Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 18 de 18
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cardiol Ther ; 13(1): 221-232, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38319533

RESUMO

INTRODUCTION: Limited data are available regarding the safety and effectiveness of 4-factor prothrombin complex concentrate (4F-PCC) in patients experiencing major hemorrhage or requiring expeditious surgical intervention, both globally and within Japan. METHODS: We executed a prospective, observational post-marketing surveillance study of patients receiving 4F-PCC for the first time between September 19, 2017 and August 15, 2018 in Japan. Patients were subjected to a comprehensive follow-up for a duration of 4 weeks. RESULTS: Of 1381 eligible patients, 1271 (92%) received a vitamin K antagonist. Among these, 58% were aged ≥ 75 years, 49% manifested atrial fibrillation, 17% presented with valvular heart disease, and 6% exhibited venous thromboembolism. The median (range) international normalized ratio was 2.67 (0.96-27.11) at baseline and 1.21 (0.45-6.61) at first measurement post-administration of 4F-PCC. The most common reason for 4F-PCC administration was intracranial hemorrhage (59.6%), followed by gastrointestinal bleeding (6.6%). Hemostatic effectiveness was achieved in 85.8% of patients. The incidences of adverse drug reactions (ADRs) and serious ADRs were 3.9% and 2.8%, respectively. Thromboembolic events (TEEs) occurred in 20 (1.5%) patients, with a mean onset of 10 days. The majority of TEEs were classified as nervous system disorders (55%). At the time of TEE, only 13% of patients resumed anticoagulant therapy. CONCLUSION: The incidence of TEEs following treatment with 4F-PCC did not surpass those observed in phase 3 trials. No novel safety signals were identified. The safety and effectiveness of 4F-PCC in Japanese real-world practice were in harmony with the observations of prior studies.

2.
J Cardiol ; 81(3): 316-322, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36208832

RESUMO

BACKGROUND: Limited data are available regarding therapies for hypertrophic cardiomyopathy (HCM). This study assessed the prevalence, clinical characteristics, and treatment patterns of HCM in Japan. METHODS: This retrospective database study analyzed data from 438 hospitals in the Japan Medical Data Vision database from 2016 to 2020. We identified 3913 patients (15 %) with obstructive HCM (oHCM) and 21,714 patients (85 %) with nonobstructive HCM (nHCM). RESULTS: The estimated total number of patients with oHCM and nHCM in 2020 among Japanese hospitals was 8500 and 43,500, respectively. The prevalence of oHCM and nHCM steadily increased by 27 % and 12 %, respectively, from 2016 to 2020, with a 1:5.2 ratio of oHCM to nHCM in 2020. The mean age of the oHCM and nHCM populations was 72 and 70 years, respectively, and comorbidities included atrial fibrillation (AF) (oHCM, 33.8 %; nHCM, 32.2 %), other arrythmia (30.1 %; 27.6 %), and stroke (16.6 %; 16.4 %). Furthermore, 45.0 % of oHCM and 37.7 % of nHCM patients had undergone at least one hospitalization. A substantial number of HCM patients aged between 20 and 59 years reported AF (oHCM, 17-37 %; nHCM, 4-24 %) and stroke (oHCM, 0-12 %; nHCM, 3-10 %). ß-blockers (oHCM, 64.0 %; nHCM, 42.1 %) were the most frequently prescribed treatment, followed by Na channel blockers (29.5 %; 5.7 %), calcium channel blockers (18.1 %; 8.8 %), direct oral anticoagulants (14.5 %; 15.2 %), and warfarin (11.0 %; 11.4 %). CONCLUSIONS: This study provides important information on the current epidemiological and clinical characteristics of HCM in Japan.


Assuntos
Fibrilação Atrial , Cardiomiopatia Hipertrófica , Acidente Vascular Cerebral , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Estudos Retrospectivos , Prevalência , Japão/epidemiologia , Cardiomiopatia Hipertrófica/epidemiologia , Cardiomiopatia Hipertrófica/terapia , Acidente Vascular Cerebral/epidemiologia , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/terapia
3.
Cardiol Ther ; 11(2): 297-308, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35426621

RESUMO

INTRODUCTION: Limited data are available regarding the prevalence of thrombotic/cardiovascular disease and treatment patterns for patients with coronavirus disease 2019 (COVID-19) in Japan. In this study we describe patients hospitalized for COVID-19 in Japan. METHODS: This retrospective database study analyzed the Japan Medical Data Vision database (416 acute care hospitals) for patients hospitalized for COVID-19 during the identification period from 1 January 1 to 30 September 2020. RESULTS: Among 9282 eligible patients, 832 (9%) had developed thrombotic disease including myocardial infarction, ischemic stroke, deep vein thromboembolism and pulmonary embolism. Intriguingly, 171(1.8%) had two thrombotic events and 25 (0.3%) had three or four thrombotic events at the same time. The data also showed that arterial thrombotic events accounted for 77% of total thrombotic events. Anticoagulant and/or antiplatelet medication was provided to 3312 patients. Even with antithrombotic medication, 21.2% of patients suffered from thrombotic diseases. CONCLUSIONS: Patients with COVID-19 could experience thrombotic complications in every blood vessel. Further optimization of medication is crucial for preventing thrombotic complications and improving prognosis.

4.
Arterioscler Thromb Vasc Biol ; 41(1): 360-376, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33086872

RESUMO

OBJECTIVE: Enhancement of LCAT (lecithin:cholesterol acyltransferase) activity has possibility to be beneficial for atherosclerosis. To evaluate this concept, we characterized our novel, orally administered, small-molecule LCAT activator DS-8190a, which was created from high-throughput screening and subsequent derivatization. We also focused on its mechanism of LCAT activation and the therapeutic activity with improvement of HDL (high-density lipoprotein) functionality. Approach and Results: DS-8190a activated human and cynomolgus monkey but not mouse LCAT enzymes in vitro. DS-8190a was orally administered to cynomolgus monkeys and dose dependently increased LCAT activity (2.0-fold in 3 mg/kg group on day 7), resulting in HDL cholesterol elevation without drastic changes of non-HDL cholesterol. Atheroprotective effects were then evaluated using Ldl-r KO×hLcat Tg mice fed a Western diet for 8 weeks. DS-8190a treatment achieved significant reduction of atherosclerotic lesion area (48.3% reduction in 10 mg/kg treatment group). Furthermore, we conducted reverse cholesterol transport study using Ldl-r KO×hLcat Tg mice intraperitoneally injected with J774A.1 cells loaded with [3H]-cholesterol and confirmed significant increases of [3H] count in plasma (1.4-fold) and feces (1.4-fold on day 2 and 1.5-fold on day3) in the DS-8190a-treated group. With regard to the molecular mechanism involved, direct binding of DS-8190a to human LCAT protein was confirmed by 2 different approaches: affinity purification by DS-8190a-immobilized beads and thermal shift assay. In addition, the candidate binding site of DS-8190a in human LCAT protein was identified by photoaffinity labeling. CONCLUSIONS: This study demonstrates the potential of DS-8190a as a novel therapeutic for atherosclerosis. In addition, this compound proves that a small-molecule direct LCAT activator can achieve HDL-C elevation in monkey and reduction of atherosclerotic lesion area with enhanced HDL function in rodent.


Assuntos
Aterosclerose/prevenção & controle , Ativadores de Enzimas/farmacologia , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Placa Aterosclerótica , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Linhagem Celular , HDL-Colesterol/sangue , Modelos Animais de Doenças , Ativação Enzimática , Humanos , Macaca fascicularis , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Receptores de LDL/deficiência , Receptores de LDL/genética , Especificidade da Espécie , Regulação para Cima
5.
Bioorg Med Chem Lett ; 25(18): 3914-20, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26238323

RESUMO

To obtain potent liver X receptor (LXR) agonists, a structure-activity relationship study was performed on a series of tert-butyl benzoate analogs. As the crystal structure analysis suggested applicable interactions between the LXR ligand-binding domain and the ligands, two key functional groups were introduced. The introduction of the hydroxyl group on the C6-position of the benzoate part enhanced the agonistic activity in a cell-based assay, and the carboxyl group in terminal improved the pharmacokinetic profile in mice, respectively. The obtained compound 32b increased blood ABCA1 mRNA expression without plasma TG elevation in both mice and cynomolgus monkeys.


Assuntos
Benzoatos/farmacologia , Descoberta de Drogas , Hidrocarbonetos Fluorados/farmacologia , Receptores Nucleares Órfãos/agonistas , Animais , Benzoatos/administração & dosagem , Benzoatos/química , Relação Dose-Resposta a Droga , Humanos , Hidrocarbonetos Fluorados/administração & dosagem , Hidrocarbonetos Fluorados/química , Receptores X do Fígado , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
6.
Biochim Biophys Acta ; 1811(12): 1136-45, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21875689

RESUMO

The nuclear receptors Liver X receptors, LXRα and LXRß, regulate cholesterol and triglyceride metabolism. We and others have previously reported that synthetic LXR agonists reduced atherosclerosis in models of mouse with no detectable plasma cholesteryl ester transfer protein (CETP) activity, which plays an important role in reverse cholesterol transport. In the present study, we investigated the effect of LXR activation in rabbits to elucidate the influence of CETP activity. First, we cloned rabbit LXRs cDNA. The data indicated that rabbit LXRα was mostly highly expressed in the liver, whereas LXRß expression was ubiquitous. Next, we investigated the effect of LXR agonist on lipid levels. Treatment with LXR agonist T0901317 increased plasma CETP activity and consequently elevated LDL, but no change in HDL. High cholesterol (HC) diet-feeding, which is thought to provide oxysterols as the natural agonists, could also increase expression of CETP and other LXR target genes. Finally, we tested T0901317 in the atherosclerosis intervention study. Chronic administration of T0901317 significantly reduced atherosclerosis in HC diet-fed rabbits despite less favorable lipid profiles, i.e. increases of plasma triglycerides and no change of HDL. T0901317 induced ATP-binding cassette transporters ABCA1 and ABCG1 and suppressed inflammatory genes expression in the aorta, suggesting that direct actions of LXR agonist on vascular gene expression are likely to contribute to the antiatherogenic effect. The present work strongly supports the idea that LXR agonists could be beneficial as therapeutic agents for treatment of atherosclerosis.


Assuntos
Aterosclerose/sangue , Proteínas de Transferência de Ésteres de Colesterol/sangue , Expressão Gênica , Hidrocarbonetos Fluorados/farmacologia , Receptores Nucleares Órfãos/agonistas , Transdução de Sinais , Sulfonamidas/farmacologia , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Sequência de Aminoácidos , Animais , Anticolesterolemiantes/farmacologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/etiologia , Aterosclerose/genética , Colesterol/sangue , Colesterol/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado , Dados de Sequência Molecular , Receptores Nucleares Órfãos/metabolismo , Coelhos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triglicerídeos/sangue
7.
Arterioscler Thromb Vasc Biol ; 30(11): 2219-25, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20798376

RESUMO

OBJECTIVE: To investigate whether cholesterol efflux to high-density lipoprotein (HDL) via ATP-binding cassette transporter G1 (ABCG1) modulates the interaction of caveolin (Cav) 1 and endothelial NO synthase (eNOS). METHODS AND RESULTS: ABCG1 promotes cholesterol and 7-oxysterol efflux from endothelial cells (ECs) to HDL. It was previously reported that ABCG1 protects against dietary cholesterol-induced endothelial dysfunction by promoting the efflux of 7-oxysterols to HDL. Increased cholesterol loading in ECs is known to cause an inhibitory interaction between Cav-1 and eNOS and impaired NO release. In human aortic ECs, free cholesterol loading promoted the interaction of Cav-1 with eNOS, reducing eNOS activity. These effects of cholesterol loading were reversed by HDL in an ABCG1-dependent manner. HDL also reversed the inhibition of eNOS by cholesterol loading in murine lung ECs, but this effect of HDL was abolished in Cav-1-deficient murine lung ECs. Increased interaction of Cav-1 with eNOS was also detected in aortic homogenates of high-cholesterol diet-fed Abcg1(-/-) mice, paralleling a decrease in eNOS activity and impaired endothelial function. CONCLUSIONS: The promotion of cholesterol efflux via ABCG1 results in a reduced inhibitory interaction of eNOS with Cav-1.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Caveolina 1/metabolismo , HDL-Colesterol/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/biossíntese , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Animais , Células Endoteliais , Humanos , Camundongos
8.
Atherosclerosis ; 212(1): 139-45, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20494359

RESUMO

Liver X receptors (LXRs), LXRalpha and LXRbeta, are members of the nuclear receptor superfamily and regulate the expression of genes involved in the regulation of cholesterol and fatty acid metabolism. Human plasma, unlike mouse plasma, contains cholesteryl ester transfer protein (CETP), which plays an important role in reverse cholesterol transport (RCT). LXRs induce CETP transcription via a direct repeat 4 element in the CETP promoter. However, the specific roles of the individual LXR subtypes in CETP expression and their consequences on plasma lipoprotein metabolism are still unclear. Here we showed that synthetic LXR agonist enhanced plasma CETP activity and resulted in non-high density lipoprotein (non-HDL) increase and HDL decrease in cynomolgus monkeys and human CETP transgenic mice. To address the relative importance of the two LXR subtypes, we investigated the effect of the suppression of both LXR subtypes on CETP expression in HepG2 cells. CETP expression induced by the LXR agonist was significantly reduced by LXRalpha knock-down, but not by LXRbeta. Consistent with these data, CETP promoter activity was enhanced by LXRalpha activation, whereas LXRbeta activation had only a minor effect. Furthermore, we investigated the effect of genetic deficiency of both LXR subtypes in human CETP transgenic mice. LXRalpha deficiency abolished the augmentation of plasma CETP activity and hepatic CETP expression induced by the synthetic LXR agonist, consequently increasing HDL and decreasing non-HDL, whereas LXRbeta deficiency did not affect CETP activation. These findings indicate that LXRalpha has an essential role in the regulation of CETP expression and maintaining RCT.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Lipídeos/sangue , Receptores Nucleares Órfãos/metabolismo , Animais , Colesterol/sangue , Proteínas de Transferência de Ésteres de Colesterol/genética , Relação Dose-Resposta a Droga , Jejum/sangue , Regulação da Expressão Gênica , Células Hep G2 , Humanos , Hidrocarbonetos Fluorados/farmacologia , Lipoproteínas HDL/sangue , Receptores X do Fígado , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/deficiência , Receptores Nucleares Órfãos/genética , Regiões Promotoras Genéticas , Interferência de RNA , RNA Mensageiro/metabolismo , Sulfonamidas/farmacologia , Transfecção
9.
J Clin Invest ; 118(11): 3701-13, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18924609

RESUMO

Plasma HDL levels are inversely related to the incidence of atherosclerotic disease. Some of the atheroprotective effects of HDL are likely mediated via preservation of EC function. Whether the beneficial effects of HDL on ECs depend on its involvement in cholesterol efflux via the ATP-binding cassette transporters ABCA1 and ABCG1, which promote efflux of cholesterol and oxysterols from macrophages, has not been investigated. To address this, we assessed endothelial function in Abca1(-/-), Abcg1(-/-), and Abca1(-/-)Abcg1(-/-) mice fed either a high-cholesterol diet (HCD) or a Western diet (WTD). Non-atherosclerotic arteries from WTD-fed Abcg1(-/-) and Abca1(-/-)Abcg1(-/-) mice exhibited a marked decrease in endothelium-dependent vasorelaxation, while Abca1(-/-) mice had a milder defect. In addition, eNOS activity was reduced in aortic homogenates generated from Abcg1(-/-) mice fed either a HCD or a WTD, and this correlated with decreased levels of the active dimeric form of eNOS. More detailed analysis indicated that ABCG1 was expressed primarily in ECs, and that these cells accumulated the oxysterol 7-ketocholesterol (7-KC) when Abcg1(-/-) mice were fed a WTD. Consistent with these data, ABCG1 had a major role in promoting efflux of cholesterol and 7-KC in cultured human aortic ECs (HAECs). Furthermore, HDL treatment of HAECs prevented 7-KC-induced ROS production and active eNOS dimer disruption in an ABCG1-dependent manner. Our data suggest that ABCG1 and HDL maintain EC function in HCD-fed mice by promoting efflux of cholesterol and 7-oxysterols and preserving active eNOS dimer levels.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Colesterol na Dieta/efeitos adversos , Colesterol/metabolismo , Endotélio Vascular/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Cetocolesteróis/metabolismo , Lipoproteínas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Óxido Nítrico Sintase Tipo III/metabolismo
10.
Cell Metab ; 7(5): 365-75, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18460328

RESUMO

High-density lipoprotein (HDL) has been identified as a potential target in the treatment of atherosclerotic vascular disease. The failure of torcetrapib, an inhibitor of cholesteryl ester transfer protein (CETP) that markedly increased HDL levels in a clinical trial, has called into doubt the efficacy of HDL elevation. Recent analysis suggests that failure may have been caused by off-target toxicity and that HDL is functional and promotes regression of atherosclerosis. New studies highlight the central importance of the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 in reducing macrophage foam cell formation, inflammation, and atherosclerosis. A variety of approaches to increasing HDL may eventually be successful in treating atherosclerosis.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Aterosclerose/terapia , Colesterol/metabolismo , Lipoproteínas HDL/metabolismo , Animais , Aterosclerose/metabolismo , Humanos
11.
J Clin Invest ; 117(12): 3900-8, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17992262

RESUMO

HDLs protect against the development of atherosclerosis, but the underlying mechanisms are poorly understood. HDL and its apolipoproteins can promote cholesterol efflux from macrophage foam cells via the ATP-binding cassette transporters ABCA1 and ABCG1. Experiments addressing the individual roles of ABCA1 and ABCG1 in the development of atherosclerosis have produced mixed results, perhaps because of compensatory upregulation in the individual KO models. To clarify the role of transporter-mediated sterol efflux in this disease process, we transplanted BM from Abca1(-/-)Abcg1(-/-) mice into LDL receptor-deficient mice and administered a high-cholesterol diet. Compared with control and single-KO BM recipients, Abca1(-/-)Abcg1(-/-) BM recipients showed accelerated atherosclerosis and extensive infiltration of the myocardium and spleen with macrophage foam cells. In experiments with isolated macrophages, combined ABCA1 and ABCG1 deficiency resulted in impaired cholesterol efflux to HDL or apoA-1, profoundly decreased apoE secretion, and increased secretion of inflammatory cytokines and chemokines. In addition, these cells showed increased apoptosis when challenged with free cholesterol or oxidized LDL loading. These results suggest that the combined effects of ABCA1 and ABCG1 in mediating macrophage sterol efflux are central to the antiatherogenic properties of HDL.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Aterosclerose/metabolismo , Colesterol/metabolismo , Células Espumosas/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas/metabolismo , Transportador 1 de Cassete de Ligação de ATP , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/genética , Aterosclerose/patologia , Colesterol/genética , Células Espumosas/patologia , Lipoproteínas/genética , Lipoproteínas HDL/genética , Lipoproteínas LDL/genética , Lipoproteínas LDL/metabolismo , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Baço/metabolismo , Baço/patologia
12.
Proc Natl Acad Sci U S A ; 104(38): 15093-8, 2007 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-17846428

RESUMO

Oxidized sterols consumed in the diet or formed on low-density lipoprotein (LDL) are toxic to endothelial cells and macrophages and are thought to have a central role in promoting atherogenesis. The ATP-binding cassette transporter ABCG1 was recently shown to promote efflux of cholesterol from macrophages to high-denisty lipoprotein (HDL). We show that HDL protects macrophages from apoptosis induced by loading with free cholesterol or oxidized LDL. The protective effect of HDL was reduced in Abcg1(-/-) macrophages, especially after loading with oxidized LDL. Similarly, HDL exerted a protective effect against apoptosis induced by 7-ketocholesterol, the major oxysterol present in oxidized LDL and atherosclerotic lesions, in Abcg1(+/+), but not in Abcg1(-/-) macrophages. In transfected 293 cells, efflux of 7-ketocholesterol and related oxysterols was completely dependent on expression of ABCG1 and the presence of HDL in media. In contrast, ABCA1 and apoA-1 did not stimulate the efflux of 7-ketocholesterol into media. HDL stimulated the efflux of 7-ketocholesterol from Abcg1(+/+), but not from Abcg1(-/-) macrophages. In Abcg1(-/-) mice fed a high-cholesterol diet, plasma levels of 7-ketocholesterol were reduced, whereas their macrophages accumulated 7-ketocholesterol. These findings indicate a specific role for ABCG1 in promoting efflux of 7-ketocholesterol and related oxysterols from macrophages onto HDL and in protecting these cells from oxysterol-induced cytotoxicity.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Apoptose , Cetocolesteróis/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Lipoproteínas/metabolismo , Macrófagos/metabolismo , Transportador 1 de Cassete de Ligação de ATP , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Células Cultivadas , Humanos , Lipoproteínas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transfecção
13.
Atherosclerosis ; 190(2): 239-47, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16626720

RESUMO

The objective of the present study was to determine whether a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, pactimibe sulfate (CS-505), could reduce atherosclerotic lesions beyond and independent of the reduction achieved by cholesterol lowering alone from two different types of lesions. (1) Early lesion model. Twelve-week-old apolipoprotein E (apoE)(-/-) mice were treated with 0.03 or 0.1% (w/w) CS-505, 0.1 or 0.3% avasimibe (CI-1011), or 3% cholestyramine for 12 weeks. Each treatment significantly reduced plasma cholesterol by a similar degree (43-48%). The antiatherosclerotic activity of 0.1% CS-505, however, was more efficacious than the effects of the other treatments (90% versus 40-50%). (2) Advanced lesion model. Twenty-four-week-old apoE(-/-) mice were treated with 0.03 or 0.1% CS-505 or 0.1% CI-1011 for 12 weeks. CS-505 at 0.1% revealed enhanced lesion reduction compared with 0.1% CI-1011 (77% versus 54%), whereas the plasma cholesterol-lowering effect of 0.1% CS-505 was almost the same as that of 0.1% CI-1011. Furthermore, immunohistochemical analysis demonstrated that CS-505 significantly reduced the number of macrophages and expression of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-13. These data indicate that CS-505 can reduce and stabilize atherosclerotic lesions. This antiatherosclerotic activity is exerted via both cholesterol lowering and direct ACAT inhibition in plaque macrophages.


Assuntos
Anticolesterolemiantes/uso terapêutico , Apolipoproteínas E/deficiência , Aterosclerose/tratamento farmacológico , Ácidos Indolacéticos/uso terapêutico , Esterol O-Aciltransferase/antagonistas & inibidores , Animais , Anticolesterolemiantes/farmacologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Linhagem Celular , Humanos , Ácidos Indolacéticos/farmacologia , Lipídeos/sangue , Camundongos , Camundongos Knockout , Monócitos/efeitos dos fármacos
14.
Eur J Pharmacol ; 540(1-3): 121-30, 2006 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-16730694

RESUMO

Pactimibe sulfate, [7-(2,2-dimethylpropanamido)-4,6-dimethyl-1-octylindolin-5-yl]acetic acid hemisulfate, a novel Acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitor, was investigated in vitro and in vivo to characterize its potential. Pactimibe exhibited dual inhibition for ACAT1 and ACAT2 (concentrations inhibiting 50% [IC50s] at micromolar levels) more potently than avasimibe. Kinetic analysis revealed pactimibe is a noncompetitive inhibitor of oleoyl-CoA (Ki value: 5.6 microM). Furthermore, pactimibe markedly inhibited cholesteryl ester formation (IC50: 6.7 microM) in human monocyte-derived macrophages, and inhibited copper-induced oxidation of low density lipoprotein more potently than probucol. Pactimibe exerted potent lipid-lowering and anti-atherosclerotic effects in atherogenic diet-fed hamsters. At doses of 3 and 10 mg/kg for 90 days, pactimibe decreased serum total cholesterol by 70% and 72%, and aortic fatty streak area by 79% and 95%, respectively. Despite similar cholesterol lowering, fatty streak area reduction was greater by 10 mg/kg. These results suggest that ACAT1/2 dual inhibitor pactimibe has anti-atherosclerotic potential beyond its plasma cholesterol-lowering activity.


Assuntos
Arteriosclerose/prevenção & controle , Ácidos Indolacéticos/farmacologia , Esterol O-Aciltransferase/antagonistas & inibidores , Acil Coenzima A/metabolismo , Animais , Catálise/efeitos dos fármacos , Linhagem Celular , Sistema Livre de Células/enzimologia , Sistema Livre de Células/metabolismo , Ésteres do Colesterol/metabolismo , Cricetinae , Dieta Aterogênica , Relação Dose-Resposta a Droga , Humanos , Hipercolesterolemia/classificação , Hipercolesterolemia/etiologia , Hipercolesterolemia/prevenção & controle , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Ácidos Indolacéticos/química , Lipídeos/sangue , Lipoproteínas LDL/genética , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Oxirredução/efeitos dos fármacos , Fosfatidilcolina-Esterol O-Aciltransferase/antagonistas & inibidores , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Coelhos , Ratos , Ratos Sprague-Dawley , Esterol O-Aciltransferase/metabolismo , Esterol O-Aciltransferase 2
15.
FEBS J ; 272(6): 1546-56, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15752369

RESUMO

Exposure of blood to tissue factor (TF) rapidly initiates the coagulation serine protease cascades. TF is expressed by macrophages and other types of cell within atherosclerotic lesions and plays an important role in thrombus formation after plaque rupture. Macrophage TF expression is induced by pro-inflammatory stimuli including lipopolysaccharide (LPS), interleukin-1beta and tumor necrosis factor-alpha. Here we demonstrate that activation of liver X receptors (LXRs) LXRalpha and LXRbeta suppresses TF expression. Treatment of mouse peritoneal macrophages with synthetic LXR agonist T0901317 or GW3965 reduced TF expression induced by pro-inflammatory stimuli. LXR agonists also suppressed TF expression and its activity in human monocytes. Human and mouse TF promoters contain binding sites for the transcription factors AP-1, NFkappaB, Egr-1 and Sp1, but no LXR-binding sites could be found. Cotransfection assays with LXR and TF promoter constructs in RAW 264.7 cells revealed that LXR agonists suppressed LPS-induced TF promoter activity. Analysis of TF promoter also showed that inhibition of TF promoter activity by LXR was at least in part through inhibition of the NFkappaB signaling pathway. In addition, in vivo, LXR agonists reduced TF expression within aortic lesions in an atherosclerosis mouse model as well as in kidney and lung in mice stimulated with LPS. These findings indicate that activation of LXR results in reduction of TF expression, which may influence atherothrombosis in patients with vascular disease.


Assuntos
Macrófagos Peritoneais/fisiologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Tromboplastina/genética , Animais , Células Cultivadas , Primers do DNA , Proteínas de Ligação a DNA , Humanos , Receptores X do Fígado , Camundongos , Camundongos Endogâmicos C57BL , Receptores Nucleares Órfãos , Mapeamento por Restrição , Tromboplastina/antagonistas & inibidores , Transfecção
16.
J Biol Chem ; 278(24): 21344-51, 2003 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-12672813

RESUMO

The KK/San obese and diabetic mouse, a mutant strain from KK obese mice, exhibits significantly low plasma triglyceride levels. In KK/San mice, genetic analysis identified a mutation in the gene encoding angiopoietinlike protein 3 (Angptl3), a liver-specific secretory protein, which had suppressive effect on lipoprotein lipase activity. In the current study, LXR ligands augmented Angptl3 mRNA expression and protein production in hepatoma cells. LXR ligands and LXR.retinoid X receptor (RXR) complex increased the promoter activity of Angptl3 gene. Serial deletion and point mutation of Angptl3 promoter identified an LXR response element (LXRE). Gel mobility shift assay showed the direct binding of LXR.RXR complex to the LXRE of the Angptl3 promoter. Furthermore, treatment of mice with synthetic LXR ligand caused triglyceride accumulation in the liver and plasma, which was accompanied by induction of hepatic mRNAs of several LXR target genes, including sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), and Angptl3. In Angptl3-deficient C57BL/6J mice, LXR ligand did not cause hypertriglyceridemia but accumulation of triglyceride in the liver. Our results demonstrate that Angptl3 is a direct target of LXR and that induction of hepatic Angptl3 accounts for hypertriglyceridemia associated with the treatment of LXR ligand.


Assuntos
Hipertrigliceridemia/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteína 3 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina , Angiopoietinas , Animais , Anticolesterolemiantes/farmacologia , Sequência de Bases , Linhagem Celular , Células Cultivadas , Proteínas de Ligação a DNA , Ensaio de Imunoadsorção Enzimática , Ácido Graxo Sintases/metabolismo , Genes Reporter , Humanos , Hidrocarbonetos Fluorados , Ligantes , Metabolismo dos Lipídeos , Lipoproteínas/metabolismo , Fígado/metabolismo , Receptores X do Fígado , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Obesos , Dados de Sequência Molecular , Mutação , Receptores Nucleares Órfãos , Plasmídeos/metabolismo , Mutação Puntual , Regiões Promotoras Genéticas , Ligação Proteica , Biossíntese de Proteínas , RNA/metabolismo , RNA Mensageiro/metabolismo , Receptores do Ácido Retinoico/metabolismo , Receptores X de Retinoides , Sulfonamidas , Fatores de Tempo , Fatores de Transcrição/metabolismo , Transcrição Gênica , Ativação Transcricional , Transfecção , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Células Tumorais Cultivadas
17.
FEBS Lett ; 536(1-3): 6-11, 2003 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-12586329

RESUMO

Liver X receptors (LXR alpha and LXR beta) are nuclear receptors, which are important regulators of cholesterol and lipid metabolism. LXRs control genes involved in cholesterol efflux in macrophages, bile acid synthesis in liver and intestinal cholesterol absorption. LXRs also regulate genes participating in lipogenesis. To determine whether the activation of LXR promotes or inhibits development of atherosclerosis, T-0901317, a synthetic LXR ligand, was administered to low density lipoprotein receptor (LDLR)(-/-) mice. T-0901317 significantly reduced the atherosclerotic lesions in LDLR(-/-) mice without affecting plasma total cholesterol levels. This anti-atherogenic effect correlated with the plasma concentration of T-0901317, but not with high density lipoprotein cholesterol, which was increased by T-0901317. In addition, we observed that T-0901317 increased expression of ATP binding cassette A1 in the lesions in LDLR(-/-) mice as well as in mouse peritoneal macrophages. T-0901317 also significantly induced cholesterol efflux activity in peritoneal macrophages. These results suggest that LXR ligands may be useful therapeutic agents for the treatment of atherosclerosis.


Assuntos
Anticolesterolemiantes/uso terapêutico , Arteriosclerose/prevenção & controle , Receptores Citoplasmáticos e Nucleares/agonistas , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Transporte Biológico , Colesterol/metabolismo , Proteínas de Ligação a DNA , Hidrocarbonetos Fluorados , Ligantes , Lipídeos/sangue , Lipoproteínas/sangue , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Receptores Nucleares Órfãos , RNA Mensageiro/biossíntese , Receptores de LDL/genética , Sulfonamidas
18.
Circulation ; 106(22): 2767-70, 2002 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-12451000

RESUMO

BACKGROUND: Dysregulation of adipocyte-derived bioactive molecules plays an important role in the development of atherosclerosis. We previously reported that adiponectin, an adipocyte-specific plasma protein, accumulated in the injured artery from the plasma and suppressed endothelial inflammatory response and vascular smooth muscle cell proliferation, as well as macrophage-to-foam cell transformation in vitro. The current study investigated whether the increased plasma adiponectin could actually reduce atherosclerosis in vivo. METHODS AND RESULTS: Apolipoprotein E-deficient mice were treated with recombinant adenovirus expressing human adiponectin (Ad-APN) or beta-galactosidase (Ad-betagal). The plasma adiponectin levels in Ad-APN-treated mice increased 48 times as much as those in Ad-betagal treated mice. On the 14th day after injection, the lesion formation in aortic sinus was inhibited in Ad-APN-treated mice by 30% compared with Ad-betagal-treated mice (P<0.05). In the lesions of Ad-APN-treated mice, the lipid droplets became smaller compared with Ad-betagal-treated mice (P<0.01). Immunohistochemical analyses demonstrated that the adenovirus-mediated adiponectin migrate to foam cells in the fatty streak lesions. The real-time quantitative polymerase chain reaction revealed that Ad-APN treatment significantly suppressed the mRNA levels of vascular cell adhesion molecule-1 by 29% and class A scavenger receptor by 34%, and tended to reduce levels of tumor necrosis factor-alpha without affecting those of CD36 in the aortic tissue. CONCLUSIONS: These findings documented for the first time that elevated plasma adiponectin suppresses the development of atherosclerosis in vivo.


Assuntos
Apolipoproteínas E/deficiência , Arteriosclerose/prevenção & controle , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas de Membrana , Proteínas/farmacologia , Receptores de Lipoproteínas , Adiponectina , Animais , Apolipoproteínas E/sangue , Apolipoproteínas E/genética , Arteriosclerose/genética , Arteriosclerose/patologia , Antígenos CD36/genética , Antígenos CD36/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Células Espumosas/metabolismo , Células Espumosas/patologia , Terapia Genética , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Imuno-Histoquímica , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , Músculo Liso Vascular/patologia , Proteínas/genética , Proteínas/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Receptores Depuradores , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptores Depuradores Classe A , Receptores Depuradores Classe B , Seio Aórtico/efeitos dos fármacos , Seio Aórtico/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...