MCAM and its Isoforms as Novel Targets in Angiogenesis Research and Therapy

Melanoma cell adhesion molecule (MCAM) (CD146) is a membrane glycoprotein of the mucin family. It is one of the numerous proteins composing the junction of the vascular endothelium, and it is expressed in other cell types such as cancer cells, smooth muscle cells, and pericytes. Some recent works were designed to highlight its structural features, its location in the endothelium, and its role in angiogenesis, vascular permeability, and monocyte transmigration, but also in the maintenance of endothelial junctions and tumor development. MCAM exists in different splice variants and is shedded from the vascular membrane by metalloproteases. Studies about MCAM spliced and cleaved variant on human angiogenic physiological and pathological models permit a better understanding on the roles initially described for this protein. Furthermore, this knowledge will help in the future to develop therapeutic and diagnostic tools targeting specifically the different MCAM variant. Recent advances in research on angiogenesis and in the implication of MCAM in this process are discussed in this chapter

Early nongenomic events in aldosterone action in renal collecting duct cells: PKCalpha activation, mineralocorticoid receptor phosphorylation, and cross-talk with the genomic response

Effects of aldosterone on its target cells have long been considered to be mediated exclusively through the genomic pathway; however, evidence has been provided for rapid effects of the hormone that may involve nongenomic mechanisms. Whether an interaction exists between these two signaling pathways is not yet established. In this study, the authors show that aldosterone triggers both early nongenomic and late genomic increase in sodium transport in the RCCD(2) rat cortical collecting duct cell line. In these cells, the early (up to 2.5 h) aldosterone-induced increase in short-circuit current (Isc) is not blocked by the mineralocorticoid receptor (MR) antagonist RU26752, it does not require mRNA or protein synthesis, and it involves the PKCalpha signaling pathway. In addition, this early response is reproduced by aldosterone-BSA, which acts at the cell surface and presumably does not enter the cells (aldo-BSA is unable to trigger the late response). The authors also show that MR is rapidly phosphorylated on serine and threonine residues by aldosterone or aldosterone-BSA. In contrast, the late (4 to 24 h) aldosterone-induced increase in ion transport occurs through activation of the MR and requires mRNA and protein synthesis. Interestingly, nongenomic and genomic aldosterone actions appear to be interdependent. Blocking the PKCalpha pathway results in the inhibition of the late genomic response to aldosterone, as demonstrated by the suppression of aldosterone-induced increase in MR transactivation activity, alpha1 Na(+)/K(+)/ATPase mRNA, and Isc. These data suggest cross-talk between the nongenomic and genomic responses to aldosterone in renal cells and suggest that the aldosterone-MR mediated increase in mRNA/protein synthesis and ion transport depends, at least in part, upon PKCalpha activation.Fil: Le Moëllic, Cathy. Inserm; FranciaFil: Ouvrard Pascaud, Antoine. Inserm; FranciaFil: Capurro, Claudia Graciela. Inserm; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cluzeaud, Francoise. Inserm; FranciaFil: Fay, Michel. Inserm; FranciaFil: Jaisser, Frederic. Inserm; FranciaFil: Farman, Nicolette. Inserm; FranciaFil: Blot Chabaud, Marcel. Inserm; Franci

Mitochondrial dysfunction and its association with age-related disorders

Aging is a complex process that features a functional decline in many organelles. Various factors influence the aging process, such as chromosomal abnormalities, epigenetic changes, telomere shortening, oxidative stress, and mitochondrial dysfunction. Mitochondrial dysfunction significantly impacts aging because mitochondria regulate cellular energy, oxidative balance, and calcium levels. Mitochondrial integrity is maintained by mitophagy, which helps maintain cellular homeostasis, prevents ROS production, and protects against mtDNA damage. However, increased calcium uptake and oxidative stress can disrupt mitochondrial membrane potential and permeability, leading to the apoptotic cascade. This disruption causes increased production of free radicals, leading to oxidative modification and accumulation of mitochondrial DNA mutations, which contribute to cellular dysfunction and aging. Mitochondrial dysfunction, resulting from structural and functional changes, is linked to age-related degenerative diseases. This review focuses on mitochondrial dysfunction, its implications in aging and age-related disorders, and potential anti-aging strategies through targeting mitochondrial dysfunction

Regulation du transport de sodium par l'aldosterone: influence de la concentration intracellulaire de sodium sur la Na-K-ATPase dans le tubule collecteur cortical de rein de lapin

SIGLEINIST T 73231 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Contribution à l'étude du rôle de CD146 soluble dans langiogenèse et de l'effet du blocage du récepteur P2Y12 sur la lésion endothéliale lors d'une angioplastie coronaire

Nous avons montré que la molécule recombinante humaine CD146 soluble (rh-sCD146) a un effet chimiotactique et angiogénique sur les cellules dérivées de progéniteurs endothéliaux (PEC) en augmentant leur capacité à migrer, à proliférer et à former des pseudo-capillaires. Des expériences réalisées in vivo sur un modèle d'ischémie de la patte chez le rat ont montré que des injections locales répétées de rh-sCD146 permettent une diminution significative du taux d'auto-amputation des animaux et une augmentation du taux de perfusion sanguin de la patte et de la densité capillaire. Dans une 2ème partie du travail, nous avons montré que l'angioplastie coronaire induit une hausse significative du nombre de cellules endothéliales circulantes (CEC) 6h après l'intervention (H6). Les lésions endothéliales, évaluées par la mesure de la variation du nombre de CEC (H6-H0), sont plus élevées chez les non-répondeurs par rapport aux bons répondeurs au Clopidogrel et sont corrélées à l'index VASPWe showed that the recombinant human soluble CD146 (rh-sCD146) has a chemotactic and angiogenic effect on endothelial progenitor derived cells (EPC) by increasing their ability to migrate, to proliferate and to form pseudo- capillaries. In an in vivo experiments model of ischemia in the rat by femoral artery ligation we showed that repeated local injections of rh-sCD146 for 12 days allows a significant reduction in the rate of animals self-amputation and an increase in the rate of blood perfusion of the leg and in the capillary density. In a second part of the work, we have shown that percutaneous coronary intervention induced a significant rise in circulating endothelial cells (CEC) levels 6h after the procedure (H6). The endothelial injury, assessed by CEC delta-change between H6 and H0, was significantly higher in the high on-treatment platelet reactivity group compared with the good responders to Clopidogrel and correlated with the Vasodilatator-Stimulated Phosphoprotein indexAIX-MARSEILLE2-Bib.electronique (130559901) / SudocSudocFranceF

The role of CD146 in renal disease: from experimental nephropathy to clinics

International audienceVascular endothelial dysfunction is a major risk factor in the development of renal diseases. Recent studies pointed out a major interest for the inter-endothelial junction protein CD146, as its expression is modulated during renal injury. Indeed, some complex mechanisms involving this adhesion molecule and its multiple ligands are observed in a large number of renal diseases in fundamental or clinical research. The purpose of this review is to summarize the most recent literature on the role of CD146 in renal pathophysiology, from experimental nephropathy to clinical trials

CD146 (Cluster of Differentiation 146)

International audienceCD146 (cluster of differentiation 146) is an adhesion molecule that is expressed by different cells constituting vessels, particularly endothelial cells. The last 30 years of research in this field have shown that CD146 plays a key role in the control of several vessel functions. Three forms of CD146 have been described, including 2 transmembrane isoforms and a soluble protein that is detectable in the plasma. These CD146 forms mediate pleiotropic functions through homophilic and heterophilic interactions with proteins present on surrounding partners. Several studies used neutralizing antibodies, siRNA, or genetically modified mice to demonstrate the involvement of CD146 in the regulation of angiogenesis, vascular permeability, and leukocyte transmigration. In this review, we will focus on the current knowledge of the roles of CD146 in vascular homeostasis and diseases associated with endothelial dysfunction

Characteristics and regulation of 11β-hydroxysteroid dehydrogenase of proximal and distal nephron

International audienceEnzymatic properties of the enzyme 11 beta-hydroxysteroid dehydrogenase (11-HSD), which confers mineralocorticoid selectivity, have been explored in the aldosterone-sensitive collecting duct (CCD) and the aldosterone-insensitive Pars Recta (PR) of the rat kidney. After incubation of freshly isolated tubular segments with [3H]corticosterone (3H-B) or [3H]dehydrocorticosterone (3H-A), the rate of transformation of 3H-B into 3H-A (dehydrogenase activity), or the reverse reaction (reductase activity) were measured by HPLC, Vmax for dehydrogenase activity was found to be 8- to 10-fold higher in CCD than PR. The enzyme functions over a very wide range (0.1-5000 nM) of corticosterone concentration. In CCD, enzyme kinetics suggest either the presence of two 11-HSD forms, differing by their affinity for corticosterone, or complex kinetics. Addition of NAD or NADP to permeabilized tubules revealed that dehydrogenase activity is NAD-dependent in CCD and NADP-dependent in PR. Cofactor addition was ineffective in intact tubules. CCD exhibited an exclusive dehydrogenase activity, whereas in PR dehydrogenase and reductase activity were found. No regulation of dehydrogenase activity could be evidenced in adrenalectomized rats receiving or not aldosterone, corticosterone or dexamethasone, for 2 h, 3 days or 4 days. We conclude that 11-HSD in the CCD and PR differs by its Vmax and cofactor dependence. Corticosteroid hormones do not influence 11-HSD activity