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1.
Eur J Nutr ; 58(2): 879-893, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29804185

RESUMEN

PURPOSE: Obesity, which is characterized by triglyceride accumulation mainly in adipocytes but also in arterial wall cells such as macrophages, is a major risk factor for developing atherosclerosis. We aimed to identify the crosstalk related to lipid metabolism and oxidation status between adipocytes and macrophages. METHODS: We used a co-culture model system with J477A.1 cultured macrophages and 3T3L1 cultured adipocytes. For an in-vivo co-culture system, we used C57BL/6 mouse peritoneal macrophages and visceral or subcutaneous adipose tissue. RESULTS: Adipocytes significantly increased reactive oxygen species generation, up to twofold, and decreased cholesterol content by 22% in the co-cultured macrophages. Macrophages significantly increased triglyceride-biosynthesis rate by twofold and decreased triglyceride-degradation rate by 30%, resulting in increased triglyceride accumulation in the co-cultured adipocytes by up to 72%. In the in-vivo mouse model, visceral adipose tissue crosstalk with macrophages resulted in a significant pro-atherogenic phenotype with respect to cellular cholesterol metabolism. In contrast, the interaction between subcutaneous adipose tissue and macrophages mostly affected cellular triglyceride metabolism. There were no significant effects on mitochondrial respiration capacity in the macrophages. Upon oxidative-stress reduction in the co-cultured cells using the polyphenol-rich antioxidant, pomegranate juice, the expression of genes related to cellular lipid accumulation was significantly reduced. CONCLUSIONS: We reveal, for the first time, that paracrine interactions between adipocytes and macrophages result in oxidative stress and lipids metabolic alterations in both cells, toward increased atherogenicity which can be reversed by phenolic antioxidants.


Asunto(s)
Adipocitos/metabolismo , Aterosclerosis/metabolismo , Metabolismo de los Lípidos/fisiología , Macrófagos/metabolismo , Estrés Oxidativo/fisiología , Tejido Adiposo/metabolismo , Animales , Antioxidantes/metabolismo , Células Cultivadas , Masculino , Ratones , Ratones Endogámicos C57BL
2.
Immunology ; 152(3): 484-493, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28672048

RESUMEN

Acquisition of a 'quiescence programme' by naive T cells is important to provide a stress-free environment and resistance to apoptosis while preserving their responsiveness to activating stimuli. Therefore, the survival and proper function of naive T cells depends on their ability to maintain quiescence. Recently we demonstrated that by preventing chronic unresolved endoplasmic reticulum (ER) stress, Schlafen2 (Slfn2) maintains a stress-free environment to conserve a pool of naive T cells ready to respond to a microbial invasion. These findings strongly suggest an intimate association between quiescence and stress signalling. However, the connection between ER stress conditions and loss of T-cell quiescence is unknown. Here we demonstrate that homeostasis of cholesterol and lipids, is disrupted in T cells and monocytes from Slfn2-mutant, elektra, mice with higher levels of lipid rafts and lipid droplets found in these cells. Moreover, elektra T cells had elevated levels of free cholesterol and cholesteryl ester due to increased de novo synthesis and higher levels of the enzyme HMG-CoA reductase. As cholesterol plays an important role in the transition of T cells from resting to active state, and ER regulates cholesterol and lipid synthesis, we suggest that regulation of cholesterol levels through the prevention of ER stress is an essential component of the mechanism by which Slfn2 regulates quiescence.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Proliferación Celular , Senescencia Celular , Colesterol/biosíntesis , Activación de Linfocitos , Mutación , Linfocitos T/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Ésteres del Colesterol/biosíntesis , Estrés del Retículo Endoplásmico , Genotipo , Hidroximetilglutaril-CoA Reductasas/metabolismo , Gotas Lipídicas/metabolismo , Microdominios de Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Mutantes , Monocitos/inmunología , Monocitos/metabolismo , Fenotipo , Linfocitos T/inmunología , Regulación hacia Arriba
3.
Arch Toxicol ; 91(4): 1709-1725, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27696135

RESUMEN

The unsaturated aldehyde acrolein is pro-atherogenic, and the polyphenol-rich pomegranate juice (PJ), known for its anti-oxidative/anti-atherogenic properties, inhibits macrophage foam cell formation, the hallmark feature of early atherosclerosis. This study aimed to investigate two unexplored areas of acrolein atherogenicity: macrophage lipid metabolism and the gut microbiota composition. The protective effects of PJ against acrolein atherogenicity were also evaluated. Atherosclerotic apolipoprotein E-deficient (apoE-/-) mice that were fed acrolein (3 mg/kg/day) for 1 month showed significant increases in serum and aortic cholesterol, triglycerides, and lipid peroxides. In peritoneal macrophages isolated from the mice and in J774A.1 cultured macrophages, acrolein exposure increased intracellular oxidative stress and stimulated cholesterol and triglyceride accumulation via enhanced rates of their biosynthesis and over-expression of key regulators of cellular lipid biosynthesis: sterol regulatory element-binding proteins (SREBPs), 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), and diacylglycerol acyltransferase1 (DGAT1). Acrolein-fed mice demonstrated a major shift in the gut microbiota composition, including a significant phylum-level change in increased Firmicutes and decreased Bacteroidetes. At the family level, acrolein significantly increased the prevalence of Ruminococcaceae and Lachnospiraceae of which the Coprococcus genus was significantly and positively correlated with serum, aortic and macrophage lipid levels and peroxidation. The pro-atherogenic effects of acrolein on serum, aortas, macrophages, and the gut microbiota were substantially abolished by PJ. In conclusion, these findings provide novel mechanisms by which acrolein increases macrophage lipid accumulation and alters the gut microbiota composition in association with enhanced atherogenesis. Moreover, PJ was found as an effective strategy against acrolein atherogenicity.


Asunto(s)
Acroleína/toxicidad , Aterosclerosis/prevención & control , Lythraceae/química , Macrófagos/efectos de los fármacos , Polifenoles/farmacología , Animales , Apolipoproteínas E/genética , Aterosclerosis/inducido químicamente , Línea Celular , Modelos Animales de Enfermedad , Microbioma Gastrointestinal/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Macrófagos/patología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/patología , Masculino , Ratones , Ratones Noqueados , Estrés Oxidativo/efectos de los fármacos , Polifenoles/aislamiento & purificación
5.
Clin Sci (Lond) ; 130(12): 1027-38, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-26993251

RESUMEN

Abdominal aortic aneurysm (AAA) is a permanent dilation of the aorta due to excessive proteolytic, oxidative and inflammatory injury of the aortic wall. We aimed to identify novel mediators involved in AAA pathophysiology, which could lead to novel therapeutic approaches. For that purpose, plasma from four AAA patients and four controls were analysed by a label-free proteomic approach. Among identified proteins, paraoxonase-1 (PON1) was decreased in plasma of AAA patients compared with controls, which was further validated in a bigger cohort of samples by ELISA. The phenylesterase enzymatic activity of PON1 was also decreased in serum of AAA patients compared with controls. To address the potential role of PON1 as a mediator of AAA, experimental AAA was induced by aortic elastase perfusion in wild-type (WT) mice and human transgenic PON1 (HuTgPON1) mice. Similar to humans, PON1 activity was also decreased in serum of elastase-induced AAA mice compared with healthy mice. Interestingly, overexpression of PON1 was accompanied by smaller aortic dilation and higher elastin and vascular smooth muscle cell (VSMC) content in the AAA of HuTgPON1 compared with WT mice. Moreover, HuTgPON1 mice display decreased oxidative stress and apoptosis, as well as macrophage infiltration and monocyte chemoattractant protein-1 (MCP1) expression, in elastase-induced AAA. In conclusion, decreased circulating PON1 activity is associated with human and experimental AAA. PON1 overexpression in mice protects against AAA progression by reducing oxidative stress, apoptosis and inflammation, suggesting that strategies aimed at increasing PON1 activity could prevent AAA.


Asunto(s)
Aneurisma de la Aorta Abdominal/metabolismo , Arildialquilfosfatasa/metabolismo , Animales , Aneurisma de la Aorta Abdominal/prevención & control , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Inflamación/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Transgénicos , Proteómica/métodos
6.
J Cardiovasc Pharmacol ; 68(2): 106-14, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27010808

RESUMEN

At high concentrations, polyphenols induce cell death, and the polyphenols-rich pomegranate juice (PJ), known for its antioxidative/antiatherogenic properties, can possibly affect cell death, including macrophage death involved in atherogenesis. In the present study, apoptotic/necrotic macrophage death was analyzed in J774A.1 macrophages and in peritoneal macrophages isolated from atherosclerotic apoE-/- mice treated with PJ. The effects of PJ were compared with those of the free radical generator 2, 2'-azobis (2-amidinopropane) dihydrochloride (AAPH). Both PJ and AAPH significantly increased J774A.1 macrophage death; however, flow cytometric and microscopic analyses using annexin V/propidium iodide revealed that PJ increased the early apoptosis of the macrophage dose dependently (up to 2.5-fold, P < 0.01), whereas AAPH caused dose-dependent increases in late apoptosis/necrosis (up to 12-fold, P < 0.001). Unlike PJ, AAPH-induced macrophage death was associated with increased intracellular oxidative stress (up to 7-fold, P < 0.001) and with lipid stress demonstrated by triglyceride accumulation (up to 3-fold, P < 0.01) and greater chromatic vesicle response to culture medium (up to 5-fold, P < 0.001). Accordingly, recombinant paraoxonase 1, which hydrolyzes oxidized lipids, attenuated macrophage death induced by AAPH, but not by PJ. Similar apoptotic and oxidative effects were found in macrophages from apoE-/- mice treated with PJ or AAPH. As macrophage apoptotic/necrotic death has considerable impact on atherosclerosis progression, these findings may provide novel mechanisms for the antiatherogenicity of PJ.


Asunto(s)
Apoptosis/efectos de los fármacos , Aterosclerosis/tratamiento farmacológico , Jugos de Frutas y Vegetales , Lythraceae , Macrófagos Peritoneales/efectos de los fármacos , Oxidantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Polifenoles/farmacología , Especies Reactivas de Oxígeno/metabolismo , Amidinas/farmacología , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Línea Celular , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Lythraceae/química , Macrófagos Peritoneales/metabolismo , Macrófagos Peritoneales/patología , Masculino , Ratones Noqueados , Necrosis , Oxidantes/aislamiento & purificación , Fitoterapia , Plantas Medicinales , Polifenoles/aislamiento & purificación
7.
Environ Toxicol ; 31(6): 713-23, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25448404

RESUMEN

Nanoparticle research has focused on their toxicity in general, while increasing evidence points to additional specific adverse effects on atherosclerosis development. Arterial macrophage cholesterol and triglyceride (TG) accumulation and foam cell formation are the hallmark of early atherogenesis, leading to cardiovascular events. To investigate the in vitro atherogenic effects of silicon dioxide (SiO2 ), J774.1 cultured macrophages (murine cell line) were incubated with SiO2 nanoparticle (SP, d = 12 nm, 0-20 µg/mL), followed by cellular cytotoxicity, oxidative stress, TG and cholesterol metabolism analyses. A significant dose-dependent increase in oxidative stress (up to 164%), in cytotoxicity (up to 390% measured by lactate dehydrogenase (LDH) release), and in TG content (up to 63%) was observed in SiO2 exposed macrophages compared with control cells. A smaller increase in macrophage cholesterol mass (up to 22%) was noted. TG accumulation in macrophages was not due to a decrease in TG cell secretion or to an increased TG biosynthesis rate, but was the result of attenuated TG hydrolysis secondary to decreased lipase activity and both adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) protein expression (by 42 and 25%, respectively). Overall, SPs showed pro-atherogenic effects on macrophages as observed by cytotoxicity, increased oxidative stress and TG accumulation. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 713-723, 2016.


Asunto(s)
Aterosclerosis/inducido químicamente , Macrófagos/efectos de los fármacos , Nanopartículas del Metal/toxicidad , Estrés Oxidativo/efectos de los fármacos , Dióxido de Silicio/toxicidad , Triglicéridos/metabolismo , Animales , Línea Celular , Macrófagos/metabolismo , Ratones , Factores de Riesgo
8.
Toxicol Ind Health ; 32(7): 1318-23, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25501254

RESUMEN

Carbon monoxide (CO) is a major constituent of traffic-related air pollution and is also produced endogenously under conditions of oxygen-mediated stress. It has been shown to affect both oxidative stress and inflammation. However, its role in lipid metabolism has been neglected. Using short exposure times, the effect of CO on J774A.1 macrophage atherogenic functions was investigated up to 16 h after exposure. Exposure of macrophages was found to be pro-atherogenic as it significantly increased triglyceride mass, up to 60%, and decreased high-density lipoprotein-mediated cholesterol efflux, up to 27%. In contrast, paraoxonase 2 lactonase activity was increased, up to 65%, and cellular oxidative stress was attenuated by 29%, compared with the control cells. The above results on lipid metabolism may lead to arterial macrophage foam cell formation, the hallmark of early atherogenesis.


Asunto(s)
Monóxido de Carbono/toxicidad , Metabolismo de los Lípidos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Arildialquilfosfatasa/metabolismo , Aterosclerosis/inducido químicamente , Aterosclerosis/diagnóstico , Células Cultivadas , HDL-Colesterol/metabolismo , Macrófagos/citología , Macrófagos/metabolismo , Ratones , Triglicéridos/metabolismo
10.
Curr Opin Lipidol ; 24(4): 339-44, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23508039

RESUMEN

PURPOSE OF REVIEW: Improving serum levels of HDL and its subfractions, as well as, oxidative/inflammatory properties has become a fundamental aim in today's atherosclerosis research. Efforts to reach this goal are paralleled by achievements in drug development toward decreasing serum LDL levels and oxidative status. RECENT FINDINGS: Paraoxonase1 (PON1) is an HDL-associated enzyme that is deemed responsible for many of the HDL's antiatherogenic and cardioprotective characteristics. PON1 is highly sensitive to variations in its milieu, and endogenous compounds (fatty acids, phospholipids), nutritional ingredients (flavonoids and other antioxidants), and environmental elements (reactive nitrogen and oxygen species, metals, surfactants), significantly affect the enzyme's activities. PON1 was shown to be responsible for some of the HDL antiatherogenic characteristics such as HDL-mediated cholesterol efflux from macrophages, and the inhibition of LDL oxidation. SUMMARY: The present review summarizes the recent literature related to various elements in PON1's milieu that regulate its activities, with an emphasis on its interrelation with components of the human carotid atherosclerotic lesion (plaque) which are in constant contact with circulating HDL-associated PON1.


Asunto(s)
Arildialquilfosfatasa/metabolismo , Aterosclerosis/enzimología , Placa Aterosclerótica/enzimología , Animales , Enfermedades de las Arterias Carótidas/enzimología , Humanos , Lipoproteínas HDL/metabolismo , Oxidación-Reducción , Estrés Oxidativo
13.
Biochem Biophys Res Commun ; 439(3): 396-400, 2013 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-23994636

RESUMEN

The aim of the present study was to analyze the metformin (MF) effect on two cellular atherogenic activities: cholesterol biosynthesis and oxidative-stress (OS) as studied in J774A.1 macrophage cell line. MF (2-5 mM) significantly and dose-dependently reduced macrophage cholesterol content and cholesterol biosynthesis rate from acetate, but not from mevalonate, by up to 68% and 71%, respectively. MF inhibitory effect on cholesterol biosynthesis was similar to that of simvastatin. In contrast to the above anti-atherogenic MF effect, MF significantly increased cellular OS as shown by enhancement of reactive oxygen species (ROS) production by up to 70%, and decrement in cellular reduced glutathione (GSH) levels by up to 67%. Macrophage paraoxonase2 (PON2) expression however, increased by MF, by up to 1.5 folds. To overcome the MF oxidation stimulation, macrophages were incubated with MF together with potent dietary antioxidants, i.e. -5 µg GAE/ml of pomegranate juice (PJ) or 30 µM of vitamin E (VE). Both of these potent antioxidants substantially reduced MF-induced OS, and in parallel, abolished MF inhibitory effect on cholesterol biosynthesis rate. We thus conclude that the inhibition of macrophage cholesterol biosynthesis by MF is related, at least in part, to MF-induced OS.


Asunto(s)
Colesterol/metabolismo , Hipoglucemiantes/farmacología , Macrófagos/efectos de los fármacos , Metformina/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/farmacología , Línea Celular , Macrófagos/metabolismo , Ratones , Vitamina E/farmacología
14.
Arterioscler Thromb Vasc Biol ; 32(2): 449-58, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22155455

RESUMEN

OBJECTIVE: The atherosclerotic lesion is characterized by lipid peroxide accumulation. Paraoxonase 1 (PON1) reduces atherosclerotic lesion oxidative stress, whereas urokinase-type plasminogen activator (uPA) increases oxidative stress in atherosclerotic lesions and contributes to the progression and complications of atherosclerosis. We hypothesized that uPA may promote oxidative stress in the arterial wall via modulation of PON1 activity. Because the liver is the main site for PON1 production, in the present study, we tested whether uPA influences PON1 expression in hepatocytes. METHODS AND RESULTS: HuH7 hepatocytes were incubated in culture with increasing concentrations of uPA. uPA decreased PON1 gene expression and activity in a dose-dependent manner and accordingly suppressed PON1 secretion from hepatocytes. This effect required uPA/uPA receptor interaction. uPA downregulated PON1 gene expression via inactivation of peroxisome proliferator-activated receptor-γ (PPARγ) activity, and this effect was dependent on uPA-mediated mitogen-activated protein kinase kinase activation. Mechanistic studies showed that uPA enhanced mitogen-activated protein kinase kinase-PPARγ interaction, resulting in PPARγ nuclear export to the cytosol. CONCLUSIONS: This study provides the first evidence that uPA interferes with PPARγ transcriptional activity in hepatocytes, resulting in downregulation of PON1 expression and its secretion to the medium. This may explain, at least in part, the prooxidative effect of uPA in the vascular wall.


Asunto(s)
Arildialquilfosfatasa/metabolismo , Núcleo Celular/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , PPAR gamma/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/farmacología , Transporte Activo de Núcleo Celular/efectos de los fármacos , Transporte Activo de Núcleo Celular/fisiología , Animales , Arildialquilfosfatasa/genética , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Hepatocitos/citología , Humanos , Quinasas Quinasa Quinasa PAM/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Endogámicas Lew , Receptores del Activador de Plasminógeno Tipo Uroquinasa/deficiencia , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Transducción de Señal/fisiología
15.
Harefuah ; 152(9): 513-5, 565, 2013 Sep.
Artículo en Hebreo | MEDLINE | ID: mdl-24364088

RESUMEN

Macrophage cholesterol and oxidized lipids accumulation and foam cell formation occur in the early stages of atherosclerosis development. In the current study we used the J774A.1 murine macrophage cell line in order to analyze two atherogenic functions: a. the ability of the cells to produce reactive oxygen species (ROS), and to increase cellular oxidative stress, and b. the ability of the cells to synthesize cholesterol, leading to cholesterol accumulation in the cells. The addition of punicalagin, or beta-sitosterol, or pomegranate juice (which contains both of the above) to simvastatin, significantly improved the statin's ability to inhibit macrophage cholesterol biosynthesis. Furthermore, the addition of pomegranate juice (or punicalagin, but not beta sitosterol) to simvastatin significantly increased the statin ability to protect the cells from oxidative stress. Taken together, the current research provides evidence for the additional cardio protection of statins, that is provided by pomegranate juice antioxidant and hypocholesterolemic effects. The use of statins in combination with pomegranate juice in hypercholesterolemic patients, may allow for the use of lower dosages of statin in order to prevent statin deleterious side effects.


Asunto(s)
Taninos Hidrolizables/farmacología , Lythraceae/química , Simvastatina/farmacología , Sitoesteroles/farmacología , Animales , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/aislamiento & purificación , Anticolesterolemiantes/farmacología , Antioxidantes/administración & dosificación , Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Bebidas , Línea Celular , Colesterol/metabolismo , Quimioterapia Combinada , Taninos Hidrolizables/administración & dosificación , Taninos Hidrolizables/aislamiento & purificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Estrés Oxidativo/efectos de los fármacos , Polifenoles/administración & dosificación , Polifenoles/aislamiento & purificación , Polifenoles/farmacología , Especies Reactivas de Oxígeno/metabolismo , Simvastatina/administración & dosificación , Sitoesteroles/administración & dosificación , Sitoesteroles/aislamiento & purificación
17.
Inorg Chem ; 51(1): 28-30, 2012 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-22148393

RESUMEN

Determination of the cellular uptake of macrocyclic iron(III) complexes by a facile method, accompanied by cell viability tests under both basal and induced oxidative stress, demonstrates that protection against intracellular oxidative stress requires reasonably high internalization and favorable anti/prooxidant profiles. Of the four tested complexes, only amphipolar iron(III) corrole met these criteria.


Asunto(s)
Citoprotección/efectos de los fármacos , Compuestos Férricos/química , Compuestos Férricos/farmacología , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Animales , Antioxidantes/química , Antioxidantes/farmacocinética , Antioxidantes/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citotoxinas/química , Citotoxinas/farmacocinética , Citotoxinas/farmacología , Compuestos Férricos/farmacocinética , Compuestos Macrocíclicos/farmacocinética , Macrófagos/efectos de los fármacos , Ratones , Estrés Oxidativo/efectos de los fármacos
18.
Artículo en Inglés | MEDLINE | ID: mdl-23243442

RESUMEN

The current paper summarizes the antioxidative and antiatherogenic effects of pomegranate polyphenols on serum lipoproteins and on arterial macrophages (two major components of the atherosclerotic lesion), using both in vitro and in vivo humans and mice models. Pomegranate juice and its by-products substantially reduced macrophage cholesterol and oxidized lipids accumulation, and foam cell formation (the hallmark of early atherogenesis), leading to attenuation of atherosclerosis development, and its consequent cardiovascular events.

20.
Redox Biol ; 52: 102313, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35447412

RESUMEN

Lower circulating levels of glycine are consistently reported in association with cardiovascular disease (CVD), but the causative role and therapeutic potential of glycine in atherosclerosis, the underlying cause of most CVDs, remain to be established. Here, following the identification of reduced circulating glycine in patients with significant coronary artery disease (sCAD), we investigated a causative role of glycine in atherosclerosis by modulating glycine availability in atheroprone mice. We further evaluated the atheroprotective potential of DT-109, a recently identified glycine-based compound with dual lipid/glucose-lowering properties. Glycine deficiency enhanced, while glycine supplementation attenuated, atherosclerosis development in apolipoprotein E-deficient (Apoe-/-) mice. DT-109 treatment showed the most significant atheroprotective effects and lowered atherosclerosis in the whole aortic tree and aortic sinus concomitant with reduced superoxide. In Apoe-/- mice with established atherosclerosis, DT-109 treatment significantly reduced atherosclerosis and aortic superoxide independent of lipid-lowering effects. Targeted metabolomics and kinetics studies revealed that DT-109 induces glutathione formation in mononuclear cells. In bone marrow-derived macrophages (BMDMs), glycine and DT-109 attenuated superoxide formation induced by glycine deficiency. This was abolished in BMDMs from glutamate-cysteine ligase modifier subunit-deficient (Gclm-/-) mice in which glutathione biosynthesis is impaired. Metabolic flux and carbon tracing experiments revealed that glycine deficiency inhibits glutathione formation in BMDMs while glycine-based treatment induces de novo glutathione biosynthesis. Through a combination of studies in patients with CAD, in vivo studies using atherosclerotic mice and in vitro studies using macrophages, we demonstrated a causative role of glycine in atherosclerosis and identified glycine-based treatment as an approach to mitigate atherosclerosis through antioxidant effects mediated by induction of glutathione biosynthesis.


Asunto(s)
Aterosclerosis , Placa Aterosclerótica , Animales , Apolipoproteínas E/genética , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/genética , Aterosclerosis/metabolismo , Modelos Animales de Enfermedad , Glutamato-Cisteína Ligasa , Glutatión/metabolismo , Glicina/farmacología , Glicina/uso terapéutico , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Placa Aterosclerótica/metabolismo , Superóxidos
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