RESUMEN
AIM: To clarify the mechanism by which pitavastatin reduced cardiovascular (CV) events more effectively than atorvastatin in the TOHO Lipid Intervention Trial Using Pitavastatin (TOHO-LIP), the changes in (Δ) non-heparinized serum level of lipoprotein lipase mass (LPL mass) during administration of the respective statins were investigated. METHODS: From TOHO-LIP data, 223 hypercholesterolemic patients with any CV risks followed at Toho University Sakura Medical Center were analyzed. The patients were randomized to pitavastatin (2 mg/day) group (n=107) or atorvastatin (10 mg/day) group (n=116), and followed for 240 weeks. In this subgroup study, the primary and secondary end points were the same as those in TOHO-LIP, and 3-point major adverse cardiovascular events (3P-MACE) was added. The relationship between ΔLPL mass during the first year and the incidences of each end point was analyzed. RESULTS: The lipid-lowering effect was not different between the two statins. Cumulative 240-week incidence of each end point was significantly lower in pitavastatin group (primary: 1.9% vs. 10.3%, secondary: 4.7% vs. 18.1%, 3P-MACE: 0.9% vs. 6.9%). Mean LPL mass (64.9 to 69.0 ng/mL) and eGFR (70.1 to 73.6 ml/min/1.73m 2) increased in pitavastatin group, but not in atorvastatin group during the first year. Cox proportional-hazards model revealed that ΔLPL mass (1 ng/mL or 1SD) contributed to almost all end points. CONCLUSIONS: Pitavastatin administration reduced CV events more efficaciously than atorvastatin despite similar LDL cholesterol-lowering effect of the two statins. Increased LPL mass during the first year by pitavastatin treatment may be associated with this efficacy.
Asunto(s)
Enfermedades Cardiovasculares , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Quinolinas , Enfermedades Cardiovasculares/prevención & control , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lipasa , Lipoproteína Lipasa , Pirroles , Quinolinas/uso terapéuticoRESUMEN
AIM: In the TOHO Lipid Intervention Trial Using Pitavastatin (TOHO-LIP), a multicenter randomized controlled trial, pitavastatin significantly reduced cardiovascular (CV) events compared to atorvastatin in patients with hypercholesterolemia. To investigate the mechanism by which pitavastatin preferentially prevents CV events, we investigated the relationship between CV events and cardio-ankle vascular index (CAVI) using the TOHO-LIP database. METHODS: For the subgroup analysis, we selected patients from a single center, Toho University Sakura Medical Center. After excluding those who had CV events at baseline or during the first year, 254 patients were enrolled. The primary end point was the same as that of TOHO-LIP, and three-point major cardiac adverse events (3P-MACE) was added as secondary end point. RESULTS: The cumulative 5-year incidence of 3P-MACE (pitavastatin 1.6%, atorvastatin 6.1%, P=0.038) was significantly lower in pitavastatin group (2 mg/day) than in atorvastatin group (10 mg/day). CAVI significantly decreased only in pitavastatin group during the first year (9.50-9.34, P=0.042), while the change in low-density lipoprotein cholesterol (LDL-C) did not differ between the two groups. The change in CAVI during the first year positively correlated with 3P-MACE and tended to be an independent predictor of 3P-MACE in Cox proportional hazards model (hazard ratio, 1.736; P=0.079). The annual change in CAVI throughout the observation period was significantly higher in subjects with CV events compared to those without. CONCLUSIONS: In this subgroup analysis, the reduction in CV events tended to be associated with the CAVI-lowering effect of pitavastatin, which was independent of the LDL-C-lowering effect.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Quinolinas/uso terapéutico , Anciano , Anticolesterolemiantes/farmacología , Atorvastatina/farmacología , Atorvastatina/uso terapéutico , Índice Vascular Cardio-Tobillo , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico , LDL-Colesterol/sangre , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Persona de Mediana Edad , Quinolinas/farmacologíaRESUMEN
Remnant lipoprotein can be measured by immunoseparation assay and polyacrylamide gel disc electrophoresis; however, these methods have some problems, such as a lack of specificity and being technically complicated. Recently, a new method, the remnant lipoprotein cholesterol homogeneous assay(RemL-C), has been established. In this study, we evaluated the basal performance of RemL-C assay. One hundred and fifty patients with diabetes mellitus were enrolled in this study. RemL-C level was higher in the midband (+) group than in the midband (-) group (p<0.01), and a strong correlation was observed between RemL-C level and remnant lipoprotein level measured by conventional method (r=0.89, p<0.01). RemL-C level correlated positively with triglyceride(TG) (r=0.94, p<0.01) and total cholesterol(TC) (r=0.39, p<0.01), negatively with high density lipoprotein(HDL-C) (r=-0.35, p<0.01) and positively with apolipoprotein (apo) CII, and apoE (apoCII: r=0.59, p<0.01, apoE: r=0.71, p<0.01). In particular, RemL-C level correlated strongly with TG and apoE. RemL-C level was significantly higher in patients with combined hyperlipidemia compared to patients with other hyperlipidemias (p<0.01). When the serum of a patient with combined hyperlipidemia was separated by sepharose 4B gel filtration, the fraction showing peak RemL-C level was observed between the fraction corresponding to VLDL and the fraction corresponding to LDL. Furthermore, the peak of RemL-C corresponded to the peak of apoE. Moreover RemL-C level correlated negatively with preheparin serum lipoprotein lipase mass that is a marker of metabolic syndrome (r=-0.30, p<0.01). These results suggest that the measurement of remnant lipoprotein by RemL-C assay reflects the quantity of intermediate-density lipoprotein. Since RemL-C measurement can be run on an automated clinical analyzer permitting quick and high throughput measurement, RemL-C levels may be useful in the screening of hyperlipidemia.
Asunto(s)
Colesterol/sangre , Lipoproteínas IDL/sangre , Lipoproteínas/sangre , Cromatografía en Gel , Diabetes Mellitus/sangre , Femenino , Humanos , Hiperlipidemias/sangre , Masculino , Persona de Mediana EdadRESUMEN
Previous reports indicate that 7-ketocholesterol (7KCHO) induces apoptosis of cultured human vascular smooth muscle cells (SMCs). We hypothesized that calcium channel blockers will inhibit SMC apoptosis induced by 7KCHO because caspase-3 activity is Ca2+ dependent and 7KCHO stimulates caspase-3 and SMC apoptosis. So, the protective effect of the calcium channel blocker nifedipine on SMC apoptosis induced by 7KCHO was investigated. When 7KCHO (50 micromol/L) was added to SMCs, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP)-biotin nick end-labeling was positive. DNA extracted from SMCs exposed to 7KCHO showed a ladder pattern on agarose electrophoresis. In the presence of extracellular Ca2+, the Ca2+ influx, caspase-3 activity, and fragmented DNA also increased in SMCs incubated with 7KCHO dose-dependently. However, in the absence of extracellular Ca2+, no effects of 7KCHO on caspase-3 activity and fragmented DNA were observed. In the presence of nifedipine, the 7KCHO-induced increases in Ca2+ influx, caspase-3 activity, and the amount of fragmented DNA decreased significantly. These results suggest that 7KCHO-induced apoptosis of SMCs is inhibited by calcium channel blockade, and that Ca2+ influx into cells mediated by 7KCHO plays an important role in 7KCHO-induced apoptosis.
Asunto(s)
Apoptosis/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Calcio/metabolismo , Cetocolesteroles/farmacología , Músculo Liso Vascular/efectos de los fármacos , Nifedipino/farmacología , Caspasa 3/metabolismo , Humanos , Etiquetado Corte-Fin in Situ , Músculo Liso Vascular/citologíaRESUMEN
AIM: We investigated the effects of a calorie-restricted low-carbohydrate diet on glucose and lipid metabolism, and body fat distribution, especially on the secretion of leptin and lipoprotein lipase from adipose tissue in Otsuka Long Evans Tokushima Fatty (OLETF) rats. METHODS: Forty-three week-old male OLETF rats were randomized into three groups (n=6 per group): the HC group (HC) was fed a diet with 60% carbohydrate; the LC group (LC) with 30% carbohydrate; and the P-HC group (P-HC) with 60% carbohydrate and pioglitazone (0.1%). The total calorie intake was restricted to 70% of the average intake from each diet (60 kcal/day). The diets were continued for 8 weeks. RESULTS: Similar decreases in body weight and serum glucose were observed in the three groups. Serum insulin concentration was significantly decreased in LC and P-HC compared to HC. Serum total cholesterol and triglycerides decreased significantly (p<0.05) in LC and P-HC compared to HC. The decrease of visceral fat area measured by computed tomography was greatest in LC among the three groups. At the end of the diet, leptin secretion from visceral adipose tissue and lipoprotein lipase (LPL) activity in subcutaneous adipose tissue were significantly higher in LC and P-HC compared to HC (p<0.05). CONCLUSION: These results indicate that under calorie-restricted conditions, low carbohydrates are much more effective than high carbohydrates in improving insulin sensitivity.
Asunto(s)
Restricción Calórica , Dieta Baja en Carbohidratos , Glucosa/metabolismo , Metabolismo de los Lípidos , Animales , Peso Corporal/fisiología , Restricción Calórica/métodos , Resistencia a la Insulina/fisiología , Leptina/metabolismo , Lipoproteína Lipasa/metabolismo , Masculino , Ratas , Ratas Endogámicas OLETFRESUMEN
Lipoprotein lipase mass in preheparin serum (preheparin LPL mass) is assumed to reflect some of the LPL production in the whole body and insulin sensitivity. While metabolic syndrome is a common underlying condition for cardiovascular diseases, biological marker of this syndrome has not been fully established. To clarify the characteristics of preheparin LPL mass in metabolic syndrome, 362 Japanese subjects were studied to examine the relationship between symptoms of metabolic syndrome and preheparin LPL mass and compare with plasma adiponectin. Furthermore the relation with urinary 8-hydroxydeoxyguanosine (8-OHdG) that reflects oxidative stress to DNA was also studied. Both preheparin LPL mass and plasma adiponectin correlated positively with HDL-cholesterol and negatively with body weight and triglyceride. Only preheparin LPL mass showed a negative correlation with fasting blood glucose and HbA1c. Both mean preheparin LPL mass and plasma adiponectin decreased with an increase in severity of the metabolic syndrome with/without obesity and with/without diabetes. The correlation coefficient between preheparin LPL mass and plasma adiponectin was r=0.562. A negative correlation between preheparin LPL mass and urinary 8-OHdG was observed. These results suggest that low preheparin LPL mass may reflect systemic oxidative stress and also a biomarker of the severity of metabolic syndrome.
Asunto(s)
Biomarcadores/sangre , Lipoproteína Lipasa/sangre , Síndrome Metabólico/sangre , Adiponectina/sangre , Adulto , Anciano , HDL-Colesterol/sangre , Femenino , Humanos , Masculino , Síndrome Metabólico/enzimología , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
We previously reported that lipoprotein lipase mass levels in preheparin serum (preheparin LPL mass) was significantly lower in type 2 diabetes mellitus compared to healthy subjects and that low preheparin LPL mass may be a high-risk factor of coronary atherosclerosis. The aim of this study was to clarify the effects of metformin on serum lipoprotein lipase mass levels (preheparin LPL mass), adiponectin and lipid metabolism in patients with type 2 diabetes mellitus. Twenty-eight patients with type 2 diabetes mellitus (HbAlc>7.0%), who were already receiving sulfonylurea agents, took metformin 500 mg orally twice daily for 3 months. Fasting blood glucose (FBG), immunoreactive insulin (basal IRI) and HbAlc decreased significantly after metformin treatment. LDL-Rm ratio decreased significantly (from 0.3521+/-0.046 to 0.3339+/-0.030, P<0.05) and preheparin LPL mass increased significantly (from 42.5+/-3.2 to 50.6+/-3.5 ng/ml, P<0.0005), but adiponectin was unchanged. The correlation of a change of LDL-Rm ratio and a change of preheparin LPL mass showed a negative correlation tendency. The changes in LDL-Rm ratio and preheparin LPL mass were independent of the hypoglycemic effect of metformin. These results suggest that metformin may increase LPL production, thereby increasing LDL particle size. These effects might be independent of the hypoglycemic effect of metformin.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Lipoproteína Lipasa/sangre , Lipoproteínas LDL/sangre , Metformina/uso terapéutico , Compuestos de Sulfonilurea/uso terapéutico , Glucemia/metabolismo , Peso Corporal , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/enzimología , Quimioterapia Combinada , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Persona de Mediana EdadRESUMEN
To clarify whether lipids deposited in human atheromatous lesions induce apoptosis of vascular smooth muscle cells (SMC) and to identify the main component in deposited lipids responsible for inducing apoptosis, we examined the effect of lipids extracted from human atheromatous lesions on apoptosis of cultured SMC and analyzed the content of cholesterol in the lipids. When lipids extracted from atheromatous lesions were added to SMC, agarose electrophoresis of DNA showed a ladder pattern, DNA fragmentation assay detected an increase of fragmented DNA, and flow cytometric analysis demonstrated an increase of apoptotic cells. When the extracted lipids were fractionated by Sep-Pak ODS column, addition of the oxysterol-rich fraction to SMC resulted in a DNA ladder pattern and positive staining of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL). The oxysterol-rich fraction also increased fragmented DNA and apoptotic cells to a greater extent than the other two fractions. HPLC analysis showed that the quantity of 7-ketocholesterol in extracted lipids was large enough to induce SMC apoptosis. These results suggest that lipids deposited in human atheromatous lesions may induce apoptosis of SMC and that oxysterols may be important factor contributing to induce apoptosis among deposited lipids.
Asunto(s)
Apoptosis/fisiología , Aterosclerosis/fisiopatología , Vasos Coronarios/citología , Cetocolesteroles/fisiología , Músculo Liso Vascular/citología , Aorta/química , Células Cultivadas , Vasos Coronarios/fisiopatología , Humanos , Etiquetado Corte-Fin in Situ , Músculo Liso Vascular/fisiopatología , Miocitos del Músculo Liso/fisiología , Túnica Íntima/patologíaRESUMEN
The effects of combination therapy of angiotensin II receptor blockers (ARBs) and a calcium antagonist, benidipine hydrochloride, on glucose and lipid metabolism and pulse pressure were studied in elderly hypertensive patients with type 2 diabetes mellitus. Twenty-five hypertensive diabetic patients aged 65 years or older, who had been receiving candesartan cilexetil, were administered benidipine hydrochloride (4 mg/day) and followed for 4 months. After 4 months, systolic and diastolic blood pressure decreased significantly from 154/91 mmHg to 139/78 mmHg (p<0.01 versus before benidipine hydrochloride administration). Body mass index (BMI) and glycosylated hemoglobin (HbA1c) were apparently reduced but the changes were not statistically significant. The serum lipid profile showed no significant changes in serum total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). Serum lipoprotein lipase mass levels (preheparin LPL mass) increased significantly from 51 to 59 ng/dl (p<0.01 versus before benidipine hydrochloride administration), and the LDL/HDL motility ratio calculated from PAG disc electrophoresis decreased significantly (p<0.05 versus before benidipine hydrochloride administration). When patients were divided into a systolic hypertension group (systolic blood pressure > or =140 mmHg and diastolic blood pressure <90 mmHg) and non-systolic hypertension group (others), preheparin LPL mass was significantly lower in the systolic hypertension group, and the decrease in pulse pressure and increase in preheparin LPL mass were significantly greater in the systolic hypertension group. Stepwise regression analysis showed that low preheparin LPL mass at baseline was associated with a decrease in pulse pressure. Add-on benidipine hydrochloride therapy in elderly hypertensive patients with type 2 diabetes mellitus significantly decreases the LDL/HDL motility ratio and pulse pressure, and significantly increases preheparin LPL mass, in addition to improving blood pressure control. These findings suggest that combination therapy with benidipine hydrochloride and candesartan cilexetil may contribute to the suppression of arteriosclerosis and may be useful for elderly hypertensive patients with diabetes mellitus.
Asunto(s)
Bencimidazoles/farmacología , Compuestos de Bifenilo/farmacología , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Tipo 2/fisiopatología , Dihidropiridinas/farmacología , Hipertensión/tratamiento farmacológico , Metabolismo de los Lípidos/efectos de los fármacos , Tetrazoles/farmacología , Anciano , Anciano de 80 o más Años , Bencimidazoles/administración & dosificación , Compuestos de Bifenilo/administración & dosificación , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diástole , Dihidropiridinas/administración & dosificación , Quimioterapia Combinada , Femenino , Heparina , Humanos , Hipertensión/complicaciones , Lípidos/sangre , Lipoproteína Lipasa/sangre , Lipoproteína Lipasa/efectos de los fármacos , Masculino , Sístole , Tetrazoles/administración & dosificaciónRESUMEN
To clarify whether probucol and statins suppress oxidative stress in diabetic patients, we studied the effects of probucol and the statin atorvastatin on urinary 8-hydroxy-2'deoxyguanosine (8-OHdG) levels in diabetics with hypercholesterolemia. A randomized, open study was performed on a total of 36 patients with type 2 diabetes and hypercholesterolemia. The patients were randomly assigned to a probucol group (500 mg/day, n = 18) or an atorvastatin group (10 mg/day, n = 18). During three months, total- and LDL-cholesterol decreased significantly in both groups. LDL-cholesterol was significantly lower in the atorvastatin group than probucol group. HDL-C decreased significantly in the probucol group and did not change in the atorvastatin group. 8-OHdG decreased significantly in both groups after 3 months; 12.4 +/- 7.5 to 8.1 +/- 4.2 ng/mg/Cr in the atorvastatin group (p < 0.05) and 12.3 +/- 8.8 to 6.8 +/- 2.6 ng/mg/Cr in the probucol group (p < 0.05), and these changes did not differ significantly between the two groups. But, in patients with high 8-OHdG levels (more than 10 ng/mg/Cr) before administration, urinary 8-OHdG decreased significantly from 19.5 +/- 4.9 to 9.2 +/- 3.4 ng/mg Cr (p < 0.01) in the atorvastatin group, and from 19.7 +/- 8.2 to 6.67 +/- 2.2 ng/mg Cr (p < 0.01) in the probucol group. Urinary 8-OHdG was significantly lower in the probucol group than in the atorvastatin group after the second and third months of administration (p < 0.05). These results suggest that while probucol and atorvastatin both reduce systemic oxidative stress, probucol might be the more useful in patients with strong oxidative stress.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Antioxidantes/uso terapéutico , Desoxiguanosina/análogos & derivados , Diabetes Mellitus Tipo 2/orina , Ácidos Heptanoicos/uso terapéutico , Hipercolesterolemia/orina , Probucol/uso terapéutico , Pirroles/uso terapéutico , 8-Hidroxi-2'-Desoxicoguanosina , Adulto , Atorvastatina , Biomarcadores/orina , Desoxiguanosina/orina , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Humanos , Hipercolesterolemia/complicaciones , Hipercolesterolemia/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Resultado del TratamientoRESUMEN
Recent studies suggest that blockade of angiotensin type 1 (AT1) receptor may have some effect on glucose and lipoprotein metabolism. Serum level of preheparin lipoprotein lipase (LPL) reflects LPL production mainly in adipocytes and is believed to be related to insulin sensitivity. We studied the effect of a selective AT1 antagonist, valsartan, on glucose, lipid metabolism and the preheparin LPL mass in 55 patients with type 2 diabetes and hypertension. Patients were randomized into a group administered valsartan 80 mg/day for 12 weeks or a group not administered valsartan (control). Blood pressure decreased significantly. HbA1c and TG levels decreased and HDL-C level increased, but these changes tended to be significantly different. TC and LDL-C levels were not significant changes. Preheparin LPL mass increased after valsartan administration compared with control (P = 0.0307), and migration ratio of LDL (LDL-Rm), which correlated negatively with LDL particle size, decreased compared with control (P < 0.0001). DeltaLDL-Rm correlated inversely with Delta preheparin LPL mass (r = -0.459). Among subjects treated with valsartan, greater improvement in preheparin LPL mass and blood pressure was observed in the subgroup with preheparin LPL mass <40 ng/ml. The results of this study suggest that valsartan may enhance LPL production in adipocytes, resulting in enlarged LDL particle size.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Antihipertensivos/farmacología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Lipoproteína Lipasa/sangre , Tetrazoles/farmacología , Valina/análogos & derivados , Anciano , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Diabetes Mellitus Tipo 2/enzimología , Femenino , Humanos , Hiperlipidemias/tratamiento farmacológico , Hipertensión/sangre , Hipertensión/enzimología , Lipoproteína Lipasa/metabolismo , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Tetrazoles/uso terapéutico , Valina/farmacología , Valina/uso terapéutico , ValsartánRESUMEN
Probucol has antioxidant and cholesterol-lowering effects. This study examined the effect of probucol on progression of diabetic nephropathy. We performed a randomized, open trial on 102 type 2 diabetes patients with clinical albuminuria (urinary albumin excretion >300 mg/g Cr). Fifty-one patients were assigned to probucol treatment (500 mg/day) and 51 to no probucol treatment. Among all patients, 40 who had serum creatinine >or=2mg/dl at baseline were defined as advanced cases. All patients were followed for a maximum 3 years. HbA1c levels were not different between two groups. High-density lipoprotein cholesterol decreased significantly in probucol group. Increase in urinary protein (g/day/month) was significantly greater in non-probucol than in probucol group. Hemodialysis was initiated in 23 patients (10 in probucol group and 13 in non-probucol group). The mean interval to initiation of hemodialysis was significantly longer in probucol group (20.7+/-8.2 months) than in non-probucol group (11.3+/-7.4 months). In advanced cases, increases of both serum creatinine and urinary protein were significantly suppressed in probucol group. In advanced cases, the hemodialysis-free rate was significantly higher in probucol group than in non-probucol group. These results suggest that probucol may suppress the progression of diabetic nephropathy.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Probucol/uso terapéutico , Anciano , Albuminuria , Presión Sanguínea , Colesterol/sangre , HDL-Colesterol/sangre , Creatinina/sangre , Progresión de la Enfermedad , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Diálisis Renal/estadística & datos numéricosRESUMEN
We previously reported that lipoprotein lipase mass level in preheparin serum (preheparin LPL mass) was significantly lower in type 2 diabetes mellitus compared to healthy subjects and increased by conventional insulin therapy using NPH (intermediate-acting) insulin. The aim of this study was to investigate the effects of intensive insulin therapy on preheparin LPL mass. Thirty-two subjects (total group) with type 2 diabetes receiving treatment by NPH insulin injection twice a day in the morning and evening were switched to basal bolus insulin (BBI) therapy (fast-acting insulin after each meal and NPH insulin before bedtime). In 14 subjects, the total daily insulin dose was not change after switching to BBI therapy (iso-dose group). After 3 months of BBI therapy, preheparin LPL mass increased significantly from 47 to 56 ng/ml in total group. Glycosylated hemoglobin and serum triglyceride levels decreased significantly, and high-density lipoprotein-cholesterol increased significantly. Low-density lipoprotein levels did not changed but increase in size was suggested by PAG disc electrophoresis. Similar changes were observed in the iso-dose group. These results suggest that BBI therapy enhances preheparin LPL mass, accompanied by antiatherogenic changes in glucose and lipid metabolism.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Insulina Isófana/uso terapéutico , Lipoproteína Lipasa/sangre , Índice de Masa Corporal , Peso Corporal , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/enzimología , Esquema de Medicación , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Insulina Isófana/administración & dosificación , Lípidos/sangre , Masculino , Persona de Mediana EdadRESUMEN
We investigated the effect of 7-ketocholesterol (7-KCHO) on the activity of matrix metalloproteinase (MMP-9) in human monocytic THP-1 cells, and the inhibition of this effect by fluvastatin. In cells incubated with 7-KCHO or cholesterol, the activity of MMP-9 was enhanced, accompanying an increase in the secretion of MMP-9 proenzyme (pro-MMP-9). However, the activity of MMP-9 and the amount of pro-MMP-9 were significantly greater following incubation with 7-KCHO than cholesterol. Neither 7-KCHO nor cholesterol influenced the amount of tissue inhibitor of metalloproteinase (TIMP)-1 secreted by THP-1 cells. When fluvastatin was added to the cells, the MMP-9 activity stimulated by 7-KCHO or cholesterol decreased significantly, accompanying a decrease in the secretion of pro-MMP-9 and TIMP-1. The inhibition of pro-MMP-9 secretion by fluvastatin was stronger in the cells incubated with 7-KCHO than with cholesterol. These results suggest that 7-KCHO activates macrophage and enhances MMP-9 activity, and its effects may be inhibited by fluvastatin.
Asunto(s)
Ácidos Grasos Monoinsaturados/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Indoles/farmacología , Cetocolesteroles/farmacología , Metaloproteinasa 9 de la Matriz/metabolismo , Monocitos/efectos de los fármacos , Línea Celular , Ensayo de Inmunoadsorción Enzimática , Fluvastatina , Humanos , Monocitos/enzimología , Inhibidor Tisular de Metaloproteinasa-1/metabolismoRESUMEN
To clarify whether an increased proliferative potential of vascular smooth muscle cells (SMC) under diabetic conditions augments the susceptibility of the cells to 7-ketocholesterol-induced apoptosis, we investigated the difference in sensitivity to 7-ketocholesterol between SMC obtained from diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and the control Long-Evans Tokushima Otsuka (LETO) rats. The outgrowth rate from aortic wall explants and cell proliferation were higher in SMC derived from OLETF rats (OLETF-derived SMC) compared to those from LETO rats (LETO-derived SMC). When 7-ketocholesterol was added to SMC, the amount of fragmented DNA increased significantly in OLETF-derived compared to LETO-derived SMC. The amount of fragmented DNA induced by 7-ketocholesterol decreased significantly in both OLETF- and LETO-derived SMC when they were incubated without fetal bovine serum. By adding PDGF-BB to LETO-derived SMC, the amount of fragmented DNA induced by 7-ketocholesterol increased significantly. These results suggest that apoptosis of SMC induced by 7-ketocholesterol may be accelerated when SMC acquire a high proliferative potential by prolonged exposure to diabetic condition.
Asunto(s)
Apoptosis/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Cetocolesteroles/farmacología , Músculo Liso Vascular/patología , Animales , Aorta Torácica/patología , Apoptosis/genética , Arteriosclerosis/etiología , Arteriosclerosis/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Fragmentación del ADN/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Ensayo de Inmunoadsorción Enzimática , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efectos de los fármacos , Ratas , Ratas Endogámicas OLETF , Ratas Long-EvansRESUMEN
This study was conducted to clarify the characteristics of colestimide responders. Forty-seven non-diabetic patients with high levels of low-density lipoprotein cholesterol (LDL-C) received colestimide at 3,000 mg/day and were followed up for 4 months. After 4 months, body weight was reduced but the change was not statistically significant. Total serum cholesterol (TC) and LDL-C levels significantly decreased from 280 to 232 mg/dl and from 195 to 150 mg/dl, respectively (p<0.01 versus before colestimide was administered). Serum triglyceride (TG) levels increased, but the change was not significant. Preheparin lipoprotein lipase mass (preheparin LPL mass) at baseline was significantly higher in colestimide responders (greater than a 20% decrease of LDL-C: n=28) than non-responders (76.2 ng/ml versus 50.3 ng/ml, p<0.05: n=19). Next, the subjects were divided into those with a high (n=33) and low (n=14) preheparin LPL mass at baseline. LDL-C levels were significantly decreased in patients with a high preheparin LPL mass while TG levels were significantly increased in patients with a low preheparin LPL mass. These results suggest that baseline preheparin LPL mass may be a marker of the response to colestimide.
Asunto(s)
Resinas de Intercambio Aniónico/farmacología , Colesterol/sangre , Epiclorhidrina/farmacología , Hiperlipidemias/metabolismo , Imidazoles/farmacología , Lipoproteína Lipasa/sangre , Resinas Sintéticas/farmacología , Triglicéridos/sangre , Resinas de Intercambio Aniónico/uso terapéutico , Peso Corporal/efectos de los fármacos , Epiclorhidrina/uso terapéutico , Femenino , Humanos , Hiperlipidemias/tratamiento farmacológico , Imidazoles/uso terapéutico , Masculino , Persona de Mediana Edad , Resinas Sintéticas/uso terapéutico , Resultado del TratamientoRESUMEN
It is known that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) enhance the expression- of the low-density lipoprotein (LDL) receptor and lower the level of LDL cholesterol in the blood. But, a triglyceride (TG)-lowering effect is also observed during their administration. To clarify the possibility that statins enhance LPL activity and its mechanism, the effects of statins on the expression of LPL in adipocytes were studied. When statins (pravastatin, simvastatin, atorvastatin and pitavastatin) were added to the culture medium of mouse 3T3-L1 preadipocytes at final concentrations of 1 microM for 3 days, LPL activity increased. Pitavastatin increased the activity the most. Western and Northern blotting showed that LPL protein and m-RNA were strongly expressed on the addition of pitavastatin. With the addition of mevalonate (10 microM, 3 days), LPL activity weakened significantly. Statins, especially pitavastatin, increased the expression of LPL in 3T3-L1 preadipocytes. The TG-lowering effect of pitavastatin might be mediated by enhancement of LPL production in adipocytes.
Asunto(s)
Células 3T3-L1/efectos de los fármacos , Ácidos Heptanoicos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Lipoproteína Lipasa/metabolismo , Pravastatina/farmacología , Pirroles/farmacología , Quinolinas/farmacología , Simvastatina/farmacología , Células 3T3-L1/enzimología , Animales , Atorvastatina , Técnicas de Cultivo de Célula , Lipoproteína Lipasa/genética , Ácido Mevalónico/farmacología , Ratones , PPAR gamma/agonistas , Pioglitazona , ARN Mensajero/metabolismo , Tiazolidinedionas/farmacologíaRESUMEN
We saw a patient with proteinuria and characteristics of lipoprotein glomerulopathy (LPG). Histologic analysis of renal biopsy showed a thrombus-like substance in the markedly dilated glomerular capillaries, which stained positive with oil red O. Increased concentration of plasma apolipoprotein E (apoE) was also noted. Those findings are consistent with the diagnostic criteria of LPG, as reported by Oikawa et al. In isoelectric focusing gel electrophoresis of apoE, a band (apoE3') between apoE3 and E2 was observed. The patient's DNA sequence exhibited a C to G substitution in exon 3 of the apoE gene at the position of the 25th amino acid, resulting in an amino acid substitution of the arginine residue for cysteine residue. To clarify the pathophysiologic role of this mutation, we investigated the binding and the uptake of apoE3' triglyceride-rich lipoproteins to human umbilical vein endothelial cells (HUVEC). The binding of apoE3'-triglyceride-rich lipoproteins to the cell-surface of HUVEC increased up to 30% to 50%, compared with apoE3-triglyceride-rich lipoproteins. But the uptake of apoE3'-triglyceride-rich lipoproteins into the cells was not different between them. These findings are consistent with the idea that an increase in binding of triglyceride-rich lipoproteins possessing apoE (Arg(25)-->Cys) to endothelial cells may promote deposition of lipid in the glomerular capillaries.
Asunto(s)
Apolipoproteínas E/metabolismo , Arginina/química , Cisteína/química , Endotelio/metabolismo , Enfermedades Renales/metabolismo , Lipoproteínas/metabolismo , Triglicéridos/metabolismo , Adulto , Sustitución de Aminoácidos , Apolipoproteínas E/química , Endotelio/citología , Humanos , Focalización Isoeléctrica , Glomérulos Renales/embriología , Glomérulos Renales/patología , Lipoproteínas/química , MasculinoRESUMEN
In advanced atherosclerotic lesions, a decrease in smooth muscle cells is observed in the cap tissue. This causes the thinning of the cap, and may lead to plaque rupture. We studied the effect of deposited lipids on the migration of vascular smooth muscle cells, and identified the main cause of the effect. The lipids were extracted from atherosclerotic lesions in the human aorta at autopsy, and separated into three fractions with a Sep-Pak ODS cartridge. Then, each fraction was added to the lower part of a chemotaxis chamber, and cultured vascular smooth muscle cells to the upper part. After 4 hours incubation, the cells that had migrated to the opposite side were counted. The oxysterol-rich fraction (10 microg/ml) inhibited the migration, whereas the cholesterol ester and free cholesterol fractions did not. Finally, we tested the pure oxysterols, 7-ketocholesterol and 27-hydroxycholesterol. Both inhibited migration, whereas the free cholesterol and cholesterol ester did not. Oxysterols generated in the lipid pool might inhibit the migration of smooth muscle cells.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Lípidos/farmacología , Músculo Liso Vascular/citología , Músculo Liso Vascular/metabolismo , Arteriosclerosis/metabolismo , Arteriosclerosis/patología , Células Cultivadas , Colesterol/farmacología , Vasos Coronarios/citología , Humanos , Hidroxicolesteroles/farmacología , Cetocolesteroles/farmacología , Lípidos/aislamiento & purificaciónRESUMEN
We investigated the mechanism by which 7-ketocholesterol damages vascular smooth muscle cells and the protective effect of the hydroxymethyl glutary CoA reductase inhibitor, pravastatin on it. When 7-ketocholesterol (50 micromol/L) was added to cultured human vascular smooth muscle cells, the extent of cell detachment increased and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling was positive. DNA extracted from the smooth muscle cells exposed to 7-ketocholesterol showed a ladder pattern on agarose electrophoresis. The fragmented DNA also increased in smooth muscle cells incubated with 7-ketocholesterol dose-dependently. In the presence of pravastatin, the cell detachment induced by 7-ketocholesterol was inhibited and the amount of fragmented DNA decreased significantly. These effects of pravastatin were inhibited by mevalonate. The results suggest that 7-ketocholesterol-induced apoptosis of vascular smooth muscle cells is inhibited by pravastatin, and mevalonate acts as a trigger of the apoptosis.