RESUMO
BACKGROUND: B-type natriuretic peptide and the N-terminal fragment of its prohormone, N-terminal pro-brain natriuretic peptide (Nt-proBNP), provide valuable prognostic information on short- and long-term mortality in patients with acute coronary syndrome AIM: To investigate the association between plasma NT-proBNP levels and ST-segment resolution (STR) after reperfusion in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: Consecutive patients from the French regional RICO survey with STEMI who were treated by primary PCI or lysis <12 h were included. Blood sample was taken on admission to measure plasma NT-proBNP. Maximal ST segment elevation was measured on the single worst ECG lead before and 90 min after reperfusion. Patients were categorized as STR(-) (<50% STR) or STR(+) (>or=50% STR). RESULTS: Of the 486 patients included, 133 (27%) were STR(-). STR(-) patients had similar cardiovascular risk factors but higher in-hospital mortality (5% vs. 1%, p=0.03) than STR(+) patients. The STR(-) group had higher median (IQR) levels of Nt-proBNP: 938 (211-3272) vs. 533 (169-1471) pg/ml, p=0.003. On multivariate analysis, the highest quartile of Nt-ProBNP, Q waves and lysis were independent risk factors for incomplete STR. DISCUSSION: Our data show a strong association between high levels of Nt-proBNP at admission and incomplete STR, suggesting that Nt-proBNP may be useful for early risk stratification in reperfusion therapy after acute myocardial infarction.
Assuntos
Infarto do Miocárdio/sangue , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Idoso , Biomarcadores/metabolismo , Diagnóstico Precoce , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/terapia , Reperfusão Miocárdica/métodosRESUMO
OBJECTIVE: In type 2 diabetes mellitus, oxidized LDL/LDL-Cholesterol ratio, an accurate estimation of in vivo LDL oxidation, has been reported elevated and associated with macrovascular disease. Because insulin therapy induces significant modification of lipid metabolism, in type 2 diabetes, we evaluated the effect of insulin treatment on oxidized LDL/LDL-C ratio in type 2 diabetic patients and analyzed the results in comparison with the modifications induced by insulin on glycaemia, plasma lipids and LDL receptors. RESEARCH DESIGN AND METHODS: Plasma oxidized LDL concentrations were measured by sandwich ELISA in 21 type 2 diabetic patients before and 3 months after the introduction of insulin therapy, and in 27 age-matched controls. RESULTS: Type 2 diabetic patients had, compared to controls, significantly increased oxidized LDL/LDL-C ratio (P<0.0001). Three months after insulin treatment, oxidized LDL/LDL-C ratio was significantly reduced (21.1+/-4.7 vs. 24.0+/-5.8 U/mmol, P<0.01). This reduction was strongly associated, in multivariate analysis, with reduction of LDL(TG/cholesterol ratio) (P=0.008), and to a lesser extent with the decrease of LDL fructosamine (P=0.034), but not with the increase of the number of LDL receptors. CONCLUSIONS: In the present study we demonstrate for the first time a lowering effect of insulin therapy on oxidized LDL/LDL-C ratio in type 2 diabetic patients. This decrease is mainly associated with the reduction of LDL TG-enrichment, and to a lesser extent with the decrease of LDL glycation, but not with the insulin-induced increase in number of LDL receptors.
Assuntos
LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/uso terapêutico , Lipoproteínas LDL/sangue , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , HDL-Colesterol/sangue , Ensaio de Imunoadsorção Enzimática , Seguimentos , Humanos , Hipoglicemiantes/uso terapêutico , Pessoa de Meia-Idade , Peso Molecular , Valores de Referência , Triglicerídeos/sangueRESUMO
The study of high density lipoprotein (HDL) alterations induced by serum incubation was undertaken by a new approach. Subfractions of HDL were separated by gradient gel electrophoresis, without preliminary ultracentrifugation, and were characterized by their size range. After dissolution of the polyacrylamide gel, each subfraction was analyzed for its total- and unesterified-cholesterol content by gas chromatography. We have observed that a general displacement of HDL cholesterol towards the subspecies of high size range occurred during serum incubation at 37 degrees C, contemporaneously with cholesterol esterification. This displacement could not be identified with a HDL3 to HDL2 conversion since it occurred within HDL3 and HDL2. It is probably the indication of a complex HDL conversion leading to particles of increased sizes. HDL alterations occurring upon serum incubation appear to be the consequence of the activity of an HDL conversion factor, which is thermolabile, non-dialysable, present in the d greater than 1.25 serum fraction and differs from lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein. They could be considered as preliminary enzymatic transformations, necessary for the action of lecithin:cholesterol acyltransferase and as the first step of a metabolic sequence including, successively, HDL conversion, cholesterol esterification by lecithin:cholesterol acyltransferase and cholesteryl ester transfer.
Assuntos
Colesterol/sangue , Lipoproteínas HDL/sangue , Adulto , Animais , Sangue , Ésteres do Colesterol/sangue , HDL-Colesterol , Eletroforese em Gel de Poliacrilamida , Feminino , Temperatura Alta , Humanos , Lipoproteínas/sangue , Lipoproteínas HDL2 , Lipoproteínas HDL3 , Masculino , Pessoa de Meia-Idade , Coelhos , Ratos , Ratos Endogâmicos , Especificidade da EspécieRESUMO
High density lipoprotein (HDL) has been shown to induce the cellular accumulation of cholesterol esters and the biosynthetis of 21-hydroxysteroids (corticosteroids) newborn rat adrenocortical cells cultivated in serum-free medium. In order to identify the component(s) of HDL responsible for these effects, we investigated the ability of rat HDL subfractions and HDL with or without apolipoprotein E to deliver cholesterol to cells and to stimulate the steroid biosynthetic pathways in adrenal cultured cells. The total cholesterol uptake from HDL2 was greater than that observed with HDL rich in apolipoprotein E (HDL1 and HDLc). Furthermore, the increase of the ratio between 21-hydroxysteroids and reductive metabolites of progesterone was higher with HDL2 than with HDL1 or HDLc. The results of competitive studies between LDL and HDL subfractions indicate that adrenal cells take up cholesterol from HDL2 and LDL by separate mechanisms but that LDL and HDL containing apolipoprotein E share the same uptake processes. In experiments with various concentrations of HDLc or HDL without apolipoprotein E, the adrenal cells displayed a higher affinity for rat HDLc than for rat HDL without apolipoprotein E. However, HDL without apolipoprotein E produced a higher enhancement of the cholesterol cell content and was 3-fold more effective in stimulating 21-hydroxylated steroid production than rat HDLc. Although these findings suggest a participation of HDL with apolipoprotein E in the HDL interaction with rat adrenal cells, the predominant effect on these cells is devoluted to HDL containing mainly apolipoprotein A.
Assuntos
Corticosteroides/biossíntese , Córtex Suprarrenal/metabolismo , Apolipoproteínas E/farmacologia , Colesterol/metabolismo , Lipoproteínas HDL/farmacologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Lipoproteínas LDL/metabolismo , Camundongos , RatosRESUMO
BACKGROUND: Atherogenic lipoproteins can impair the endothelium-dependent arterial relaxation, and circumstantial evidence suggests a beneficial role of plasma high density lipoproteins and apolipoprotein (apo) A-I in counteracting the endothelium dysfunction. In the present study, vascular reactivity was determined in control, apoE-deficient mice (apoE-KO mice), and apoE-deficient mice expressing human apoA-I (apoE-KO/HuAITg mice). METHODS AND RESULTS: In the first part of the study, control and apoE-KO mice were fed a low-fat or a high-fat diet for 23 weeks, and the vasoactive responses of isolated thoracic aortic segments to norepinephrine, sodium nitroprusside, and acetylcholine (ACh) were determined. Whereas norepinephrine, sodium nitroprusside, and ACh evoked similar vascular responses in control and apoE-KO mice fed the low-fat diet, high-fat feeding in apoE-KO mice produced a significant 3-fold increase in the mean concentration required to produce a half-maximal relaxing effect (EC(50)) of ACh as compared with control mice. This reflects a weaker sensitivity to ACh of the aortic segments from the apoE-deficient animals. In the second part of the study, the mean EC(50) for ACh after high-fat feeding was found to be 4.4-fold lower in apoE-KO/HuAITg mice than in apoE-KO mice, indicating that the reduced sensitivity to ACh of the thoracic aorta from the apoE-KO mice fed the high-fat diet is improved by the expression of human apoA-I. CONCLUSIONS: The present study demonstrates that the endothelium-dependent arterial relaxation is impaired in apoE-KO mice fed the high-fat diet. The endothelium dysfunction tends to be normalized by human apoA-I expression.
Assuntos
Apolipoproteína A-I/fisiologia , Apolipoproteínas E/deficiência , Gorduras na Dieta/administração & dosagem , Endotélio Vascular/fisiologia , Vasodilatação/fisiologia , Acetilcolina/farmacologia , Animais , Apolipoproteína A-I/análise , Arteriosclerose/fisiopatologia , Dieta Aterogênica , Feminino , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nitroprussiato/farmacologia , Norepinefrina/farmacologia , Vasodilatadores/farmacologiaRESUMO
7-Ketocholesterol is a component of oxidized LDL, which plays a central role in atherosclerosis. It is a potent inducer of cell death towards a wide number of cells involved in atherosclerosis. In this study, it is reported that 7-ketocholesterol treatment induces an increase of cytosolic-free Ca(2+) in THP-1 monocytic cells. This increase is correlated with the induction of cytotoxicity as suggested from experiments using the Ca(2+) channel blockers verapamil and nifedipine. This 7-ketocholesterol-induced apoptosis appears to be associated with the dephosphorylation of serine 75 and serine 99 of the proapoptotic protein Bcl-2 antagonist of cell death (BAD). We demonstrated that this dephosphorylation results mainly from the activation of calcium-dependent phosphatase calcineurin by the oxysterol-induced increase in Ca(2+). Moreover, this Ca(2+) increase appears related to the incorporation of 7-ketocholesterol into lipid raft domains of the plasma membrane, followed by the translocation of transient receptor potential calcium channel 1, a component of the store operated Ca(2+) entry channel, to rafts.
Assuntos
Apoptose/fisiologia , Canais de Cálcio/metabolismo , Cálcio/metabolismo , Proteínas de Transporte/metabolismo , Cetocolesteróis/farmacologia , Apoptose/efeitos dos fármacos , Calcineurina/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Membrana Celular/metabolismo , Células Cultivadas , Genes bcl-2/fisiologia , Humanos , Microdomínios da Membrana/metabolismo , Monócitos/metabolismo , Nifedipino/farmacologia , Fosforilação , Serina/metabolismo , Canais de Cátion TRPC , Verapamil/farmacologia , Proteína de Morte Celular Associada a bclRESUMO
Biological activities of oxysterols seem tightly regulated. Therefore, the ability to induce cell death of structurally related oxysterols, such as those oxidized at C7(7alpha-, 7beta-hydroxycholesterol, and 7-ketocholesterol), was investigated on U937 cells at different times of treatment in a concentration range of 5-80 microg/ml. Whereas all oxysterols accumulate inside the cells, strong inhibition of cell growth and increased permeability to propidium iodide were observed only with 7beta-hydroxycholesterol and 7-ketocholesterol, which trigger an apoptotic process characterized by the occurrence of cells with fragmented and/or condensed nuclei, and by various cellular dysfunctions: loss of mitochondrial transmembrane potential, cytosolic release of cytochrome c, activation of caspase-9 and -3 with subsequent enhanced activity of caspase-3, degradation of poly(ADP-ribose) polymerase, and increased accumulation of cellular C16 : 0 and C24 : 1 ceramide species. This ceramide generation is not attributed to caspase activation since inhibition of 7beta-hydroxycholesterol- and 7-ketocholesterol-induced apoptosis by Z-VAD-fmk (100 microM), a broad spectrum caspase inhibitor, did not reduce C16 : 0 and C24 : 1 ceramide species accumulation. Conversely, when U937 cells were treated with 7beta-hydroxycholesterol and 7-ketocholesterol in the presence of fumonisin B1 (100 microM), a specific inhibitor of ceramide synthase, C16 : 0 and C24 : 1 ceramide species production was completely abrogated whereas apoptosis was not prevented. Noteworthy, 7alpha-hydroxycholesterol induced only a slight inhibition of cell growth. Collectively, these results are consistent with the notion that the alpha or beta hydroxyl radical position of oxysterols oxidized at C7 plays a key role in the induction of the apoptotic process. In addition, our findings demonstrate that 7beta-hydroxycholesterol- and 7-ketocholesterol-induced apoptosis involve the mitochondrial signal transduction pathway and they suggest that C16 : 0 and C24 : 1 ceramide species generated through ceramide synthase play a minor role in the commitment of 7beta-hydroxycholesterol- and 7-ketocholesterol-induced cell death.
Assuntos
Apoptose , Caspases/metabolismo , Ceramidas/biossíntese , Fumonisinas , Hidroxicolesteróis/farmacologia , Cetocolesteróis/farmacologia , Células U937/efeitos dos fármacos , Clorometilcetonas de Aminoácidos/farmacologia , Apoptose/efeitos dos fármacos , Ácidos Carboxílicos/farmacologia , Caspase 3 , Caspase 9 , Inibidores de Caspase , Morte Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Grupo dos Citocromos c/metabolismo , Citosol/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Humanos , Hidroxicolesteróis/farmacocinética , Cetocolesteróis/farmacocinética , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Propídio/farmacocinética , Células U937/citologia , Células U937/metabolismoRESUMO
Apolipoprotein A-IV (apoA-IV) might play an important role in lipoprotein metabolism, including modulation of triglyceride-rich lipoprotein catabolism, reverse cholesterol transport and cholesteryl ester transfer protein (CETP) activity. Increased apoA-IV levels have been reported in plasma from NIDDM patients. The aim of the present study was to look for a possible association between plasma apoA-IV level and prevalence of macrovascular disease in NIDDM. One hundred and thirty-six NIDDM patients were studied (71 men, 65 women). Macrovascular disease was assessed in each patient by a standardized questionnaire, physical examination, resting electrocardiogram (ECG), and laboratory evaluation (ankle/arm blood pressure ratio, continuous wave Doppler velocimetry). Moreover, patients without any history of coronary heart disease and showing a normal resting ECG underwent a bicycle exercise test or a dipyridamole thallium scintigraphy to detect possible silent myocardial ischemia. Among the 136 NIDDM patients, 56 had macrovascular disease. ApoA-IV levels were significantly higher in NIDDM patients with macrovascular disease than in NIDDM patients without macrovascular disease (20.9 +/- 8.6 vs. 13.3 +/- 5.3 mg/dl; P < 0.001). The influence of different factors, such as age, BMI, cigarette smoking, hypertension, total cholesterol, triglycerides, HDL cholesterol, apoA-IV level, apoA-IV phenotype, fasting glycemia, fasting C-peptide, and microalbuminuria, on the prevalence of macrovascular disease was analyzed using a logistic regression model. In the univariate analysis, apoA-IV level (P < 0.00001), age (P = 0.0087), hypertension (P = 0.012), microalbuminuria (P = 0.018), triglycerides (P = 0.02), and fasting C-peptide (P = 0.03) were positively associated with macrovascular disease. In the multivariate analysis, macrovascular disease was positively associated only with apoA-IV (P < 0.0001) and age (P = 0.003) and negatively associated with HDL cholesterol (P = 0.013). These results indicate that increased plasma apoA-IV level is associated with an increased prevalence of macrovascular disease in NIDDM. Moreover, apoA-IV, in NIDDM patients, appears to be a better marker for macrovascular disease than triglycerides.
Assuntos
Apolipoproteínas A/sangue , Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/sangue , Biomarcadores/sangue , Glicemia/metabolismo , Pressão Sanguínea , Transtornos Cerebrovasculares , Colesterol/sangue , HDL-Colesterol/sangue , Diabetes Mellitus/sangue , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/fisiopatologia , Dipiridamol , Eletrocardiografia , Teste de Esforço , Feminino , Humanos , Hipertensão/epidemiologia , Claudicação Intermitente , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/diagnóstico por imagem , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/fisiopatologia , Obesidade , Fenótipo , Prevalência , Cintilografia , Valores de Referência , Análise de Regressão , Caracteres Sexuais , Inquéritos e Questionários , Radioisótopos de TálioRESUMO
OBJECTIVE: To determine plasma apolipoprotein A-IV (apoA-IV) levels and phenotype distribution in non-insulin-dependent diabetes mellitus (NIDDM) patients and to analyze the influence of apoA-IV phenotype on lipid profiles in NIDDM. RESEARCH DESIGN AND METHODS: Total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, HDL2 cholesterol, HDL3 cholesterol, free fatty acid, and apoA-IV levels were measured in 83 NIDDM patients and 100 normal control subjects. The apoA-IV phenotype was determined in each individual. RESULTS: In both sexes, NIDDM patients had significantly higher levels of triglyceride and free fatty acid and significantly lower levels of HDL cholesterol and HDL2 cholesterol than control subjects. In men and women, apoA-IV levels were significantly higher in diabetic patients than in control subjects (men: 17.1 +/- 7.9 vs. 12.3 +/- 3.6 mg/dl, P < 0.001; women: 18.9 +/- 9.9 vs. 11.9 +/- 3.5 mg/dl, P < 0.001). The multiple regression analysis showed that the apoA-IV level in NIDDM patients was significantly and independently related to log triglyceride (P = 0.0001) and HDL cholesterol (P = 0.01) levels. The apoA-IV phenotype distribution was not significantly different between NIDDM patients and control subjects. In the control subjects, the apoA-IV-1-2 phenotype was associated with significantly higher levels of HDL cholesterol (69 +/- 12 vs. 56 +/- 11 mg/dl, P < 0.01) and of HDL2 cholesterol (36 +/- 15 vs. 25 +/- 12 mg/dl, P < 0.05) compared with the apoA-IV-1-1 phenotype; on the other hand, HDL cholesterol and HDL2 cholesterol levels were not different between the two apoA-IV phenotypes in NIDDM patients. CONCLUSIONS: Plasma apoA-IV levels are increased in NIDDM patients. This increase in apoA-IV is related mainly to hypertriglyceridemia and, to a lesser extent, to HDL cholesterol level. The apoA-IV phenotype distribution is not different between NIDDM patients and nondiabetic control subjects. The potential protective lipid profile (characterized by increased HDL and HDL2 cholesterol levels) linked with apoA-IV-1-2 phenotype in control subjects is no longer found in NIDDM patients. We suggest that the metabolic state of NIDDM has erased the potential protective lipid profile associated with the apoA-IV-1-2 phenotype.
Assuntos
Apolipoproteínas A/sangue , Diabetes Mellitus Tipo 2/sangue , Apolipoproteínas A/genética , Glicemia/metabolismo , Peptídeo C/sangue , Colesterol/sangue , HDL-Colesterol/sangue , Ácidos Graxos não Esterificados/sangue , Feminino , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo , Valores de Referência , Análise de Regressão , Caracteres Sexuais , Triglicerídeos/sangueRESUMO
The oxysterols, 7beta-hydroxycholesterol and 7-ketocholesterol, are involved in the cytotoxicity of oxidized LDL. To elucidate their molecular mechanisms, the human promonocytic leukemia cells U937 and U4 were used. U4 cells overexpressing Bcl-2 were obtained by transfection of U937 cells. 7Beta-hydroxycholesterol and 7-ketocholesterol induced nuclear condensation and/or fragmentation, internucleosomal DNA fragmentation, and IL-1beta secretion, which were partially inhibited by Bcl-2 overexpression. These findings underline that these oxysterols could constitute major risk factors in atherosclerosis by their cytotoxicity and their ability to induce IL-1beta release which might favor the recruitment of immunocompetent cells in the atherosclerotic plaque.
Assuntos
Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hidroxicolesteróis/farmacologia , Interleucina-1/metabolismo , Cetocolesteróis/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Apoptose/genética , Humanos , Leucemia/metabolismo , Leucemia/patologia , Células Tumorais CultivadasRESUMO
Among oxysterols oxidized at C7 (7alpha-, 7beta-hydroxycholesterol, and 7-ketocholesterol), 7beta-hydroxycholesterol and 7-ketocholesterol involved in the cytotoxicity of oxidized low density lipoproteins (LDL) are potent inducers of apoptosis. Here, we asked whether all oxysterols oxidized at C7 were able to trigger apoptosis, to stimulate interleukin (IL)-Ibeta and/or tumor necrosis factor (TNF)-alpha secretion, and to enhance adhesion molecule expression (intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin) on human umbilical venous endothelial cells (HUVECs). Only 7beta-hydroxycholesterol and 7-ketocholesterol were potent inducers of apoptosis and of IL-1beta secretion. TNF-alpha secretion was never detected. Depending on the oxysterol considered, various levels of ICAM-1, VCAM-1 and E-selectin expression were observed. So, oxysterols oxidized at C7 differently injure and activate HUVECs, and the alpha- or beta-hydroxyl radical position plays a key role in apoptosis and IL-1beta secretion.
Assuntos
Apoptose/fisiologia , Moléculas de Adesão Celular/biossíntese , Endotélio Vascular/efeitos dos fármacos , Hidroxicolesteróis/farmacologia , Interleucina-1/metabolismo , Cetocolesteróis/farmacologia , Arteriosclerose/metabolismo , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Selectina E/biossíntese , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/biossíntese , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/biossínteseRESUMO
Previous investigations of our laboratory have shown that 7-ketocholesterol was a potent inducer of apoptosis involving a release of cytochrome c into the cytosol, and a lipid peroxidation process that could be the consequence of a production of radical oxygen species. According to these considerations, we asked whether some antioxidants were able to counteract 7-ketocholesterol-induced apoptosis, and whether prevention of cell death was associated with the impairment of mitochondrial events implied in the commitment to apoptosis, i.e., opening of the mitochondrial megachannels leading to the loss of the mitochondrial transmembrane potential (DeltaPsim), and release of cytochrome c from mitochondria into the cytosol. To this end, we studied the effects of glutathione (15 mM), N-acetylcysteine (15 mM), vitamin E (100 microM), vitamin C (50 microM) and melatonin (1 mM) on U937 cells treated with 7-ketocholesterol (40 microg/ml). Only glutathione, N-acetylcysteine, and vitamin E prevented apoptosis measured by the occurrence of cells with condensed and/or fragmented nuclei, as well as the loss of DeltaPsim, and the release of cytochrome c. However, all the antioxidants used were potent inhibitors of the production of O(2)(*) occuring under treatment with 7-ketocholesterol. Collectively, our data demonstrate that impairment of apoptosis by glutathione, N-acetylcysteine, and vitamin E correlates with the prevention of mitochondrial dysfunctions, and they underline that the ability of antioxidants to counteract 7-ketocholesterol-induced apoptosis does not only depend on their capability to inhibit the production of O(2)(*).
Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cetocolesteróis/farmacologia , Acetilcisteína/farmacologia , Apoptose/fisiologia , Ácido Ascórbico/farmacologia , Grupo dos Citocromos c/metabolismo , Citosol/efeitos dos fármacos , Citosol/metabolismo , Radicais Livres/metabolismo , Glutationa/farmacologia , Humanos , Membranas Intracelulares/efeitos dos fármacos , Membranas Intracelulares/metabolismo , Cinética , Melatonina/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Microscopia Eletrônica , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Superóxidos/metabolismo , Células U937 , Vitamina E/farmacologiaRESUMO
We report 3 sisters treated for cerebrotendinous xanthomatosis. We treated one, with a severe neurologic form of the illness, with chenodeoxycholic acid, then lovastatin and simvastatin. These drugs had different efficacy and tolerance, but induced no clinical improvement. Her sisters, without neurologic symptoms, received chenodeoxycholic acid, which normalized the cholestanol level. Optimal treatment of this illness must begin before there is significant clinical symptomatology.
Assuntos
Encefalopatias/tratamento farmacológico , Ácido Quenodesoxicólico/uso terapêutico , Lovastatina/análogos & derivados , Lovastatina/uso terapêutico , Tendões , Xantomatose/tratamento farmacológico , Adulto , Anticolesterolemiantes/uso terapêutico , Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Feminino , Humanos , Doenças Musculares/diagnóstico por imagem , Doenças Musculares/tratamento farmacológico , Doenças Musculares/genética , Sinvastatina , Tomografia Computadorizada por Raios X , Xantomatose/diagnóstico por imagem , Xantomatose/genéticaRESUMO
The immunoreactivity of human apolipoprotein B (apo B) towards 5 monoclonal antibodies was studied by enzyme immunoassay in native and in vitro oxidized low density lipoproteins (LDL). LDL oxidative modifications were obtained by incubation with either copper ions or an association of lipoxygenase and phospholipase A2. The monoclonal antibodies used in the inhibition analysis were directed to epitopes located in the amino-terminal region (1D1), in the middle part (2D8, L7, 4G3) and in the carboxy-terminal region (L3) of the apo B molecule. The results demonstrated that the immuno-reactivity of 1D1 epitope was little affected by LDL oxidation with copper ions or lipoxygenase plus phospholipase A2, whereas the immunoreactivity of the other epitopes were markedly decreased by these LDL modifications. Immunoreactivity changes were more important in L3 and L7 epitopes than in 2D8 and 4G3 epitopes. Since it is known that L3 and L7 epitopes are located in apo B domains rich in lipid-associated peptides whereas 1D1 is in a domain poor in such peptides, these results suggest a relationship between the lipid environment of an apo B epitope and its susceptibility to alteration by LDL oxidation.
Assuntos
Apolipoproteínas B/imunologia , Epitopos/imunologia , Lipoproteínas LDL/metabolismo , Anticorpos Monoclonais , Cromatografia em Gel , Cobre , Eletroforese em Gel de Poliacrilamida , Humanos , Lipoproteínas LDL/imunologia , Lipoxigenase , Oxirredução , Fosfolipases A , Fosfolipases A2RESUMO
Non-insulin-dependent diabetes mellitus (NIDDM) is associated with low high density lipoprotein (HDL) cholesterol and apoA-I, related to an increased apoA-I fractional catabolic rate. This stable isotope kinetic experiment, using L-[1-(13)C] leucine, was designed to study the effect of insulin therapy on HDL apoA-I and A-II metabolism in poorly controlled NIDDM patients. A kinetic study was performed in five control subjects and in six NIDDM patients before and two months after the introduction of insulin therapy. ApoA-I and A-II were modelled using a monoexponential function. Insulin treatment was able to correct neither the low HDL apoA-I concentration observed in NIDDM patients (1.14+/-0.19 vs. 1.16+/-0. 12 g l(-1) (controls: 1.33+/-0.14)), nor the HDL apoA-I hypercatabolism (0.39+/-0.11 vs. 0.34+/-0.05 pool d(-1), (controls: 0.23+/-0.01, P< 0.01)). HDL apoA-I production rate was increased in NIDDM patients compared to control subjects and was not modified by insulin (0.45+/-0.12 vs. 0.39+/-0.08 g d(-1) l(-1), (controls: 0. 31+/-0.04, P< 0.05)). HDL apoA-II kinetic parameters were initially not significantly different between NIDDM patients and control subjects, and were not modified by insulin. The decreased insulin sensitivity, assessed by the insulin suppressive test, was not modified by insulin therapy in NIDDM patients. HDL apoA-I fractional catabolic rate was significantly correlated to HDL triglyceride/cholesteryl ester and triglyceride/protein ratios, which were significantly higher in NIDDM patients than in controls and were not modified by insulin therapy. The persistence of insulin resistance and of high neutral lipid exchanges between triglyceride rich lipoproteins and HDL in insulin-treated NIDDM patients probably explain the inefficiency of insulin therapy to correct HDL apoA-I metabolic abnormalities.
Assuntos
Apolipoproteína A-I/efeitos dos fármacos , Apolipoproteína A-I/metabolismo , Proteínas de Transporte/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicoproteínas , Insulina/administração & dosagem , Metabolismo dos Lipídeos , Adulto , Idoso , Proteínas de Transporte/análise , Proteínas de Transferência de Ésteres de Colesterol , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Resistência à Insulina , Cinética , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Probabilidade , Valores de Referência , Estatísticas não Paramétricas , Falha de TratamentoRESUMO
The aim of the present study was to search in type IIb hyperlipidemic patients for putative concomitant effects of simvastatin on the physicochemical characteristics of low density lipoproteins (LDL) and high density lipoproteins (HDL), as well as on the activities of the cholesteryl ester transfer protein (CETP) and the phospholipid transfer protein (PLTP) that were determined in both endogenous lipoprotein-dependent and endogenous lipoprotein-independent assays. In a double-blind, randomized trial, patients received either placebo (one tablet/day; n = 12) or simvastatin (20 mg/day; n = 12) for a period of 8 weeks after a 5-week run-in period. Simvastatin, unlike placebo, reduced the lipid and apolipoprotein B contents of the most abundant LDL-1, LDL-2, and LDL-3 subfractions without inducing significant changes in the overall size distribution of LDL and HDL. Whereas simvastatin significantly increased PLTP activity in an endogenous lipoprotein-dependent assay (P < 0.01), no variation was observed in a lipoprotein-independent assay. Simvastatin significantly decreased plasma CETP activity in an endogenous lipoprotein-dependent assay (P < 0.01), and the reduction in plasma cholesteryl ester transfer rates was explained by a 16% drop in CETP mass concentration (P < 0.01). In contrast, the specific activity of CETP was unaffected by the simvastatin treatment reflecting at least in part the lack of significant alteration in plasma triglyceride-rich lipoprotein acceptors. The simvastatin-induced changes in plasma CETP mass levels correlated positively with changes in plasma CETP activity (r = 0.483, P = 0.0561), in total cholesterol levels (r = 0.769; P < 0.01), and in LDL-cholesterol levels (r = 0.736; P < 0.01). Whereas the observations suggest that simvastatin might exert concomitant beneficial effects on plasma CETP and LDL levels, neither plasma cholesteryl ester transfer activity nor plasma phospholipid transfer activity appeared as the main determinants of the LDL and HDL distribution profiles in type IIb hyperlipidemic patients.
Assuntos
Proteínas de Transporte/efeitos dos fármacos , Glicoproteínas , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Transferência de Fosfolipídeos , Sinvastatina/administração & dosagem , Adulto , Idoso , Proteínas de Transporte/sangue , Proteínas de Transferência de Ésteres de Colesterol , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas HDL/efeitos dos fármacos , Lipoproteínas LDL/sangue , Lipoproteínas LDL/efeitos dos fármacos , Masculino , Proteínas de Membrana/sangue , Pessoa de Meia-Idade , Valores de Referência , Resultado do TratamentoRESUMO
A number of studies have reported that a variant allele (S2) of the apo AI/CIII/AIV complex is associated with high plasma lipid levels in some populations and furthermore that the frequency of this allele is 2-5-fold higher in patient groups with premature coronary heart disease compared to control groups. This study shows in the healthy "English" population that the S2 allele is associated with elevated plasma apo CIII levels but not with low apo AI levels. In addition, it shows that the allele is associated with elevated plasma levels of apo B in men. Regression analysis shows in both men and women that apo CIII levels are positively correlated with plasma triglyceride levels and moreover that they are a stronger predictor of this parameter than apo AI, B or AIV. Apo CIII levels are also an independent predictor of total plasma cholesterol and HDL-cholesterol levels in males and females, respectively. Together these data suggest that a genetic predisposition to develop elevated plasma levels of apo CIII, alone or in combination with elevated plasma apo AIV levels, is the primary defect responsible for the association of the S2 allele with hyperlipidemia and/or premature CHD.
Assuntos
Apolipoproteínas A/genética , Apolipoproteínas C/sangue , Apolipoproteínas C/genética , Adulto , Alelos , Apolipoproteína A-I , Apolipoproteína C-III , Apolipoproteínas A/sangue , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo Genético , Triglicerídeos/sangueRESUMO
Cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) activities were measured in sera from 32 normolipidemic women and men consuming diets enriched in lauric, palmitic, or oleic acids. Serum CETP activity, measured as the rate of radiolabeled cholesteryl esters transferred from HDL toward serum apo B-containing lipoproteins, was higher with the palmitic acid diet (25.1+/-2.5%) than with the lauric acid (23.7+/-2.4%) and the oleic acid (24.0+/-2.7%) diets (P = 0.0028 and 0.0283, respectively). CETP mass concentrations, as measured with an enzyme-linked immunosorbent assay were increased after the lauric acid diet (2.57+/-0.63 mg/l) and the palmitic acid diet (2.49+/-0.64 mg/l) as compared with the oleic acid diet (2.34+/-0.45 mg/l) (P = 0.0035 and 0.0249, respectively). In contrast with CETP, serum PLTP activity, as measured as the rate of radiolabeled phosphatidylcholine transferred from liposomes toward serum HDL, was significantly higher with the lauric acid diet (23.5+/2.6%) than with the palmitic acid diet (22.5+/-2.5%) (P = 0.0013), while no significant differences were noted when comparing the saturated diets versus the oleic acid diet (23.0+/-2.3%). No significant alterations in the mean apparent diameter of LDL, and in the relative proportions of individual HDL subpopulations were observed from one dietary period to another. Nevertheless, lipid transfer activities correlated significantly with the relative abundance of HDL2b, HDL2a, HDL3b, and HDL3c, with opposite tendencies being observed for cholesteryl ester transfer and phospholipid transfer activities. In general, serum CETP activity correlated negatively with HDL cholesterol, but positively with triglyceride concentrations after the dietary interventions, and the relations with serum lipids were just the opposite for PLTP activity. In addition, CETP and PLTP activities correlated negatively when subjects consumed the standardized diets (P < 0.05 in all cases), but not when subjects consumed their habitual diet. It is concluded that serum lipid transfer activities in normolipidemic subjects can be significantly affected by the fatty acid content of the diet, with differential effects on CETP and PLTP activities.
Assuntos
Proteínas de Transporte/sangue , Gorduras na Dieta/administração & dosagem , Glicoproteínas , Ácidos Láuricos/administração & dosagem , Proteínas de Membrana/sangue , Ácido Oleico/administração & dosagem , Ácido Palmítico/administração & dosagem , Proteínas de Transferência de Fosfolipídeos , Adulto , Proteínas de Transferência de Ésteres de Colesterol , Ésteres do Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/etiologia , Masculino , Pessoa de Meia-Idade , Fosfolipídeos/sangue , Valores de Referência , Triglicerídeos/sangueRESUMO
The authors investigated the relationship between plasma lipids and the risk for cortical infarction (61 cases) and transient ischaemic attacks (TIA) (35 cases) compared with matched controls. They observed a maximal increase of total cholesterol, of very low-density lipoprotein and low-density lipoprotein (LDL), triglycerides, total apolipoprotein (Apo), B,LDL-Apo B and Apo-A1, and small size high-density lipoprotein (HDL) and large size HDL whose separation was not possible. In contrast they observed a decrease of HDL-ApoE, a distribution of LDL in a single fraction and the presence of LDL of low weight in the group with cortical infarction with or without cardiac arrhythmias. For the first time, we describe a decrease of the HDL-ApoE/total ApoE ratio. TIA differed from the former group by a low level of HDL and the lack of abnormalities of Apo-A1, distribution of small and large size HDL, and in the distribution and the weight of LDL. These data suggest that previously demonstrated differences in LDL-cholesterol and HDL-cholesterol levels between patients with ischaemic stroke and control subjects may apply to patients with cortical infarction, and that in TIA there are changes in the distribution and the weight of LDL.
Assuntos
Infarto Cerebral/sangue , Ataque Isquêmico Transitório/sangue , Lipoproteínas/sangue , Idoso , Estudos de Casos e Controles , Córtex Cerebral , Feminino , Humanos , Masculino , Estudos Prospectivos , Fatores de RiscoRESUMO
The influence of native low-density lipoprotein (LDL) on the inhibition of endothelium-dependent relaxation previously induced by oxidized LDL was investigated with intact rabbit aortic rings. We also tried to assess oxysterol involvement in the native lipoprotein effects. Lipoprotein fractions (1 mg protein/ml) were tested for their ability to inhibit the vasorelaxation induced by acetylcholine in aorta rings previously precontracted by noradrenaline vs. that in control strips in Krebs buffer. Co-incubation of oxidized and native LDL reinforced the oxidized LDL-induced inhibition, compared to the impairment evoked by oxidized LDL alone (E(max)=43.3+/-6.7% and 61. 4+/-5.4%, respectively; P<0.05). Finally, smaller amounts of 7-oxy-cholesterols were recovered in organ baths after co-incubation of native and oxidized LDL than after incubation of oxidized LDL alone. Conversely, more oxy-cholesterols were found in the strip vessels under the same conditions (% of oxysterol incorporation: 0. 05158 vs. 0.10199, r=0.703). Together these results suggest that the strengthening of oxidized LDL-induced inhibition by native LDL is dependent on an oxysterol effect on arterial wall cells. Mechanisms involved in this phenomenon remain to be investigated.