RESUMO
Four new alkaloids Chaeronepaline-A (1), Chaeronepaline-B (2), Chaeronepaline-C (3), and Chaeronepaline-D (4) were isolated from Corydalis chaerophylla D.C. collected from Nepal and their structures were elucidated by spectroscopic data, 1D, 2D NMR and mass spectrometry. The structures were established as 3,12- Dimethoxy-5,6-dihydroisoquinolino [2,1-b] isoquinolin- 7- ium- 2, 9- diol (1), 7-methyl-5, 6, 7, 8-tetrahydroisoquinoline- 2, 3- methylenedioxy- (8-> 9)- 10, 12- methylenedioxy- benzoic-16-acid (2), 7- methyl-5, 6, 7, 8- tetrahydro- 8H-spiro-9,14-dihydroxy-11,12-methylenedioxy-indane-isoquinoline (3) and 7- methyl-5, 6, 7, 8- tetrahydro- 8H-spiro-9,14-dihydroxy-11,12-methylenedioxy-indane-isoquinoline-N-oxide (4). The new alkaloids were tested in human hepatoma cell line to assess their ability to modulate the expression of low-density lipoprotein receptor (LDL-R), of proprotein convertase subtilisin/kexin 9 (PCSK9) and to affect cellular cholesterol biosynthesis with the aim to evaluate their potential hypocholesterolemic effect. Results indicated that compounds 2 and 3 upregulate the LDLR, and inhibited the cholesterol biosynthesis with compound 2, which also reduced the secretion of PCSK9 by Huh7 cells. These in vitro data indicated a potential hypocholesterolemic effect of compound 2 that requires further in vivo validation.
RESUMO
Angiopoietin-like 3 (ANGPTL3) is a hepatokine acting as a negative regulator of lipoprotein lipase (LPL). Vupanorsen, an ANGPTL3 directed antisense oligonucleotide, showed an unexpected increase in liver fat content in humans. Here, we investigated the molecular mechanism linking ANGPTL3 silencing to hepatocyte fat accumulation. Human hepatocarcinoma Huh7 cells were treated with small interfering RNA (siRNA) directed to ANGPTL3, human recombinant ANGPTL3 (recANGPTL3), or their combination. Using Western blot, Oil Red-O, biochemical assays, and ELISA, we analyzed the expression of genes and proteins involved in lipid metabolism. Oil Red-O staining demonstrated that lipid content increased after 48 h of ANGPTL3 silencing (5.89 ± 0.33 fold), incubation with recANGPTL3 (4.08 ± 0.35 fold), or their combination (8.56 ± 0.18 fold), compared to untreated cells. This effect was also confirmed in Huh7-LX2 spheroids. A total of 48 h of ANGPTL3 silencing induced the expression of genes involved in the de novo lipogenesis, such as fatty acid synthase, stearoyl-CoA desaturase, ATP citrate lyase, and Acetyl-Coenzyme A Carboxylase 1 together with the proprotein convertase subtilisin/kexin 9 (PCSK9). Time-course experiments revealed that 6 h post transfection with ANGPTL3-siRNA, the cholesterol esterification by Acyl-coenzyme A cholesterol acyltransferase (ACAT) was reduced, as well as total cholesterol content, while an opposite effect was observed at 48 h. Under the same experimental conditions, no differences in secreted apoB and PCSK9 were observed. Since PCSK9 was altered by the treatment, we tested a possible co-regulation between the two genes. The effect of ANGPTL3-siRNA on the expression of genes involved in the de novo lipogenesis was not counteracted by gene silencing of PCSK9. In conclusion, our in vitro study suggests that ANGPTL3 silencing determines lipid accumulation in Huh7 cells by inducing the de novo lipogenesis independently from PCSK9.
Assuntos
Lipogênese , Pró-Proteína Convertase 9 , Humanos , Lipogênese/genética , Subtilisinas , Inativação Gênica , RNA Interferente Pequeno/genética , Colesterol , Angiopoietinas/genética , Coenzima A , Proteína 3 Semelhante a AngiopoietinaRESUMO
Immune system (IS) functionality is warranted by inter-dependent processes that balance body defences without exceeding in inflammation. An ideal nutraceutical approach should sustain the protective IS activity while controlling inflammation. The potential immunomodulatory activity of the food supplement (FS) AminoDefence was studied in resting macrophages RAW264.7 and following stimulation of bacterial- and viral-associated inflammation trough LPS and PolyI:C treatments, respectively. In unstimulated macrophages, the formulation exerted a dose-dependent immunostimulant activity by up-regulating NO, IL-6, TNF-α and MCP-1 release, while it dampened the aberrant release of these factors induced by pro-inflammatory stimuli. Exploring the contribution of single components Echinacea purpurea (E. purpurea) extract and quercetin, used at proportional concentrations than in whole formulation, a more pronounced immunostimulant effect was observed for E. purpurea, and an anti-inflammatory activity for quercetin. Hence, AminoDefence exerts an immunomodulatory activity in macrophages by effectively stimulating a protective inflammatory response and limiting it in cases of excessive inflammation.
Assuntos
Quercetina , Fator de Necrose Tumoral alfa , Humanos , Extratos Vegetais/farmacologia , Adjuvantes Imunológicos , Inflamação , CitocinasRESUMO
BACKGROUND: Increasing evidence highlights the importance of novel players in Alzheimer's disease (AD) pathophysiology, including alterations of lipid metabolism and neuroinflammation. Indeed, a potential involvement of Proprotein convertase subtilisin/kexin type 9 (PCSK9) in AD has been recently postulated. Here, we first investigated the effects of PCSK9 on neuroinflammation in vitro. Then, we examined the impact of a genetic ablation of PCSK9 on cognitive performance in a severe mouse model of AD. Finally, in the same animals we evaluated the effect of PCSK9 loss on Aß pathology, neuroinflammation, and brain lipids. METHODS: For in vitro studies, U373 human astrocytoma cells were treated with Aß fibrils and human recombinant PCSK9. mRNA expression of the proinflammatory cytokines and inflammasome-related genes were evaluated by q-PCR, while MCP-1 secretion was measured by ELISA. For in vivo studies, the cognitive performance of a newly generated mouse line - obtained by crossing 5XFADHet with PCSK9KO mice - was tested by the Morris water maze test. After sacrifice, immunohistochemical analyses were performed to evaluate Aß plaque deposition, distribution and composition, BACE1 immunoreactivity, as well as microglia and astrocyte reactivity. Cholesterol and hydroxysterols levels in mouse brains were quantified by fluorometric and LC-MS/MS analyses, respectively. Statistical comparisons were performed according to one- or two-way ANOVA, two-way repeated measure ANOVA or Chi-square test. RESULTS: In vitro, PCSK9 significantly increased IL6, IL1B and TNFΑ mRNA levels in Aß fibrils-treated U373 cells, without influencing inflammasome gene expression, except for an increase in NLRC4 mRNA levels. In vivo, PCSK9 ablation in 5XFAD mice significantly improved the performance at the Morris water maze test; these changes were accompanied by a reduced corticohippocampal Aß burden without affecting plaque spatial/regional distribution and composition or global BACE1 expression. Furthermore, PCSK9 loss in 5XFAD mice induced decreased microgliosis and astrocyte reactivity in several brain regions. Conversely, knocking out PCSK9 had minimal impact on brain cholesterol and hydroxysterol levels. CONCLUSIONS: In vitro studies showed a pro-inflammatory effect of PCSK9. Consistently, in vivo data indicated a protective role of PCSK9 ablation against cognitive impairments, associated with improved Aß pathology and attenuated neuroinflammation in a severe mouse model of AD. PCSK9 may thus be considered a novel pharmacological target for the treatment of AD.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Camundongos , Humanos , Animais , Camundongos Transgênicos , Pró-Proteína Convertase 9/uso terapêutico , Secretases da Proteína Precursora do Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/uso terapêutico , Doenças Neuroinflamatórias , Cromatografia Líquida , Inflamassomos , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Ácido Aspártico Endopeptidases/uso terapêutico , Espectrometria de Massas em Tandem , Doença de Alzheimer/metabolismo , RNA Mensageiro , Colesterol , Peptídeos beta-Amiloides/metabolismo , Modelos Animais de DoençasRESUMO
Identifying oncological applications for drugs that are already approved for other medical indications is considered a possible solution for the increasing costs of cancer treatment. Under the hypothesis that nutritional stress through fasting might enhance the antitumour properties of at least some non-oncological agents, by screening drug libraries, we find that cholesterol biosynthesis inhibitors (CBIs), including simvastatin, have increased activity against cancers of different histology under fasting conditions. We show fasting's ability to increase CBIs' antitumour effects to depend on the reduction in circulating insulin, insulin-like growth factor-1 and leptin, which blunts the expression of enzymes from the cholesterol biosynthesis pathway and enhances cholesterol efflux from cancer cells. Ultimately, low cholesterol levels through combined fasting and CBIs reduce AKT and STAT3 activity, oxidative phosphorylation and energy stores in the tumour. Our results support further studies of CBIs in combination with fasting-based dietary regimens in cancer treatment and highlight the value of fasting for drug repurposing in oncology.
Assuntos
Jejum , Sinvastatina , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Dieta , Insulina , ColesterolRESUMO
The impact of JAK/STAT inhibitors, which are used in various inflammatory diseases, on cardiovascular risk is controversial and has recently raised safety concerns. Our study investigates the direct effects of tofacitinib on macrophage cholesterol metabolism, which is crucial for atherosclerosis plaque development and stability. Cultured human macrophages THP-1 were used to assess the impact of tofacitinib on cell cholesterol efflux and synthesis via radioisotopic methods, and on cholesterol uptake by measuring the cell cholesterol content with a fluorometric assay. The cholesterol acceptors and donors were either standard lipoproteins or sera from patients with juvenile idiopathic arthritis (JIA) and from control subjects. Tofacitinib significantly increased the macrophage cholesterol efflux to all acceptors; it reduced cholesterol uptake from both the normal and hypercholesterolemic sera; and it reduced cholesterol synthesis. The treatment of macrophages with tofacitinib was able to increase the cholesterol efflux and decrease cholesterol uptake when using sera from untreated JIA patients with active disease as cholesterol acceptors and donors, respectively. In conclusion, our in vitro data support the concept that tofacitinib has a favorable impact on macrophage cholesterol metabolism, even in the presence of sera from rheumatologic patients, and suggest that other mechanisms may be responsible for the cardiovascular risk associated with tofacitinib use in selected patient populations.
Assuntos
Artrite Juvenil , Inibidores de Janus Quinases , Humanos , Metabolismo dos Lipídeos , Piperidinas/farmacologia , Inibidores de Janus Quinases/efeitos adversos , MacrófagosRESUMO
OBJECTIVES: Cholesterol efflux capacity (CEC) measures the ability of high-density lipoprotein (HDL) to remove cholesterol from macrophages and reduce the lipid content of atherosclerotic plaques. CEC inversely associated with cardiovascular risk beyond HDL-cholesterol levels. CEC through the ATP-binding-cassette G1 (ABCG1) membrane transporter is impaired in rheumatoid arthritis (RA). We evaluated associations of ABCG1-CEC with coronary atherosclerosis, plaque progression and cardiovascular risk in RA. METHODS: Coronary atherosclerosis (noncalcified, partially, fully-calcified, low-attenuation plaque) was assessed with computed tomography angiography in 140 patients and reevaluated in 99 after 6.9 ± 0.3 years. Cardiovascular events including acute coronary syndromes, stroke, cardiovascular death, claudication, revascularization and hospitalized heart failure were recorded. ABCG1-CEC was measured in Chinese hamster ovary cells as percentage of effluxed over total intracellular cholesterol. RESULTS: ABCG1-CEC inversely associated with extensive atherosclerosis (≥5 plaques) (adjusted odds ratio 0.50 [95% CI 0.28-0.88]), numbers of partially-calcified (rate ratio [RR] 0.71 [0.53-0.94]) and low-attenuation plaques (RR 0.63 [0.43-0.91] per standard deviation increment). Higher ABCG1-CEC predicted fewer new partially-calcified plaques in patients with lower baseline and time-averaged CRP and fewer new noncalcified and calcified plaques in those receiving higher mean prednisone dose. ABCG1-CEC inversely associated with events in patients with but not without noncalcified plaques, with Assuntos
Artrite Reumatoide
, Doenças Cardiovasculares
, Doença da Artéria Coronariana
, Animais
, Cricetinae
, Humanos
, Prednisona
, Células CHO
, Fatores de Risco
, Cricetulus
, Colesterol
, Inflamação
, Fatores de Risco de Doenças Cardíacas
, Proteínas de Membrana Transportadoras
, Trifosfato de Adenosina
RESUMO
In tumors, the multi drug resistance phenomenon may occur through the efflux of chemotherapeutic drugs out of cancer cells, impeding their accumulation, and eventually reducing their toxicity. This process is mediated by transporters overexpressed in the plasma membranes of tumor cells, among which is the P-glycoprotein/multidrug resistance 1/ATP-binding cassette B1 (P-gp/MDR1/ABCB1). The aim of this study was to explore the effect of a new molecule, called AIF-1, on ABCB1 activity. In a cellular model of non-small cell lung cancer (NSCLC), AIF-1 significantly inhibited ABCB1 activity, which was evaluated by the fluorimetric measurement of the intracellular accumulation of calcein. AIF-1 also significantly increased the intracellular content of doxorubicin, which was evaluated by confocal microscopy and LC-MS/MS analysis. This effect translated to higher cytotoxicity of doxorubicin and reduced cellular proliferation. Finally, in a murine xenograft model, the tumor volume increased by 267% and 148% on average in mice treated with vehicle and doxorubicin alone, respectively. After the co-administration of doxorubicin with AIF-1, tumor volume increased by only 13.4%. In conclusion, these results suggest enhancement of the efficacy of the chemotherapeutic drug doxorubicin by AIF-1, laying the basis for the future development of new ABCB1 inhibitors for tumor treatment.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cromatografia Líquida , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral , Neoplasias Pulmonares/tratamento farmacológico , Espectrometria de Massas em Tandem , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Doxorrubicina/metabolismoRESUMO
OBJECTIVE: Excessive cholesterol accumulation in macrophages is the pivotal step underlying atherosclerotic plaque formation. We here explore factors in the serum of patients with RA, and mechanisms through which they interact with and influence cholesterol loading capacity (CLC) of macrophages. METHODS: In a cross-sectional observational cohort of 104 patients with RA, CLC was measured as intracellular cholesterol content in human THP-1-derived macrophages after incubation with patient serum. Low-density lipoprotein (LDL) oxidation was measured in terms of oxidized phospholipids on apoB100-containing particles (oxPL-apoB100). Antibodies against oxidized LDL (anti-oxLDL), proprotein convertase subtilisin/Kexin type-9 (PCSK9) and high-sensitivity CRP were also quantified. All analyses adjusted for atherosclerotic cardiovascular disease (ASCVD) risk score, obesity, total LDL, statin use, age at diagnosis, and anti-oxLDL IgM. RESULTS: OxPL-apoB100, anti-oxLDL IgG and PCSK9 were positively associated with CLC (all P < 0.020). OxPL-apoB100 directly influenced CLC only in dual RF- and ACPA-positive patients [unstandardized b (95% bootstrap CI)=2.08 (0.38, 3.79)]. An indirect effect of oxPL-apoB100 on CLC through anti-oxLDL IgG increased, along with level of CRP [index of moderated mediation = 0.55 (0.05-1.17)]. CRP also moderated yet another indirect effect of oxPL-apoB100 on CLC through upregulation of PCSK9, but only among dual-seropositive patients [conditional indirect effect = 0.64 (0.13-1.30)]. CONCLUSION: Oxidized LDL can directly influence CLC in dual-seropositive RA patients. Two additional and independent pathways-via anti-oxLDL IgG and PCSK9-may mediate the effects of oxPL-apoB100 on CLC, depending on CRP and seropositivity status. If externally validated, these findings may have clinical implications for cardiovascular risk prevention.
Assuntos
Artrite Reumatoide , Aterosclerose , Humanos , Pró-Proteína Convertase 9 , Proteína C-Reativa/metabolismo , Estudos Transversais , Lipoproteínas LDL/metabolismo , Colesterol/metabolismo , Macrófagos/metabolismo , Aterosclerose/metabolismo , Imunoglobulina G/metabolismoRESUMO
The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) involvement in Alzheimer's disease (AD) is poorly investigated. We evaluated the in vitro PCSK9 modulation of astrocyte cholesterol metabolism and neuronal cholesterol supplying, which is fundamental for neuronal functions. Moreover, we investigated PCSK9 neurotoxic effects. In human astrocytoma cells, PCSK9 reduced cholesterol content (−20%; p < 0.05), with a greater effect in presence of beta amyloid peptide (Aß) (−37%; p < 0.01). PCSK9 increased cholesterol synthesis and reduced the uptake of apoE-HDL-derived cholesterol (−36%; p < 0.0001), as well as the LDL receptor (LDLR) and the apoE receptor 2 (ApoER2) expression (−66% and −31%, respectively; p < 0.01). PCSK9 did not modulate ABCA1- and ABCG1-cholesterol efflux, ABCA1 levels, or membrane cholesterol. Conversely, ABCA1 expression and activity, as well as membrane cholesterol, were reduced by Aß (p < 0.05). In human neuronal cells, PCSK9 reduced apoE-HDL-derived cholesterol uptake (−41%; p < 0.001) and LDLR/apoER2 expression (p < 0.05). Reduced cholesterol internalization occurred also in PCSK9-overexpressing neurons exposed to an astrocyte-conditioned medium (−39%; p < 0.001). PCSK9 reduced neuronal cholesterol content overall (−29%; p < 0.05) and increased the Aß-induced neurotoxicity (p < 0.0001). Our data revealed an interfering effect of PCSK9, in cooperation with Aß, on brain cholesterol metabolism leading to neuronal cholesterol reduction, a potentially deleterious effect. PCSK9 also exerted a neurotoxic effect, and thus represents a potential pharmacological target in AD.
Assuntos
Doença de Alzheimer , Pró-Proteína Convertase 9 , Humanos , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Peptídeos beta-Amiloides , Astrócitos/metabolismo , Meios de Cultivo Condicionados , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Receptores de LDL/metabolismo , Apolipoproteínas E , Colesterol , HDL-Colesterol , Neurônios/metabolismo , SubtilisinasRESUMO
OBJECTIVES: Cholesterol loading capacity (CLC) describes the ability of serum to deliver cholesterol to cells. It is linked to foam cell formation, a pivotal step in atherosclerotic plaque development. We evaluate the associations of CLC with coronary atherosclerosis presence, burden and cardiovascular risk in patients with rheumatoid arthritis (RA). METHODS: Coronary atherosclerosis (any, high-risk low-attenuation plaque and obstructive plaque) was evaluated with CT angiography in 141 patients. Participants were prospectively followed for 6.0±2.4 years and cardiovascular events including cardiac death, myocardial infarction, unstable angina, stroke, claudication, revascularisation and hospitalised heart failure were recorded. CLC was quantified as intracellular cholesterol in human macrophages after incubation with patient serum. RESULTS: CLC was not linked to overall plaque presence or burden after adjustments for atherosclerotic cardiovascular disease (ASCVD) score, statin use and low-density lipoprotein cholesterol. However, CLC associated with presence and numbers of any, low-attenuation and obstructive plaques exclusively in biologic disease-modifying antirheumatic drugs (bDMARD) non-users (p for interaction ≤0.018). CLC associated with cardiovascular event risk overall after adjustments for ASCVD and number of segments with plaque (HR=1.76 (95% CI 1.16 to 2.67) per 1 SD increase in CLC, p=0.008). Additionally, bDMARD use modified the impact of CLC on event risk; CLC associated with events in bDMARD non-users (HR=2.52 (95% CI 1.36 to 4.65) per 1SD increase in CLC, p=0.003) but not users. CONCLUSION: CLC was linked to long-term cardiovascular event risk in RA and associated with high-risk low attenuation and obstructive coronary plaque presence and burden in bDMARD non-users. Its prospective validation as a predictive biomarker may be, therefore, warranted.
Assuntos
Artrite Reumatoide , Colesterol , Doença da Artéria Coronariana , Macrófagos , Placa Aterosclerótica , Antirreumáticos/uso terapêutico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Biomarcadores , Colesterol/sangue , Colesterol/química , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/etiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipoproteínas LDL/uso terapêutico , Macrófagos/metabolismo , Placa Aterosclerótica/complicações , Placa Aterosclerótica/tratamento farmacológicoRESUMO
Chronic kidney disease (CKD) is a long-term condition characterized by a gradual loss of kidney functions, usually accompanied by other comorbidities including cardiovascular diseases (hypertension, heart failure and stroke) and diabetes mellitus. Therefore, multiple pharmacological prescriptions are very common in these patients. Epidemiological and clinical observations have shown that polypharmacy may increase the probability of adverse drug reactions (ADRs), possibly through a higher risk of drug-drug interactions (DDIs). Renal impairment may further worsen this scenario by affecting the physiological and biochemical pathways underlying pharmacokinetics and ultimately modifying the pharmacodynamic responses. It has been estimated that the prevalence of DDIs in CKD patients ranged between 56.9% and 89.1%, accounting for a significant increase in healthcare costs, length and frequency of hospitalization, with a detrimental impact on health and quality of life of these patients. Despite these recognized high-risk conditions, scientific literature released on this topic is still limited. Basing on the most commonly prescribed therapies in patients with CKD, the present short review summarizes the current state of knowledge of the putative DDIs occurring in CKD patients undergoing polytherapy. The most relevant underlying mechanisms and their clinical significance are also debated.
RESUMO
Reverse cholesterol transport (RCT) is a physiological mechanism protecting cells from an excessive accumulation of cholesterol. When this process begins in vascular macrophages, it acquires antiatherogenic properties, as has been widely demonstrated in animal models. Dietary lipids, despite representing a fundamental source of energy and exerting multiple biological functions, may induce detrimental effects on cardiovascular health. In the present review we summarize the current knowledge on the mechanisms of action of the most relevant classes of dietary lipids, such as fatty acids, sterols and liposoluble vitamins, with effects on different steps of RCT. We also provide a critical analysis of data obtained from experimental models which can serve as a valuable tool to clarify the effects of dietary lipids on cardiovascular disease.
Assuntos
Transporte Biológico , Colesterol , Gorduras na Dieta , Animais , Doenças Cardiovasculares , HDL-Colesterol , Ácidos Graxos , Humanos , Macrófagos/metabolismo , Modelos Animais , RoedoresRESUMO
Long non-coding RNAs (lncRNAs) are emerging regulators of pathophysiological processes including atherosclerosis. Using RNA-seq profiling of the intima of lesions, here we identify a macrophage-specific lncRNA MAARS (Macrophage-Associated Atherosclerosis lncRNA Sequence). Aortic intima expression of MAARS increases by 270-fold with atherosclerotic progression and decreases with regression by 60%. MAARS knockdown reduces atherosclerotic lesion formation by 52% in LDLR-/- mice, largely independent of effects on lipid profile and inflammation, but rather by decreasing macrophage apoptosis and increasing efferocytosis in the vessel wall. MAARS interacts with HuR/ELAVL1, an RNA-binding protein and important regulator of apoptosis. Overexpression and knockdown studies verified MAARS as a critical regulator of macrophage apoptosis and efferocytosis in vitro, in an HuR-dependent manner. Mechanistically, MAARS knockdown alters HuR cytosolic shuttling, regulating HuR targets such as p53, p27, Caspase-9, and BCL2. These findings establish a mechanism by which a macrophage-specific lncRNA interacting with HuR regulates apoptosis, with implications for a broad range of vascular disease states.
Assuntos
Aterosclerose/metabolismo , Núcleo Celular/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Apoptose , Aterosclerose/genética , Aterosclerose/fisiopatologia , Núcleo Celular/genética , Proteína Semelhante a ELAV 1/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Transporte Proteico , RNA Longo não Codificante/genética , Especificidade da EspécieRESUMO
It has been well established that moderate alcohol consumption inversely correlates with cardiovascular morbidity and mortality, whereas binge alcohol drinking increases cardiovascular disease risk. The aim of this study was to assess in vivo the impact of different drinking patterns on reverse cholesterol transport (RCT); the atheroprotective process leading to the removal of excess cholesterol from the body. RCT was measured with a standardized, radioisotope-based technique in three groups of atherosclerosis-prone apolipoprotein E knock out mice: Placebo group, receiving water, which would mimic the abstainers; moderate group, receiving 0.8 g/kg alcohol/day for 28 days, which would mimic a moderate intake; binge group, receiving 0.8 g/kg alcohol/day for 5 days/week, followed by the administration of 2.8 g/kg alcohol/day for 2 days/week, which would mimic a heavy intake in a short period. Mice in the binge drinking group displayed an increase in total cholesterol, high density lipoprotein cholesterol (HDL-c) and non-HDL-c (all p < 0.0001 vs. placebo), and a significantly reduced elimination of fecal cholesterol. The moderate consumption did not lead to any changes in circulating lipids, but slightly improved cholesterol mobilization along the RCT pathway. Overall, our data confirm the importance of considering not only the total amount, but also the different consumption patterns to define the impact of alcohol on cardiovascular risk.