Interaction(s) entre les récepteurs des imidazolines et les récepteurs a2-adrénergiques dans la régulation centrale de la fonction cardio-vasculaire

Au cours de ce travail, nous nous sommes attachés à élucider le mécanisme d'action des antihypertenseurs centraux de type clonidine, drogues hybrides puisqu'elles se lient à la fois les récepteurs I1-imidazoliniques (RI1) et les récepteurs a2-adrénergiques (Ra2).Des drogues synthétisées tout récemment se sont montrées extrêmement sélectives des RI1 car elles reconnaissent ces récepteurs mais sont dépourvues d'affinité et d'activité a2A-adrénergique. L'utilisation conjointe de ces ligands sélectifs des RI1 et de souris génétiquement modifiées (souris D79N) de façon à rendre les Ra2A non fonctionnels (sous-type impliqué dans la régulation centrale de la pression artérielle) nous a permis de démontrer qu'il est possible d'abaisser la PA en agissant sélectivement et exclusivement sur les RI1.Par ailleurs, nous démontrons qu'il existe une synergie potentialisatrice entre les mécanismes I1-imidazoliniques et a2A-adrénergiques dans la régulation centrale de la pression artérielle. Ainsi, une drogue sélective des RI1 est capable de potentialiser l'effet hypotenseur d'un agoniste sélectif des Ra2. Cette synergie a été mise en évidence dans le noyau rostral ventrolatéral du bulbe rachidien, site d'action des antihypertenseurs centraux de type clonidine. Nous montrons également qu'un antihypertenseur hybride, la rilménidine, est moins efficace chez la souris D79N que chez la souris sauvage.Ces résultats démontrent que les effets hypotenseurs centraux de drogues hybrides de type clonidine résultent à la fois de mécanismes I1-imidazoliniques et a2-adrénergiques, le premier facilitant le second.Enfin, nous démontrons que la participation fonctionnelle des Ra2 est nécessaire aux effets hypotenseurs d'origine centrale de drogues non catécholaminergiques et dépourvues d'activité a2-adrénergique.This work was designed to clarify the mechanism of action of clonidine-like drugs. These antihypertensive drugs are hybrid compounds which bind both I1-imidazoline receptors (I1R) and a2-adrenoceptors (a2AR).New imidazoline compounds have been recently synthesized. They are highly selective for I1R because they bind these receptors but are totally devoid of any a2-adrenergic affinity and activity.? The combined use of these drugs in genetically modified mice (D79N mice) with impaired a2AAR (the a2AR subtype involved in central blood pressure regulation) enabled us to demonstrate that it is possible to lower blood pressure by acting selectively and exclusively on I1R.Moreover we demonstrate that a synergy occurs between I1-imidazolinic and a2A-adrenergic mechanisms in central blood pressure regulation. Thus, a drug selective for I1R potentiates the hypotensive effect of an agonist selective for a2AR. At least, the synergy takes place in the rostroventrolateral medulla: the site of action of clonidine-like drugs. We also show that a hybrid antihypertensive drug, rilmenidine, is less efficient in D79N mice than in wild type mice.These data strongly suggest that the hypotensive effects of hybrid clonidine-like drugs result both from an I1-imidazolinic mechanism and an a2-adrenergic one, the former potentiating the latter.Finally, we demonstrate that a2AR are functionally involved in the central hypotensive effect of non catecholaminergic drugs devoid of any a2-adrenergic property.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Biological Relevance of RGD‐Integrin Subtype‐Specific Ligands in Cancer

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LRP1 Controls Intracellular Cholesterol Storage and Fatty Acid Synthesis through Modulation of Wnt Signaling.

International audienceThe low-density lipoprotein receptor-related protein LRP1 is a cell surface receptor with functions in diverse physiological pathways, including lipid metabolism. Here we show that LRP1-deficient fibroblasts accumulate high levels of intracellular cholesterol and cholesteryl-ester when stimulated for adipocyte differentiation. We demonstrate that LRP1 stimulates a canonical Wnt5a signaling pathway that prevents cholesterol accumulation. Moreover, we show that LRP1 is required for lipolysis and stimulates fatty acid synthesis independently of the noradrenergic pathway, through inhibition of GSK3beta and its previously unknown target acetyl-CoA carboxylase (ACC). As a result of ACC inhibition, mature LRP1-deficient adipocytes of adult mice are hypotrophic, and lower uptake of fatty acids into adipose tissue leads to their redistribution to the liver. These results establish LRP1 as a novel integrator of adipogenic differentiation and fat storage signals

Cav1/EREG/YAP Axis in the Treatment Resistance of Cav1-Expressing Head and Neck Squamous Cell Carcinoma

International audienceThe EGFR-targeting antibody cetuximab (CTX) combined with radiotherapy is the only targeted therapy that has been proven effective for the treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Recurrence arises in 50% of patients with HNSCC in the years following treatment. In clinicopathological practice, it is difficult to assign patients to classes of risk because no reliable biomarkers are available to predict the outcome of HPV-unrelated HNSCC. In the present study, we investigated the role of Caveolin-1 (Cav1) in the sensitivity of HNSCC cell lines to CTX-radiotherapy that might predict HNSCC relapse. Ctrl- and Cav-1-overexpressing HNSCC cell lines were exposed to solvent, CTX, or irradiation, or exposed to CTX before irradiation. Growth, clonogenicity, cell cycle progression, apoptosis, metabolism and signaling pathways were analyzed. Cav1 expression was analyzed in 173 tumor samples and correlated to locoregional recurrence and overall survival. We showed that Cav1-overexpressing cells demonstrate better survival capacities and remain proliferative and motile when exposed to CTX-radiotherapy. Resistance is mediated by the Cav1/EREG/YAP axis. Patients whose tumors overexpressed Cav1 experienced regional recurrence a few years after adjuvant radiotherapy ± chemotherapy. Together, our observations suggest that a high expression of Cav1 might be predictive of locoregional relapse of LA-HNSC

Respective contributions of α-adrenergic and non-adrenergic mechanisms in the hypotensive effect of imidazoline-like drugs

1. The hypotensive effect of imidazoline-like drugs, such as clonidine, was first attributed to the exclusive stimulation of central α 2-adrenoceptors (α 2ARs). 2. However, a body of evidence suggests that non-adrenergic mechanisms may also account for this hypotension. 3. This work aims (i) to check whether imidazoline-like drugs with no α 2adrenergic agonist activity may alter blood pressure (BP) and (ii) to seek a possible interaction between such a drug and an α 2ARs agonist α-methylnoradrenaline (α-MNA). 4. We selected S23515 and S23757, two imidazoline-like drugs with negligible affinities and activities at α 2ARs but with high affinities for non-adrenergic imidazoline binding sites (IBS). 5. S23515 decreased BP dose-dependently (-27±5% maximal effect) when administered intracisternally (i.c.) to anaesthetized rabbits. The hypotension induced by S23515 (100 μg kg -1 i.c.) was prevented by S23757 (1 mg kg -1 i.c.) and efaroxan (10 μgkg -1 i.c.), while these compounds, devoid of haemodynamic action by themselves, did not alter the hypotensive effect of α-MNA (3 and 30 μg kg -1 i.c.). Moreover, the α 2ARs antagonist rauwolscine (3 μg kg -1 i.c.) did not prevent the effect of S23515. 6. Finally, whilst 3 μg kg -1 of S23515 or 0.5 μg kg -1 of α-MNA had weak hypotensive effects, the sequential i.c. administration of these two drugs induced a marked hypotension (-23±2%). 7. These results indicate that an imidazoline-like drug with no α 2-adrenergic properties lowers BP and interacts synergistically with an α 22ARs agonist.link_to_subscribed_fulltex

Differential Signaling by Adaptor Molecules LRP1 and ShcA Regulates Adipogenesis by the Insulin-like Growth Factor-1 Receptor*

The low density lipoprotein receptor-related protein (LRP1) is a transmembrane receptor that integrates multiple signaling pathways. Its cytoplasmic domain serves as docking sites for several adaptor proteins such as the Src homology 2/α-collagen (ShcA), which also binds to several tyrosine kinase receptors such as the insulin-like growth factor 1 (IGF-1) receptor. However, the physiological significance of the physical interaction between LRP1 and ShcA, and whether this interaction modifies tyrosine kinase receptor signaling, are still unknown. Here we report that LRP1 forms a complex with the IGF-1 receptor, and that LRP1 is required for ShcA to become sensitive to IGF-1 stimulation. Upon IGF-1 treatment, ShcA is tyrosine phosphorylated and translocates to the plasma membrane only in the presence of LRP1. This leads to the recruitment of the growth factor receptor-bound protein 2 (Grb2) to ShcA, and activation of the Ras/MAP kinase pathway. Conversely, in the absence of ShcA, IGF-1 signaling bifurcates toward the Akt/mammalian target of rapamycin pathway and accelerates adipocyte differentiation when cells are stimulated for adipogenesis. These results establish the LRP1-ShcA complex as an essential component in the IGF-1-regulated pathway for MAP kinase and Akt/mammalian target of rapamycin activation, and may help to understand the IGF-1 signaling shift from clonal expansion to growth-arrested cells and differentiation during adipogenesis