Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

The purpose of this study was to investigate whether skeletal muscle sarcoplasmic reticulum (SR) Ca2+ transport efficiency and expression levels of major SR Ca2+ regulatory proteins are associated with resting metabolic rate (RMR) in humans. Twenty five healthy and weight stable participants with mean age, height and weight of 22±3.6 years, 174.6±8.0 cm and 72.8±21 kg respectively, were recruited for the study. RMR was calculated using the Weir equation based upon measures of VO2 and VCO2, which were collected using the Vmax breath by breath indirect calorimetry system. Ca2+-ATPase activity, Ca2+ uptake and Ca2+ leak analyses were performed in vitro on homogenates that were prepared from vastus lateralis muscle biopsies. Ionophore (IONO) ratio was assessed by measuring Ca2+-ATPase activity in the presence and absence of Ca2+ Ionophore. The coupling ratio, a measure of SR Ca2+ transport efficiency, was calculated by taking the ratio of Ca2+ uptake to Ca2+-ATPase activity. Expression levels of the major SR Ca2+ regulatory proteins, including SERCA1a, SERCA2a, phospholamban (PLN), and calsequestrin (CSQ) were assessed using Western blotting techniques. Pearson correlation coefficient analysis demonstrated a weak but significant negative correlation between coupling ratio and RMR (r2= 0.2108, p =0.0240). Content of the SR Ca2+ regulatory proteins, IONO ratio and Ca2+ leak were not found to be significantly related to either RMR or coupling ratio, with the exception of the ratio of SERCA1a to SERCA2a, which showed a weak but significant positive relationship with RMR (r2=0.1781, p=0.0400). Thus, the relationship between coupling ratio and RMR is not influenced by Ca2+ leak, SERCA pump efficiency or the SR Ca2+ regulatory proteins. Overall, these results suggest that the efficiency of SR Ca2+ transport is weakly related to whole body RMR. Further analysis is needed to assess this relationship, and to determine which SR Ca2+ handling properties are influencing the relationship between coupling ratio and RMR.

The purpose of this study was to investigate whether skeletal muscle sarcoplasmic reticulum (SR) Ca2+ transport efficiency and expression levels of major SR Ca2+ regulatory proteins are associated with resting metabolic rate (RMR) in humans. Twenty five healthy and weight stable participants with mean age, height and weight of 22±3.6 years, 174.6±8.0 cm and 72.8±21 kg respectively, were recruited for the study. RMR was calculated using the Weir equation based upon measures of VO2 and VCO2, which were collected using the Vmax breath by breath indirect calorimetry system. Ca2+-ATPase activity, Ca2+ uptake and Ca2+ leak analyses were performed in vitro on homogenates that were prepared from vastus lateralis muscle biopsies. Ionophore (IONO) ratio was assessed by measuring Ca2+-ATPase activity in the presence and absence of Ca2+ Ionophore. The coupling ratio, a measure of SR Ca2+ transport efficiency, was calculated by taking the ratio of Ca2+ uptake to Ca2+-ATPase activity. Expression levels of the major SR Ca2+ regulatory proteins, including SERCA1a, SERCA2a, phospholamban (PLN), and calsequestrin (CSQ) were assessed using Western blotting techniques. Pearson correlation coefficient analysis demonstrated a weak but significant negative correlation between coupling ratio and RMR (r2= 0.2108, p =0.0240). Content of the SR Ca2+ regulatory proteins, IONO ratio and Ca2+ leak were not found to be significantly related to either RMR or coupling ratio, with the exception of the ratio of SERCA1a to SERCA2a, which showed a weak but significant positive relationship with RMR (r2=0.1781, p=0.0400). Thus, the relationship between coupling ratio and RMR is not influenced by Ca2+ leak, SERCA pump efficiency or the SR Ca2+ regulatory proteins. Overall, these results suggest that the efficiency of SR Ca2+ transport is weakly related to whole body RMR. Further analysis is needed to assess this relationship, and to determine which SR Ca2+ handling properties are influencing the relationship between coupling ratio and RMR.

Abstract Ciprofloxacin was incorporated to plain bioresorbable self-reinforced polylactide/glycolyde 80/20 screws and tacks (ciprofloxacin releasing SR-PLGA). These implants were compared to otherwise similar conventional fixation devices. The effect of the ciprofloxacin addition on the pull-out force of screws and tacks was evaluated in human cadaver cranial bones. SR-PLGA tacks applied to cranial bone with a special applicator gun had a similar holding power as screws. Addition of the antibiotic compromised the strength of the screws so that ciprofloxacin-containing PLGA screws had lower pull-out strength than corresponding plain PLGA screws. Scanning electron microscopy showed that the fibrillar strip-like microstructure of plain SR-PLGA screws turned into a coarse uni-axial platelet-like pattern as a result of ciprofloxacin addition. It is concluded that this type of 4 mm long and 1.5 mm diameter ciprofloxacin-containing screws can only be used in non-load-bearing or slightly load-bearing applications. Tissue reactions elicited by plain bioresorbable self-reinforced polylactide/glycolide (SR-PLGA) 80/20 screws were compared to similar but ciprofloxacin-releasing SR-PLGA fixation devices in rabbit cranial bone. Plain and ciprofloxacin-PLGA 80/20 screws elicited only mild inflammatory reactions upon implantation in rabbit cranial bone, but they did not interfere with osteoblast activity in up to 72 week long follow-up. Release of the antibiotic from ciprofloxacin-PLGA screws was gradual and the drug concentration in bone tissues was still higher at 8 weeks than the minimal inhibitory concentration (MIC) of ciprofloxacin for S. aureus (0.1–1.0 μg/g). Ciprofloxacin-releasing SR-PLGA screws can find clinical usage in the prevention of implant-related infections in osteofixation in craniomaxillofacial bones in non-load-bearing or slightly load-bearing applications. Larger 6 mm long and 2 mm diameter ciprofloxacin-releasing tacks had a similar holding power to cranial bone as conventional tacks. Tacks can be recommended for clinical use as the application procedure saves time and costs.

We present global and regional correlations between whole-rock values of Sr/Y and La/Yb and crustal thickness for intermediate rocks from modern subduction-related magmatic arcs formed around the Pacific. These correlations bolster earlier ideas that various geochemical parameters can be used to track changes of crustal thickness through time in ancient subduction systems. Inferred crustal thicknesses using our proposed empirical fits are consistent with independent geologic constraints for the Cenozoic evolution of the central Andes, as well as various Mesozoic magmatic arc segments currently exposed in the Coast Mountains, British Columbia, and the Sierra Nevada and Mojave- Transverse Range regions of California. We propose that these geochemical parameters can be used, when averaged over the typical lifetimes and spatial footprints of composite volcanoes and their intrusive equivalents to infer crustal thickness changes over time in ancient orogens.

Tématem diplomové práce je mezinárodní pracovní migrace Slováků na českém trhu práce. Míra ekonomické aktivity v České republice klesá, čeští specialisté opouštějí zemi a nepříznivě se vyvíjejí také hlavní demografické ukazatele. Migrace slovenské pracovní síly by mohla alespoň částečně řešit tento problém. Tato práce se zabývá historickým vývojem českého a slovenského trhu práce. Další část této práce analyzuje legislativní, ekonomické a demografické postavení Slováků žijících a pracujících na území ČR. S ohledem na makroekonomický vývoj České republiky je v poslední části naznačen také předpokládaný vývoj mezinárodní pracovní migrace ze Slovenska.

TESIS PARA OPTAR AL GRADO DE MAGÍSTER EN FINANZAS / Vitolo, Giancarlo [Parte I mediante el método de múltiplos], Avila Balucani, Daniel Alejandro [Parte II mediante el método de flujo de caja descontado] / El trabajo desarrollado a continuación, tiene como principal objetivo efectuar la valoración de la empresa AES Panamá SRL y estimar el precio de su acción, a través de la metodología de flujos de caja descontados (FCD). Esta metodología se basa en el modelo multiperiodo de Modigliani-Miller, que consiste principalmente en modelar los flujos de caja libre de la compañía sobre un horizonte de tiempo determinado, para luego ser descontados a su valor presente. Además de estos flujos de caja, el valor presente debe ser determinado para flujos de caja más allá del horizonte de proyección comúnmente llamado valor terminal o perpetuidad. Bajo esta metodología determinar la tasa de descuento es uno de los factores fundamentales. Para esto se deben considerar aspectos claves como el riesgo, comportamientos históricos y el rendimiento mínimo esperado por compradores o vendedores con una expectativa mínima de rentabilidad. En esta valoración utilizamos una tasa de costo de capital, calculada a través de la fórmula WACC, la cual consiste en un promedio ponderado entre el costo de la deuda (kb) y la rentabilidad exigida por los accionistas (kp). Para realizar la valoración a través de esta metodología, es necesario determinar una estructura de capital objetivo a largo plazo para la compañía, la cual puede obtenerse en base al análisis retrospectivo de las cifras presentadas en sus estados financieros. Como parte de la valoración completa de la empresa bajo este método, debemos identificar y adicionar sus activos prescindibles (activos no necesarios para la operación de la empresa) y ajustar el exceso o déficit de capital de trabajo que haya al momento de la valoración. Como último paso en esta valoración, se determina el valor económico del patrimonio restando al valor obtenido de la empresa el valor presente de la deuda financiera al momento de la valoración. Adicionalmente a la valoración a través del método de FCD, estimaremos el valor de la empresa AES Panamá SRL y el precio de su acción por el método de múltiplos. Este método consiste básicamente en estimar el valor de una empresa analizando la relación de las razones financieras de compañías que pertenecen a la misma industria tomadas como benchmark. AES Panamá, es una empresa que genera y vende electricidad en el mercado panameño y mercado eléctrico regional (MER), es la mayor compañía de generación en Panamá en términos de capacidad instalada y energía despachada promedio, donde el 93% de la capacidad firme de las plantas de la Compañía se encuentra contratada bajo varios acuerdos de compra - venta de potencia y energía con compañías de distribución, grandes clientes y la compañía generadora AES Changuinola. La energía excedente es vendida en el mercado ocasional a los precios establecidos en el mismo (precio spot) Para la ejecución de esta valoración se usaron los estados financieros de la empresa y de compañías que componen la industria desde el 30 de junio de 2013 hasta el 30 de septiembre de 2017, por otra parte, se extrajeron los datos presentados por la Bolsa de Valores de Panamá, donde pudimos compilar la información sobre de la estructura de capital, el patrimonio económico, principales competidores de la industria y estructura de la deuda y demás información necesaria para poder analizar, modelar y realizar las proyecciones de los flujos de caja de la empresa con un horizonte de evaluación de 5 años. Ya finalizada la valoración de AES Panamá al 30 de junio de 2017 con diferentes metodologías, obtuvimos como resultados que con el método de flujos de caja descontados el valor de la empresa o del patrimonio es de USD $1,067,808 en miles y un precio por acción de USD $4.97, por otro lado, el método de valoración en base a múltiplos de la industria, el ratio que presenta una mejor estimación es el del precio sobre ventas (Price to sales ratio) arrojando una estimación del valor de la empresa por USD $1,032,656 en miles y un precio por acción de USD $2.98. Debido a que AES Panamá es una empresa que no tranza o cotiza sus acciones en la Bolsa, actualmente no contamos con el valor efectivo de la acción a la fecha, solo tenemos como referencia en valor contable del precio de la acción. A pesar de no tener información pública comparable de la compañía, luego de realizar los procedimientos de valoración y analizar las estimaciones, consideramos que los resultados son lo suficientemente precisos para confiar en los valores que arrojan las diferentes metodologías aplicadas

Das Herz ist physiologisch auf einen fein regulierten und ausgeglichenen bioenergetischen Energiehaushalt angewiesen, um auf akute Belastungssituationen adäquat reagieren zu können und oxidativen Stress zu vermeiden. Ca2+ reguliert zentral sowohl die zyklischen Kontraktions-/Relaxationsprozesse (ECC) als auch unmittelbar den mitochondrialen Metabolismus. Der ECC liegt in den Kardiomyozyten die Ca2+- Freisetzung durch die RyR2 zu Grunde; die IP3 Rezeptoren des sarkoplasmatischen Retikulums (SR) führen davon unabhängig zu einer Ca2+ Freisetzung aus dem SR. Diese IP3R vermittelten Signale werden in den räumlich nahe gelegenen Mitochondrien zum Teil über den mRyR1 in die mitochondriale Matrix aufgenommen und stimulieren dort langfristig die oxidative Phosphorylierung und den Erhalt der antioxidativen Kapazität. Die enge räumliche Nähe zwischen SR und Mitochondrien wird durch Strukturproteine wie Mitofusin 2 (Mfn2) ergänzt, die das SR mit der äußeren Mitochondrienmembran koppeln und so die Ca2+-Interaktion beeinflussen. Ziel der Arbeit war, den Effekt von Mfn2 Defizienz auf die IP3 induzierte mitochondriale Ca2+-Regulation in Kardiomyozyten zu evaluieren. Dazu erfolgten Fluoreszenzfärbungen an adulten isolierten Ventrikelkardiomyozyten kardiospezifischer Mfn2 Knock-Out (KO) Mäusen bzw. deren wildtypischen Geschwistertieren (WT). Erhobene Parameter umfassten das mitochondriale Ca2+, das mitochondriale Membranpotenzial, die mitochondriale Superoxidbildung und mitochondriale ATP-Gehalt. Die Ergebnisse bestätigten eine Signalachse, bei der die Stimulation von isolierten murinen Kardiomyozyten mit dem IP3 Agonisten ET-1 zu einer mitochondrialen Ca2+ Aufnahme führte, dem Erhalt des mitochondrialen Membranpotenzials diente und der ATP Gehalt stiegt. Bei induzierter kardiospezifischer Ablation von Mfn2 geht diese SR-mitochondriale Interaktion verloren, und es entstand ein energetisches Defizit sowie eine verminderte Superoxidbildung. Bei beta-adrenerger Stimulation mit Isoproterenol (ISO) resultierte in WT zwar eine mitochondriale Ca2+-Aufnahme, allerdings ein Abfall des ATP-Gehaltes. In den Mfn2 defizienten Kardiomyozyten zeigte sich eine Steigerung des ATP-Gehaltes auch auf beta-adrenerge Stimulation, die einen energetischen Kompensationsmechanismus in den Mfn2 KO Tieren vermuten lässt. Dies identifiziert Mfn2 als kritische Strukturkomponente für die basale bioenergetische Adaptation der durch IP3R-mRyR1 vermittelten Signalachse unter physiologischen Bedingungen. / Under physiological conditions the heart needs a finely tuned bioenergetic adaptation system to adequately match sudden changes in the workload and to avoid oxidative stress. Ca2+ regulates the excitation-contraction-coupling (ECC) as well as the mitochondrial metabolism. The ECC is based on the release of Ca2+ via the RyR2 while the IP3 receptor (IP3R) releases Ca2+ independently from the sarcoplasmatic reticulum (SR). The signals from the latter are taken up by the surrounding mitochondria via the mRyR1 channel to stimulate both the basal oxidative phosphorylation and the antioxidative capacity. The close functional relationship between mitochondria and SR is affected by membrane-coupling proteins like mitofusin 2 (Mfn2) that may influence the Ca2+ transmission. This work aimed at evaluating the effect of Mfn2 deficiency on the IP3-induced mitochondrial calcium regulation in cardiomyocytes. Mitochondrial Ca2+ uptake, membrane potential, redox state and ATP generation were monitored in isolated ventricular cardiomyocytes of cardio-specific mitofusin 2 Knock-out (KO) mice and their wildtype littermates (WT) via fluorescent staining using laser scanning confocal microscopy. The results show that stimulation with the IP3 agonist ET-1 led to mitochondrial calcium uptake, ATP generation and maintained mitochondrial membrane potential. The cardio-specific loss of the tethering protein Mfn2 resulted in an energetic deficit and decreased levels of superoxide. Beta adrenergic receptor activation with isoproterenol (ISO) in WT resulted in a mitochondrial calcium uptake but decreased ATP content, while leading in Mfn2 KO cardiomyocyte to increased levels of ATP, pointing probably towards an energetic compensatory mechanism. Taken together these results propose Mfn2 as a critical structural component that affects under physiological conditions the privileged SR-mitochondrial metabolic feedback mechanism via IP3R and mRYR1 to maintain normal cardiac function and bioenergetics.

Recent evidence suggests that the macrophage scavenger receptor class A (SR-A, aka, CD204) plays a role in the induction of innate immune and inflammatory responses. We investigated whether SR-A will cooperate with Toll-like receptors (TLRs) in response to TLR ligand stimulation. Macrophages (J774/a) were treated with Pam2CSK4, (TLR2 ligand), Polyinosinic:polycytidylic acid (Poly I:C) (TLR3 ligand), and Lipopolysaccharides (LPS) (TLR4 ligand) for 15min in the presence or absence of fucoidan (the SR-A ligand). The levels of phosphorylated IκBα (p-IκBα) were examined by Western blot. We observed that Poly I:C and LPS alone, but not Pam2CSK4 or fucoidan increased the levels of p-IκBα. However, LPS-induced increases in p-IκBα levels were further enhanced when presence of the fucoidan. Immunoprecipitation and double fluorescent staining showed that LPS stimulation promotes SR-A association with TLR4 in the presence of fucoidan. To further confirm our observation, we isolated peritoneal macrophages from SR-A deficient (SR-A-/-), TLR4-/- and wild type (WT) mice, respectively. The peritoneal macrophages were treated with LPS for 15min in the presence and absence of fucoidan. We observed that LPS-stimulated TNFα and IL-1β production was further enhanced in the WT macrophages, but did not in either TLR4-/- or SR-A-/- macrophages, when fucoidan was present. Similarly, in the presence of fucoidan, LPS-induced IκBα phosphorylation, NF-κB binding activity, and association between TLR4 and SR-A were significantly enhanced in WT macrophages compared with LPS stimulation alone. The data suggests that SR-A is needed for LPS-induced inflammatory responses in macrophages.

L’effet athéroprotecteur des Lipoprotéines de Haute Densité (HDL) est principalement attribué à leur rôle clé dans Transport Retour du Cholestérol (RCT), un processus par lequel le cholestérol excédentaire des cellules périphériques est capté par les particules HDL pour être amené au foie où il sera préférentiellement sécrété dans les voies biliaires, puis excrété dans les fèces. Deux voies indépendantes ont été identifiées comme étant impliquées dans l’endocytose hépatique du HDL. La première est la voie ecto-F1-ATPase/P2Y13 dans laquelle l’apoA-I (apolipoprotéine majoritaire des HDL) se lie à la F1-ATPase exprimé à la surface des hépatocytes (ecto-F1-ATPase) et stimule l’hydrolyse d’ATP en ADP. L’ADP ainsi généré active le récepteur purinergique P2Y13 pour stimuler l’endocytose de l’holoparticule HDL (protéines + lipides) via un troisième récepteur différent de SR-BI. Les souris invalidées pour P2Y13 présentent une diminution des sécrétions de lipides biliaires accompagnée d’une diminution du RCT des macrophages vers les fèces sous régime normolipidique. Un régime riche en cholestérol (1.25% cholestérol) accentue ce phénotype. La voie SR-BI, quant à elle, est responsable de la captation sélective du cholestérol estérifié des HDL par le foie. Les souris invalidées pour SR-BI spécifiquement au niveau du foie (SR-BI KOfoie) présentent une hypercholestérolémie principalement attribuée à une augmentation du HDL-C et développent des plaques d’athérosclérose sous régime hypercholestérolémique. Dans une étude récente, nous avons montré que l’invalidation de P2Y13 dans le modèle murin proathérogène apoE KO induit une augmentation du développement d’athérosclérose associée à une diminution des sécrétions de lipides biliaires et du RCT des macrophages vers les fèces. De plus, dans ces souris, l’expression hépatique transcriptionnelle et protéique de SR-BI étaient fortement augmentées par rapport aux souris apoE KO, suggérant qu’un possible mécanisme de compensation pourrait exister entre les récepteurs P2Y13 et SR-BI. L’objectif de ma thèse a été d’étudier la contribution respective des récepteur P2Y13 et SR-BI dans le métabolisme du HDL-C et le développement de l’athérosclérose. Nous avons croisé des souris P2Y13 KO avec des souris SR-BI KOfoie et nous avons obtenu des souris doublement invalidées (P2Y13 x SR-BIfoie dKO). Le phénotype métabolique des souris dKO a été étudié sous régime normolipidique et hypercholestérolémique et le développement d’athérosclérose sous régime hypercholestérolémique. Par rapport aux souris sauvages, les souris dKO sous régime normolipidique, présentent une augmentation du cholestérol plasmatique similaire à celle observée chez les souris SR-BI KOfoie, principalement imputable à une augmentation du HDL-C. Les souris dKO, mais pas les souris SR-BI KO, montrent une diminution des sécrétions de lipides biliaires comparable à celle observée chez les souris P2Y13 KO. Ce phénotype métabolique observé chez les souris dKO est accentué sous régime hypercholestérolémique et est associé à une augmentation des plaques d’athérosclérose par rapport aux souris SR-BI KOfoie. L’ensemble des résultats montrent que la délétion hépatique de SR-BI contribue essentiellement à une augmentation des taux plasmatiques de cholestérol, et plus particulièrement HDL-C. La délétion de P2Y13, quant à elle, n’induit aucune variation des lipides plasmatiques mais contribue principalement à une diminution des sécrétions de lipides biliaires qui contribue au développement de l’athérosclérose chez les souris invalidées pour SR-BI hépatique. Ces résultats soutiennent le concept selon lequel le flux de cholestérol transporté par les HDL des tissus périphériques vers le foie et les voies de sécrétions biliaires est plus important dans l’athéro-protection que la concentration plasmatique en HDL-C. L’activation du récepteur P2Y13 constitue une approche thérapeutique intéressante pour cibler les HDL contre le développement de l’athérosclérose. / The atheroprotective effect of High Density Lipoproteins (HDL) is mostly attributed to their central role in Reverse Cholesterol Transport (RCT), a process whereby excess cholesterol is taken up from peripheral cells to be processed into HDL particles, then later delivered to the liver where it is preferentially secreted into the bile, either as free cholesterol or after transformation into bile acids, to be further excreted into the feces. Two independent pathways have been identified as being involved in the hepatic HDL uptake. The first one involves the ecto-F1-ATPase/P2Y13 pathway. Briefly, apoA-I (main HDL apolipoprotein) binds to the F1-ATPase expressed ectopically at the surface of the hepatocyte (ecto-F1-ATPase) and stimulates hydrolysis of extracellular ATP into ADP. The generated ADP selectively activates the purinergic receptor P2Y13 resulting in subsequent endocytosis of the HDL-holoparticle (i.e. protein and lipid moieties) through a low-affinity binding site distinct from SR-BI. Mice deficient for P2Y13 display decreased biliary lipids secretion associated to an impaired macrophage-to-feces RCT when fed a Chow Diet (CD), phenotype emphasized when fed a High Cholesterol Diet (HCD). Differently, the SR-BI pathway mediates selective HDL-cholesteryl ester uptake by the liver. Mice with liver-specific SR-BI deficiency (SR-BI-KOliver) display a hypercholesterolemia mainly due to an increase on HDL-C and develop atherosclerosis when fed a HCD. In a recent study, we showed that P2Y13 extinction in the pro-atherogenic mouse model apoE-KO resulted in an increase of atherosclerotic plaque development associated to a decreased biliary lipid secretion and macrophage-to-feces RCT. Moreover, in these mice, mRNA and protein level of hepatic SR-BI were consistently increased as compared to apoE KO mice, suggesting that a possible compensatory mechanism might exist between P2Y13 and SR-BI receptors. My thesis aimed to study the respective contribution of P2Y13 and hepatic SR-BI in HDL-C metabolism and atherosclerosis development. We crossbred P2Y13 KO with SR-BI KOliver mice and obtained double knockout mice (P2Y13 x SR-BIliver dKO). The phenotype of dKO mice was analysed with regards to HDL-C metabolism either on CD or after 20 weeks of HCD, and to atherosclerosis development on HCD. When fed a CD, dKO mice, showed an increase in plasma cholesterol compared to WT mice similar to that observed in SR-BI KOliver mice, mainly due to an increase in HDL-C. DKO, but not SR-BI KOliver mice, showed impaired biliary lipid secretion to the same extent than P2Y13 KO mice. HCD accentuated the metabolic phenotype of dKO mice, with an increase in atherosclerotic lipid lesions in dKO mice compared to SR-BI KOliver mice. The phenotypic features of P2Y13 x SR-BIliver dKO mice show that hepatic extinction of SR-BI essentially contributes to an increase of HDL-C levels. Conversely, P2Y13 extinction does not induce any change in plasma lipoprotein levels but mainly contributes to a decrease of hepato-biliary cholesterol secretions, which translates into an increased atherosclerosis development, on top of SR-BI hepatic extinction. These results support the concept that the dynamic flux of cholesterol transported by HDL from macrophage foam cells to the liver for further bile secretion is essential for athero-protection rather than steady-state HDL-C concentration. In the future of HDL-therapies, P2Y13 receptor activation constitutes an interesting therapeutic approach against atherosclerosis development.