress the diastolic dysfunction of diabetes. Atorvastatin changed the RNA expression of 9 genes in the β-adrenergic pathway and corrected the protein expression of β1-adrenoceptor and β1/β3-adrenoceptor ratio, and multidrug resistance protein 4 (MRP4). Nitric oxide synthase (NOS) inhibition abolished the beneficial effects of atorvastatin on the β-adrenoceptor response.Atorvastatin restored the positive inotropic effect of the β-adrenoceptor stimulation in diabetic cardiomyopathy. This effect is mediated by multiple modifications in expression of proteins in the β-adrenergic signaling pathway, particularly through the NOS pathway

SARS-CoV-2 vaccination efficacy on hospitalisation and variants

International audienceWe report data regarding three countries with similar healthcare systems which had three different vaccinal strategies between 1st of January and 10th of April 2021: rapid full vaccination (Israel), rapid first-dose vaccination (United Kingdom) and a delayed vaccination strategy (France)