RESUMO
Obesity-associated type 2 diabetes mellitus is associated with the development of insulin resistance. Among several metabolites, resolvins that are metabolites of eicosapentaenoic acid have been shown to exert insulin-sensitizing effects; however, the role of resolvin E3 (RvE3) in glucose metabolism has not been studied. In this study, the effect of RvE3 on glucose metabolism in mice with high-fat diet-induced obesity and 3T3L1 adipocytes was studied. C57BL/6 mice fed a high-fat diet were administered RvE3, for which insulin tolerance, oral glucose tolerance tests, and the homeostasis model assessment of insulin resistance, were performed. RvE3 treatment significantly improved insulin sensitivity and glucose tolerance and regulated protein kinase B (Akt) phosphorylation in the adipose tissue. Moreover, RvE3 treatment enhanced the insulin-stimulated glucose transporter 4 (Glut4) translocation, glucose uptake, phosphatidylinositol-3-kinase (PI3K) activity, and Akt phosphorylation in 3T3L1 adipocytes, whereas a PI3K inhibitor inhibited the enhanced insulin-stimulated glucose uptake induced by RvE3. These findings indicate that RvE3 likely improves insulin sensitivity, resulting in the upregulation of glucose uptake in adipocytes by activating the PI3K/Akt signaling pathways. Collectively, the findings of this study show that RvE3 may play a role in glucose homeostasis and could be used as a potential therapeutic target for developing treatments for obesity-associated diabetes.
Assuntos
Adipócitos/efeitos dos fármacos , Ácidos Graxos Insaturados/farmacologia , Hipoglicemiantes/farmacologia , Resistência à Insulina , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Transportador de Glucose Tipo 4/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de SinaisRESUMO
We hypothesized that cholesterol efflux capacity is more useful than the lipid profile as a marker of the presence and the severity of coronary artery disease (CAD). Therefore, we investigated the associations between the presence and the severity of CAD and both the percentage of cholesterol efflux capacity and total cholesterol efflux capacity and the lipid profile including the high-density lipoprotein cholesterol (HDL-C) level in patients who underwent coronary computed tomography angiography (CTA). The subjects consisted of 204 patients who were clinically suspected to have CAD and underwent CTA. We isolated HDL from plasma by ultracentrifugation and measured the percentage of cholesterol efflux capacity using 3H-cholesterol-labeled J774 macrophage cells and calculated total cholesterol efflux capacity as follows: the percentage of cholesterol efflux capacity/100× HDL-C levels. While the percentage of cholesterol efflux capacity was not associated with the presence or the severity of CAD, total cholesterol efflux capacity and HDL-C in patients with CAD were significantly lower than those in patients without CAD. In addition, total cholesterol efflux capacity and HDL-C, but not the percentage of cholesterol efflux capacity, significantly decreased as the number of coronary arteries with significant stenosis increased. Total cholesterol efflux capacity was positively correlated with HDL-C, whereas the percentage of cholesterol efflux capacity showed only weak association. In a logistic regression analysis, the presence of CAD was independently associated with total cholesterol efflux capacity, in addition to age and gender. Finally, a receiver-operating characteristic curve analysis indicated that the areas under the curves for total cholesterol efflux capacity and HDL-C were similar. In conclusion, the percentage of cholesterol efflux capacity using the fixed amount of isolated HDL was not associated with CAD. On the other hand, the calculated total cholesterol efflux capacity that was dependent of HDL-C levels had a significant correlation with the presence of CAD.
Assuntos
HDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/complicações , Estenose Coronária/diagnóstico por imagem , Idoso , Biomarcadores/sangue , Linhagem Celular , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Feminino , Humanos , Japão , Modelos Logísticos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Curva ROC , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: It is controversial whether statins improve high-density lipoprotein (HDL) function, which plays an important role in reverse cholesterol transport in vivo. The aim of the present study was to clarify the effects of rosuvastatin and atorvastatin on reverse cholesterol transport in macrophage cells in vivo and their underlying mechanisms. APPROACH AND RESULTS: Male C57BL mice were divided into 3 groups (rosuvastatin, atorvastatin, and control groups) and orally administered rosuvastatin, atorvastatin, or placebo for 6 weeks under feeding with a 0.5% cholesterol+10% coconut oil diet. After administration, although there were no changes in plasma HDL cholesterol levels among the groups, plasma from the rosuvastatin group showed an increased ability to promote ATP-binding cassette transporter A1-mediated cholesterol efflux ex vivo. In addition, capillary electrophoresis revealed a shift in HDL toward the pre-ß HDL fraction only in the rosuvastatin group. Mice in all 3 groups were intraperitoneally injected with (3)H-cholesterol-labeled and cholesterol-loaded macrophages and then were monitored for the appearance of (3)H-tracer in plasma and feces. The amount of (3)H-tracer excreted into feces during 48 hours in the rosuvastatin group was greater than that in the control group. Finally, (3)H-cholesteryl oleate-HDL was intravenously injected into all groups, blood samples were taken, and the count of (3)H-cholesterol was analyzed. Plasma (3)H-cholesteryl oleate-HDL changed similarly, and no differences in fractional catabolic rates were observed. CONCLUSIONS: Rosuvastatin enhanced the ATP-binding cassette transporter A1-dependent HDL efflux function of reverse cholesterol transport, and this finding highlights the potential of rosuvastatin for the regression of atherosclerosis.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/efeitos dos fármacos , Aterosclerose/prevenção & controle , Colesterol na Dieta/sangue , Dieta Hiperlipídica , Dislipidemias/tratamento farmacológico , Fluorbenzenos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Macrófagos/efeitos dos fármacos , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Apolipoproteína A-I/metabolismo , Aterosclerose/sangue , Aterosclerose/etiologia , Atorvastatina , Transporte Biológico , Linhagem Celular , Ésteres do Colesterol/sangue , HDL-Colesterol/sangue , VLDL-Colesterol/sangue , Modelos Animais de Doenças , Dislipidemias/sangue , Dislipidemias/complicações , Feminino , Ácidos Heptanoicos/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pirróis/farmacologia , Rosuvastatina Cálcica , Fatores de TempoRESUMO
BACKGROUND: Smoking cessation reduces the risk of cardiovascular disease (CVD) and improves clinical outcomes in public health. We studied the effect of smoking cessation on high-density lipoprotein (HDL) functionality. METHODSâANDâRESULTS: We randomly treated 32 smokers with varenicline or a transdermal nicotine patch as part of a 12-week smoking cessation program (The VN-SEESAW Study). The plasma lipid profiles, plasma and HDL malondialdehyde (MDA) levels, HDL subfractions as analyzed by capillary isotachophoresis, cholesterol efflux capacity, and antiinflammatory activity of HDL were measured before and after the anti-smoking intervention. After smoking cessation, HDL-C, apoA-I levels and HDL subfractions were not significantly different from the respective baseline values. However, cholesterol efflux capacity and the HDL inflammatory index (HII) were significantly improved after smoking cessation. The changes in both parameters (%∆ cholesterol efflux capacity and ∆HII) were also significantly improved in the successful smoking cessation group compared with the unsuccessful group. The changes in cholesterol efflux capacity and HII also correlated with those in end-expiratory CO concentration and MDA in HDL, respectively. CONCLUSIONS: Our findings indicate that smoking cessation leads to improved HDL functionality, increased cholesterol efflux capacity and decreased HII, without changing HDL-C or apoA-I levels or HDL subfractions. This may be one of the mechanisms by which smoking cessation improves the risk of CVD.
Assuntos
Lipoproteínas HDL/sangue , Abandono do Hábito de Fumar , Fumar/sangue , 1-Alquil-2-acetilglicerofosfocolina Esterase/sangue , Administração Cutânea , Adulto , Apolipoproteína A-I/sangue , Benzazepinas/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Colesterol/metabolismo , HDL-Colesterol/sangue , Agonistas Colinérgicos/uso terapêutico , Feminino , Humanos , Inflamação , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Macrófagos/metabolismo , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Nicotina/administração & dosagem , Nicotina/uso terapêutico , Oxirredução , Quinoxalinas/uso terapêutico , Receptores Nicotínicos , Fatores de Risco , VareniclinaRESUMO
OBJECTIVES: This study was conducted to verify the effectiveness of Anterior Support Screw (AS2) for unstable femoral trochanteric fractures. DESIGN: A multicenter, prospective, randomized controlled trial SETTING: This study was conducted across 15 academic medical centers in Japan PATIENTS/PARTICIPANTS: We enrolled 240 cases of femoral trochanteric fractures with posterior crushing and intramedullary displacement of proximal bone fragments across 15 institutions in Japan. INTERVENTION: All patients were subjected to a reduction in which the anterior cortex was brought into contact. The patients were randomly assigned to the anterior support screw group (AS2 group) and the non-screw group (control group). MAIN OUTCOME MEASUREMENTS: Two computed-tomography (CT) scans were taken immediately after surgery and early postoperative period (day 14-21) to investigate the reduction loss rate of the anterior cortex and sliding distances in the early postoperative period. RESULTS: The reduction loss rate was 4.5 % in the AS2 group and 16.8 % in the control group, indicating a significantly lower reduction loss rate in the AS2 group (p = 0.003). The average sliding distance was 1.8 mm in the AS2 group and 2.8 mm in the control group, indicating a significantly shorter sliding distance in the AS2 group (p < 0.0001). CONCLUSION: Adding a screw in front of the intramedullary nail significantly reduces reduction loss, and maintains anterior bony contact. This study also showed that these screws suppress the sliding distance during the postoperative period. LEVEL OF EVIDENCE: Therapeutic Level I.
RESUMO
OBJECTIVE: We evaluated whether a novel inducible cholesterol efflux (iCE) peptide [Fukuoka University Apolipoprotein A-I Mimetic Peptide (FAMP)] protects against myocardial ischemia reperfusion injury (IRI) through a nitric oxide (NO) pathway by an improvement of high-density lipoprotein (HDL) functionality. METHODS AND RESULTS: Male C57BL6/J mice were intraperitoneally injected with phosphate buffer as a control, low-dose (10 mg/kg) or high-dose (50 mg/kg) of FAMP before 18 h of IRI (n=6-12 in each group). After 30 min of ischemia followed by 6h of reperfusion, blood pressure, and infarct size were measured and cardiac function was evaluated by a Millar catheter. FAMP significantly improved stroke volume, cardiac output, left ventricular ejection fraction, and infarct size. FAMP significantly preserved cytochrome C in the mitochondrial fraction and inhibited its release into the cytosolic fraction in the heart, but did not significantly reduce mRNA levels of monocyte chemoattractant protein-1 or interluekin-6. In a TdT-mediated dUTP nick end labeling (TUNEL) assay, FAMP significantly suppressed the appearance of TUNEL-positive nuclear. We also performed same experiments with endothelial nitric oxide synthase-knockout (eNOS-KO) mice and FAMP-induced improvements of cardiac function were not observed in eNOS-KO mice. CONCLUSIONS: FAMP activated HDL-functionality and improved cardiac function in a model of myocardial IRI. It may have anti-apoptotic effects by protecting mitochondria through a NO pathway as a pleiotropic effect.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/uso terapêutico , Quimiocina CCL2/genética , Regulação da Expressão Gênica , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Óxido Nítrico/metabolismo , RNA/genética , Função Ventricular Esquerda/fisiologia , Animais , Western Blotting , Quimiocina CCL2/biossíntese , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de SinaisRESUMO
BACKGROUND/OBJECTIVE: HDL has various atheroprotective functions and improves endothelial function. Apolipoprotein A-I (apoA-I) is a major protein of HDL and plays a crucial role in HDL functions. We developed a novel apoA-I mimetic peptide, FAMP (Fukuoka University ApoA-I Mimetic Peptide). It is unclear whether an apoA-I mimetic peptide can promote neovascularization in vivo. Here, we investigated the effect of FAMP on endothelial nitric oxide synthase (eNOS) activation and angiogenesis in a murine hindlimb ischemia model. METHODS AND RESULTS: Intramuscular administration of FAMP significantly enhanced blood flow recovery and increased capillary density in the ischemic limb of mice fed a high-cholesterol diet (HCD). In a gait analysis, FAMP ameliorated functional recovery compared with that in the control group. FAMP significantly activated Akt, ERK, and eNOS phosphorylation in endothelial cells, and improved the migratory functions of human aortic endothelial cells (HAECs). LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), significantly inhibited the activation of eNOS by FAMP. FAMP had no beneficial effects on blood flow recovery in eNOS(-/-) mice. CONCLUSIONS: FAMP promoted recovery from hindlimb ischemia through a nitric oxide (NO)-related pathway by activation of a PI3K/Akt pathway. FAMP may become a new therapeutic agent for the future clinical treatment of critical limb ischemia (CLI).
Assuntos
Apolipoproteína A-I/uso terapêutico , Materiais Biomiméticos/uso terapêutico , Membro Posterior/irrigação sanguínea , Isquemia/tratamento farmacológico , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/uso terapêutico , Sequência de Aminoácidos , Animais , Apolipoproteína A-I/genética , Apolipoproteína A-I/farmacologia , Materiais Biomiméticos/farmacologia , Células Cultivadas , Membro Posterior/efeitos dos fármacos , Humanos , Isquemia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: We elucidated the effect of newly developed Fukuoka Apolipoprotein A-I Mimetic Peptide (FAMP) on in vivo macrophage reverse cholesterol transport (RCT) and the underlying mechanisms. METHODS AND RESULTS: Cholesteryl ester transfer protein transgenic mice were divided into FAMP, and placebo control groups, and injected with FAMP or phosphate buffer saline intraperitoneally for 5 days. The FAMP group showed a significant decrease in plasma high-density lipoprotein cholesterol (HDL-C), and plasma from the FAMP group had an increased ability to promote ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux from bone marrow macrophages ex vivo. Furthermore, mice were injected intraperitoneally with (3)H-cholesterol-labeled and cholesterol-loaded macrophages and monitored for the appearance of (3)H-tracer. The amount of (3)H-tracer excreted into feces over 48h in the FAMP group was significantly higher than that in the control group. (3)H-cholesterol ester (CE)-HDL was injected intravenously and (3)H-cholesterol in blood was counted. In the FAMP group, plasma (3)H-CE-HDL decreased rapidly, and treatment with FAMP markedly increased the fractional catabolic rate. CONCLUSIONS: The administration of FAMP promoted ABCA1-dependent efflux ex vivo, HDL turnover in vivo, and macrophage RCT in vivo despite reduced plasma HDL-C levels. FAMP might have atheroprotective potential.
Assuntos
Apolipoproteína A-I/fisiologia , HDL-Colesterol/metabolismo , Macrófagos/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Aterosclerose/tratamento farmacológico , Transporte Biológico , Materiais Biomiméticos , Camundongos , Camundongos TransgênicosRESUMO
BACKGROUND: It is unclear whether gender and aging influence the characteristics of patients who undergo coronary artery bypass grafting (CABG). METHODS: We retrospectively reviewed a clinical database of 1,498 patients (male/female = 1133/365, age 67 ± 9 years) who underwent CABG at Fukuoka University Hospital from 1994 to 2010. RESULTS: Male showed significantly younger, higher percentages (%) of smoking and hyperuricemia (HU), higher levels of serum creatinine, and lower % hypertension (HT) and diabetes mellitus (DM), and lower levels of left ventricular ejection fraction than female. In multivariate analysis, all parameters identified independent variables associated with the gender difference. Next, we divided the patients into 5 groups according to age, and each group was then separated by gender. The % of males significantly decreased with aging, whereas % female significantly increased. Although % smoking and estimated glomerular filtration rate (eGFR), and body mass index (BMI) in all patients, males and females significantly decreased with aging, HU, left ventricular end diastolic pressure and the number of significantly stenosed coronary vessels were not associated with gender or aging. Interestingly, % HT in all patients and males significantly increased with aging, whereas that in females was not associated with aging. Serum low-density lipoprotein cholesterol levels in males significantly decreased with aging, while those in all patients and females were not associated with aging. In this contemporary data set, the decreases in % smoking and eGFR with aging were common characteristics in male and female patients. In addition, there were gender and aging differences in % smoking, % HT, BMI and eGFR, whereas no differences were observed in % DM, % dyslipidemia or % HU. CONCLUSIONS: Before CABG, high-risk patients with coronary artery disease who is going to undergo CABG may need to be managed more strictly considering to gender and age to avoid CABG.
Assuntos
Envelhecimento , Ponte de Artéria Coronária , Doença das Coronárias/cirurgia , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Índice de Massa Corporal , Ponte de Artéria Coronária/estatística & dados numéricos , Doença das Coronárias/epidemiologia , Doença das Coronárias/etiologia , Doença das Coronárias/fisiopatologia , Complicações do Diabetes/epidemiologia , Feminino , Hospitais Universitários , Humanos , Hipertensão/complicações , Hiperuricemia/complicações , Japão/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Distribuição por Sexo , Fumar/efeitos adversos , Volume Sistólico , Resultado do TratamentoRESUMO
OBJECTIVE: Many patients still have high blood pressure (BP) after treatment with high-dose angiotensin II type 1 receptor blockers (ARBs) or Preminent® (medium-dose of losartan (50 mg/day)/hydrochlorothiazide (HCTZ) (12.5 mg/day)). Therefore, we analyzed whether Micombi®BP (high-dose telmisartan (80 mg/day)/HCTZ (12.5 mg/day)) could provide better results with regard to efficacy and safety for patients with uncontrolled hypertension. METHODS: In total, 44 hypertensive patients (22 males, age 71±14 years) who showed uncontrolled BP despite the use of high-dose ARBs or Preminent® were enrolled in this study. We used a changeover design in which the patients were switched from high-dose ARBs or Preminent® to Micombi®BP. We analyzed BP, heart rate (HR), and biochemical parameters before and after treatment for 3 months. RESULTS: Systolic BP and diastolic BP significantly decreased (125±15/69±11 mmHg) and 85% of the patients achieved their target BP at 3 months after changeover. Patients who switched from ARBs and those who switched from Preminent® showed similar BP-lowering effects. In addition, the reductions in BP after 3 months in patients with or without chronic kidney disease and in those with or without metabolic syndrome (MetS) were also similar. There were no significant changes in HR during the study period. Although blood levels of potassium, hemoglobin A1c and uric acid (UA) significantly increased after 3 months for all of the patients, none of the patients showed serious adverse effects. CONCLUSION: High-dose telmisartan/HCTZ therapy was associated with a significant reduction in BP and helped patients achieve their target BP.
Assuntos
Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Benzoatos/efeitos adversos , Benzoatos/uso terapêutico , Hidroclorotiazida/efeitos adversos , Hidroclorotiazida/uso terapêutico , Hipertensão/tratamento farmacológico , Idoso , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacologia , Benzoatos/administração & dosagem , Benzoatos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Formas de Dosagem , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hidroclorotiazida/administração & dosagem , Hidroclorotiazida/farmacologia , Hipertensão/sangue , Hipertensão/complicações , Hipertensão/fisiopatologia , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/tratamento farmacológico , Potássio/sangue , Telmisartan , Resultado do Tratamento , Ácido Úrico/sangueRESUMO
AIM: In-stent restenosis (ISR) remains the major limitation of percutaneous coronary intervention (PCI), and the mechanism of ISR is neointimal growth. Higher serum total bilirubin (TBIL) inhibits the inflammatory response and the proliferation of vascular smooth muscle cells; however, the relationship between TBIL and ISR is still unclear. This study aimed to determine whether the serum bilirubin level is associated with ISR after coronary stenting in patients with coronary artery disease. METHODS: This study investigated 1076 consecutive patients who underwent coronary stenting and follow-up angiography (average period: 236 days) using the Fukuoka University Hospital Registry. We used multivariate logistic regression analysis to identify independent predictors of ISR. RESULTS: The baseline TBIL level was significantly lower in patients with ISR at follow-up compared to those without ISR [0.53 ± 0.26 mg/dL vs. 0.62 ± 0.69 mg/dL, p= 0.036]. When we divided the patients into 4 groups according to their baseline TBIL level ["low", "low-normal", "high-normal group" and "high" (0.18 ± 0.04, 0.50 ± 0.13, 0.93 ± 0.12 and 2.11 ± 2.68 mg/dL)], the ISR rate at follow-up was significantly correlated with the TBIL level [31.0, 32.3, 22.1, and 15.6%, respectively; p= 0.008 for trend]. A significant negative correlation between the TBIL level and ISR was revealed by multivariate analyses [odds ratio, 0.6; 95% confidence interval, 0.39-0.89, p= 0.015]. This risk reduction was comparable to those of other known ISR risk factors and covariates. CONCLUSION: To the best of our knowledge, this is the first report to demonstrate that a higher TBIL level may be a useful independent predictor of ISR risk after PCI.