Wine and cardiovascular health beyond antioxidant properties

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Procédés pour l’identification de nouveaux composés activateurs des ERα dans la production du monoxyde d’azote endothélial

La présente invention décrit l\u27utilisation de composés chimiques dérivés de la delphinidine dans des procédés de criblage pour identifier des composés capables d\u27activer sélectivement le récepteur aux œ strogènes ERa, et de stimuler la production de monoxyde d\u27azote (NO) par l\u27endothélium, de tels composés pouvant être par la suite incorporés dans des compositions pharmaceutiques destinées à traiter notamment les maladies cardiovasculaires

The role of Smoothened and Hh signaling in neovascularization

New vessel formation plays a key role not only in physiological processes such as embryonic development and wound repair but also during several pathological situations. In this respect, favoring neovascularization represents a promising therapeutic approach that would allow inducing tissue repair. Among the candidate proteins able to modulate neovascularization, evidence show that the administration of recombinant hedgehog (Hh) protein, gene, or cell therapy based on Hh transfer or using extracellular vesicles as vectors enhance new vessel formation. Here, we summarized the role of Hh pathway on angiogenesis and its therapeutic potential during myocardial infarction and diabetes

Engineered microparticles bearing the morphogen Sonic Hedgehog protect endothelial cells against actinomycin D-induced apoptosis

It has been reported that microparticles generated from T lymphocytes undergoing activation and apoptosis, bear the morphogen Sonic Hedgehog (MPsShh+), and possessed the dual ability to increase NO and reduce ROS productions. Here, we investigated whether MPsShh+ protected human umbical vein endothelial cells (HUVECs) against actinomycin D (ActD)-induced apoptosis. MPsShh+ were obtained by activation of human lymphocyte with phytohemagglutinin and then, by stimulation with phorbol-12 myristate-13 acetate and ActD. HUVECs were grown for 24 h in absence or presence of pro-apoptotic agent, ActD (1 μg/mL), and/or 10 μg protein/mL of MPsShh+. Apoptosis evaluation was based on flow cytometry, TUNEL labelling and cytochrome c release. We showed that MPsShh+ treatment significantly prevented HUVECs apoptosis evoked by ActD. Also, caspases inhibitor z-vad.fmk (50 μM ) reduced cell death either in presence or in absence of MPsShh+, indicating the implication of caspases in ActD-induced apoptosis. To investigate the implication of Shh pathway in this effect, its agonist SAG and its antagonist CUR61414 were tested. SAG reduced apoptosis in a dose-dependent manner; by itself, CUR61414 had no effect on its own but abolished the antiapoptotic effect of MPsShh, revealing a contribution of Shh pathway. In contrast, MPsShh+ were still able to reduce apoptosis in the presence of NO synthase inhibitor, L-NA (100 μM ), or when the PI3-kinase and ERK were inhibited with LY294002 (10 μM ) and U0126 (10 μM ) respectively, showing that these pathways were not associated with protection against apoptosis. Besides, we explored changes in ROS production at different times, by electronic paramagnetic resonance. ROS levels were increased in ActD-treated cells at 2 h and 10 h. This elevation was prevented by MPsShh+ only at 2 h. When sources of ROS, xanthine oxidase, NAD(P)H oxidase and respiratory chain complex I, were inhibited using allopurinol (50 μM ), apocynin (100 μM ) and rotenone (5 μM), respectively, we found that only rotenone reduced ActD-induced apoptosis. Also, the superoxide dismutase (SOD) mimetic, MnTMPyP (100 μM ), reduced ActD-evoked cell death and the protective effect of MPsShh+. These results indicate that, under these experimental conditions, MPsShh+ may act in the early phase of apoptosis at mitochondrial level and behave as a SOD mimetic. These findings provide additional mechanisms by which MPsShh+ exert their vasculoprotective effects, preserving integrity of endothelial monolayer. Supported by ANR-07-PHYSIO-010-01

Microparticles are vectors of paradoxical information in vascular cells including the endothelium: role in health and diseases

Both inflammation and thrombosis can be orchestrated by the interactions between circulating cells, such as leukocytes and platelets, with vascular, endothelial and smooth muscle cells, which, during activation or apoptosis, can release circulating microparticles (MPs). Indeed, MPs are membrane vesicles with procoagulant and proinflammatory properties. MPs are present in blood from healthy individuals and in patients under several pathological states, for instance sepsis, preeclampsia, Crohn\u27s disease and diabetes, strengthening the notion that MPs may play a role in these diseases. Circulating MPs or those generated in vitro from apoptotic T cells display deleterious effects on endothelial and/or vasomotor function. In contrast, MPs might be protective to endothelial cells. We have shown that MPs harboring the morphogen sonic hedgehog may represent a new therapeutic approach against endothelial dysfunction during acute severe endothelial injury. Indeed, these types of MPs induce NO release, decrease production of reactive oxygen species and induce angiogenesis from endothelial cells. This protective role for the endothelium was confirmed also by their in vivo injection in mice in which they were also able to reverse endothelial dysfunction in a model of heart ischemia/reperfusion. On the contrary, MPs from preeclamptic women compared to those from normal pregnant women showed pro-inflammatory properties in the vascular wall inducing vascular hyporeactivity in vessels from humans and mice. These effects were associated with complex interactions between NO and cyclooxygenase systems via endothelial cell activation. Altogether, these findings suggest that MPs can be considered as vectors of biological messages for vascular homeostasis, during immunity and inflammation