RESUMO
A one-year-and-nine-month-old Japanese boy was admitted with hypertriglyceridemia (fasting triglycerides 2548 mg/dL). After close examination, he was diagnosed with lipoprotein lipase (LPL) deficiency (compound heterozygous) and was immediately started on a fat-restricted dietary therapy. He responded well to the regimen (1200 kcal/day, 20 g fat/day) and his triglycerides decreased to 628 mg/dL within 7 days of starting the dietary therapy. It was decided to manage his illness without using any drugs because he was still an infant and responded well to a fat-restricted diet. During his hospital stay, dietitians provided him with nutritional counseling using a food exchange list, which was designed to easily calculate the fat content by including foods that are commonly served. His family quickly learned the skills to prepare a fat-restricted diet. Moreover, since dietary restrictions may have impaired the child's growth and development, the dietitians continued to intervene regularly after the child was discharged from the hospital. The dietitians confirmed that the patient was receiving nutritional intake appropriate for his growth and discussed the dietary concerns in his daily life and how to participate in school events that involved eating and drinking. Nutritional counseling was provided every 3-4 months from disease onset to age 23 years, except for a 14-month break at age 20 years. The patient grew up without developing acute pancreatitis, a serious complication of LPL deficiency. The long-term intervention of dieticians is necessary to achieve a balance between living on a strict diet for disease management and ensuring appropriate nutritional intakes for growth/development.
Assuntos
Hiperlipoproteinemia Tipo I , Pancreatite , Humanos , Criança , Lactente , Masculino , Adulto Jovem , Adulto , Hiperlipoproteinemia Tipo I/terapia , Doença Aguda , Aconselhamento , Triglicerídeos , Lipase LipoproteicaRESUMO
We previously suggested that the consumption of natto and viscous vegetables as part of a Japanese-style meal based on white rice (WR) reduced postprandial glucose and insulin levels in healthy subjects. The aim of the present study was to assess whether a single breakfast of natto and viscous vegetables or the same breakfast consumed for 2 weeks could improve glucose control, insulin sensitivity, lipid metabolism and oxidative stress in overweight subjects with impaired glucose tolerance (IGT). A total of eleven free-living subjects with IGT followed a randomised, crossover breakfast intervention for 2 weeks. The test meal included boiled WR with natto (viscous fermented soyabeans), Japanese yam and okra. The control meal included WR with non-viscous boiled soyabeans, potatoes and broccoli. Both meals contained comparable amounts of carbohydrate, fat, protein and fibre. The test meal reduced acute glucose and insulin responses compared to the control meal in the study participants. Insulin sensitivity was assessed using the composite insulin sensitivity index (CISI) after both the test and control meal periods. The test meal resulted in improvements in CISI compared to the baseline, whereas no significant changes were observed after the control meal period. Serum levels of both total and LDL-cholesterol were assessed before and after the test meal period and found to decrease significantly. There was also a tendency towards reduced serum malondialdehyde-modified LDL and N(É)-carboxymethyllysine. No differences were observed in the measures of chronic glycaemic control. Thus, we conclude that a breakfast of natto and viscous vegetables consumed for 2 weeks improves insulin sensitivity, serum lipid and oxidative stress.
Assuntos
Intolerância à Glucose/complicações , Intolerância à Glucose/dietoterapia , Sobrepeso/complicações , Sobrepeso/dietoterapia , Alimentos de Soja , Verduras , Adulto , Biomarcadores/sangue , LDL-Colesterol/sangue , Estudos Cross-Over , Feminino , Intolerância à Glucose/metabolismo , Humanos , Resistência à Insulina , Japão , Metabolismo dos Lipídeos , Lipídeos/sangue , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Sobrepeso/metabolismo , Estresse Oxidativo , ViscosidadeRESUMO
BACKGROUND: The aim of the present study was to determine whether nutrition assessment helps predict clinical outcomes (COs) in infants who have undergone cardiac surgery. METHODS: Study subjects were infants, aged less than 18 months, who had undergone cardiac surgery between April 2007 and August 2008. The nutrition parameters assessed include Onodera's prognostic nutritional index (PNI), height for age, weight for height, and weight for age. COs included mortality rate during hospitalization, length of stay in intensive care unit (LOS-1), length of stay in the hospital after surgery (LOS-2), and duration of mechanical ventilation support. Method-1: the correlation between nutrition parameters and COs was examined by statistical analysis. Method-2: the cutoff point of nutrition parameters was determined using the minimum P value approach. RESULTS: The following results were obtained: Results-1: PNI was the only nutrition parameter found to be correlated with LOS-1. Results-2: the cutoff point for PNI as a predictor of LOS-1 was 55. CONCLUSIONS: It appeared that preoperative PNI was the most influential factor on LOS-1 for infants after they underwent cardiac surgery. The PNI cutoff point 55 in infants who underwent cardiac surgery seems to be the best predictor of CO.
Assuntos
Avaliação Nutricional , Estado Nutricional/fisiologia , Avaliação de Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/epidemiologia , Procedimentos Cirúrgicos Torácicos , Feminino , Mortalidade Hospitalar , Humanos , Lactente , Fenômenos Fisiológicos da Nutrição do Lactente/fisiologia , Recém-Nascido , Tempo de Internação , Masculino , Valor Preditivo dos Testes , Prognóstico , Respiração Artificial , Fatores de Risco , Resultado do TratamentoRESUMO
OBJECTIVE: Diabetes mellitus is associated with increased oxidative stress, which induces oxidation of tetrahydrobiopterin (BH4) in vessel wall. Without enough BH4, eNOS is uncoupled to L-arginine and produces superoxide rather than NO. We examined the role of uncoupled eNOS in vascular remodeling in diabetes. METHODS AND RESULTS: Diabetes mellitus was produced by streptozotocin in C57BL/6J mice. Under stable hyperglycemia, the common carotid artery was ligated, and neointimal formation was examined 4 weeks later. In diabetic mice, the neointimal area was dramatically augmented. This augmentation was associated with increased aortic superoxide formation, reduced aortic BH4/dihydrobiopterin (BH2) ratio, and decreased plasma nitrite and nitrate (NOx) levels compared with nondiabetic mice. Chronic BH4 treatment (10 mg/kg/d) reduced the neointimal area in association with suppressed superoxide production and inflammatory changes in vessels. BH4/BH2 ratio in vessel wall was preserved, and plasma NOx levels increased. Furthermore, in the presence of diabetes, overexpression of bovine eNOS resulted in augmentation of neointimal area, accompanied by increased superoxide production in the endothelium. CONCLUSIONS: In diabetes, increased oxidative stress by uncoupled NOSs, particularly eNOS, causes augmentation of vascular remodeling. These findings indicate restoration of eNOS coupling has an atheroprotective benefit in diabetes.
Assuntos
Artérias Carótidas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Endotélio Vascular/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Aorta/metabolismo , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Biopterinas/farmacologia , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Colesterol/sangue , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , GTP Cicloidrolase/metabolismo , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nitratos/sangue , Nitritos/sangue , Estreptozocina , Superóxidos/metabolismoRESUMO
The long-term benefits of nitroglycerin therapy are limited by tolerance development. Understanding the precise nature of mechanisms underlying nitroglycerin-induced endothelial cell dysfunction may provide new strategies to prevent tolerance development. In this line, we tested interventions to prevent endothelial dysfunction in the setting of nitrate tolerance. When bovine aortic endothelial cells (BAECs) were continuously treated with nitric oxide (NO) donors, including nitroglycerin, over 2-3 days, basal production of nitrite and nitrate (NO(x)) was diminished. The diminished basal NO(x) levels were mitigated by intermittent treatment allowing an 8-h daily nitrate-free interval during the 2- to 3-day treatment period. Addition of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin restored the basal levels of NO(x) that were decreased by continuous nitroglycerin treatment of BAECs. Apocynin caused significant improvement of increased mRNA and protein levels of endothelial nitric oxide synthase (eNOS) in BAECs given nitroglycerin continuously over the treatment period. Apocynin also reduced endothelial production of reactive oxygen species (ROS) after continuous nitroglycerin treatment. These results showed an essential similarity to the effects of a nitrate-free interval. Application of the NOS inhibitor N(omega)-nitro- l-arginine methyl ester caused a recovery effect on basal NO(x) and eNOS expression but was without effect on ROS levels in continuously NO donor-treated BAECs. In conclusion, the present study characterized abnormal features and functions of endothelial cells following continuous NO donor application. We suggest that inhibition of NADPH oxidase, by preventing NO donor-induced endothelial dysfunction, may represent a potential therapeutic strategy that confers protection from nitrate tolerance development.
Assuntos
Acetofenonas/administração & dosagem , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , NADPH Oxidases/antagonistas & inibidores , Nitratos/metabolismo , Doadores de Óxido Nítrico/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Animais , Bovinos , Células Cultivadas , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Tolerância a Medicamentos/fisiologia , Inibidores Enzimáticos/administração & dosagemRESUMO
OBJECTIVE: When the availability of tetrahydrobiopterin (BH4) is deficient, endothelial nitric oxide synthase (eNOS) produces superoxide rather than NO (uncoupled eNOS). We have shown that the atherosclerotic lesion size was augmented in apolipoprotein E-deficient (ApoE-KO) mice overexpressing eNOS because of the enhanced superoxide production. In this study, we addressed the specific importance of uncoupled eNOS in atherosclerosis, and the potential mechanistic role for specific versus nonspecific antioxidant strategies in restoring eNOS coupling. METHODS AND RESULTS: We crossed mice overexpressing eNOS in the endothelium (eNOS-Tg) with mice overexpressing GTP-cyclohydrolase I (GCH), the rate-limiting enzyme in BH4 synthesis, to generate ApoE-KO/eNOS-Tg/GCH-Tg mice. As a comparison, ApoE-KO/eNOS-Tg mice were treated with vitamin C. Atherosclerotic lesion formation was increased in ApoE-KO/eNOS-Tg mice compared with ApoE-KO mice. GCH overexpression in ApoE-KO/eNOS-Tg/GCH-Tg mice increased vascular BH4 levels and reduced plaque area. This reduction was associated with decreased superoxide production from uncoupled eNOS. Vitamin C treatment failed to reduce atherosclerotic lesion size in ApoE-KO/eNOS-Tg mice, despite reducing overall vascular superoxide production. CONCLUSION: In contrast to vitamin C treatment, augmenting BH4 levels in the endothelium by GCH overexpression reduced the accelerated atherosclerotic lesion formation in ApoE-KO/eNOS-Tg mice, associated with a reduction of superoxide production from uncoupled eNOS.
Assuntos
Antioxidantes/farmacologia , Aterosclerose/fisiopatologia , Biopterinas/análogos & derivados , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Análise de Variância , Animais , Apolipoproteínas E/deficiência , Ácido Ascórbico/farmacologia , Aterosclerose/metabolismo , Biopterinas/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Feminino , GTP Cicloidrolase/análise , GTP Cicloidrolase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Probabilidade , Espécies Reativas de Oxigênio/metabolismo , Sensibilidade e Especificidade , Superóxidos/metabolismoRESUMO
UNLABELLED: The effect of beta antagonists in the diabetic vascular lesion is controversial. We investigated the effect of celiprolol hydrochloride, a beta1 antagonist and mild beta2 agonist, on the lesions and function in type II male Otsuka Long-Evans Tokushima Fatty (OLETF) diabetic rats. OLETF rats were fed regular chow with or without atenolol (25 mg/kg/day) or celiprolol (100 mg/kg/day) treatment (group DM, no treatment; group DM-a, atenolol treatment; group DM-c, celiprolol treatment), and treatment was continued for 31 days. Separately, normoglycemic control rats, LETO, were prepared as group C. On day 3, endothelial cells of the right internal carotid artery were removed by balloon injury, and the rats were evaluated 4 weeks after balloon injury. The plasma glucose and lipid levels were unchanged throughout the treatment period. Intimal thickening was observed in the right carotid artery in the DM and DM-a groups; however, little thickening was observed in those of DM-c rats. Acetylcholine-induced NO-dependent relaxation in arteries was improved in DM-c rats compared with DM and DM-a rats (maximum relaxation DM 30.8+/-4.5, DM-a 37.4+/-3.9, DM-c 48.8+/-4.6%, *P<0.05 vs. DM for DM-c rats). Tone-related basal NO release and acetylcholine-induced NO-dependent relaxation in the arteries and plasma NO(x) (sum of NO(2)(-) and NO(3)(-)) were greater in DM-c and C groups than in DM and DM-a groups. The serum TNFalpha levels did not increase in DM-c rats compared with those of the DM or DM-a groups, and were comparable with those of group C. CONCLUSION: In conclusion, Celiprolol improves endothelial function in the arteries of OLETF rats, and further restore it 4 weeks after endothelial denudation in the arteries of OLETF rats. NO and O(2)(-) may have a role in the important underlying mechanisms by reducing the TNFalpha levels.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1 , Agonistas de Receptores Adrenérgicos beta 2 , Celiprolol/uso terapêutico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Endotélio Vascular/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Aorta Abdominal/metabolismo , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Celiprolol/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/prevenção & controle , Masculino , Nitratos/sangue , Óxido Nítrico/metabolismo , Nitritos/sangue , Ratos , Ratos Long-Evans , Superóxidos/metabolismoRESUMO
Senescence may contribute to the pathogenesis of atherosclerosis. Although the bioavailability of nitric oxide (NO) is limited in senescence, the effect of NO on senescence and its relationship to cardiovascular risk factors have not been investigated fully. We studied these factors by investigating senescence-associated beta-galactosidase (SA-beta-gal) and human telomerase activity in human umbilical venous endothelial cells (HUVECs). Treatment with NO donor (Z)-1-[2-(2-aminoethyl)-N-(2-aminoethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO) and transfection with endothelial NO synthase (eNOS) into HUVECs each decreased the number of SA-beta-gal positive cells and increased telomerase activity. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) abolished the effect of eNOS transfection. The physiological concentration of 17beta-estradiol activated hTERT, decreased SA-beta-gal-positive cells, and caused cell proliferation. However, ICI 182780, an estrogen receptor-specific antagonist, and L-NAME each inhibited these effects. Finally, we investigated the effect of NO bioavailability on high glucose-promoted cellular senescence of HUVECs. Inhibition by eNOS transfection of this cellular senescence under high glucose conditions was less pronounced. Treatment with L-arginine or L-citrulline of eNOS-transfected cells partially inhibited, and combination of L-arginine and L-citrulline with antioxidants strongly prevented, high glucose-induced cellular senescence. These data demonstrate that NO can prevent endothelial senescence, thereby contributing to the anti-senile action of estrogen. The ingestion of NO-boosting substances, including L-arginine, L-citrulline, and antioxidants, can delay endothelial senescence under high glucose. We suggest that the delay in endothelial senescence through NO and/or eNOS activation may have clinical utility in the treatment of atherosclerosis in the elderly.
Assuntos
Senescência Celular/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Óxido Nítrico/farmacologia , Aterosclerose/etiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Células Cultivadas , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/prevenção & controle , Células Endoteliais/metabolismo , Feminino , Humanos , Menopausa , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Espécies Reativas de Oxigênio/metabolismo , Telomerase/metabolismo , TransfecçãoRESUMO
OBJECTIVE: We have reported that inducible nitric oxide synthase (iNOS) is present only in deep areas of plaque in atherosclerosis. However, the role of iNOS in the development of atherosclerosis is not well known. We therefore investigated the relevance of iNOS inhibition. METHODS AND RESULTS: Seven groups of male rabbits were fed a 0.5% high-cholesterol diet (HCD) for 8 weeks. Gp1-HCD was fed HCD only; Gp2-O17 was fed HCD with ONO1714, an iNOS inhibitor; Gp3-AG was fed HCD with amino-guanidine (AG), an iNOS inhibitor; Gp4-AR was fed HCD with l-arginine; Gp5-AR-O17 was fed HCD with l-arginine with ONO1714; Gp6-LNA was fed HCD with l-NAME (a NOS inhibitor); and Gp7-LN-O17 was fed HCD with l-NAME plus ONO1714. ONO1714 decreased atherosclerosis by about 70% (area occupied by lesions: 3.0+/-0.4% in Gp2-O17 versus 10.3+/-1.6% in Gp1-HCD) and also decreased atherosclerosis in Gp7-LN-O17. The ONO compound enhanced the atheroprotective effect of l-arginine. Amino-guanidine also showed an anti-atherosclerotic effect. Tone-related basal NO release and acetylcholine-induced NO-dependent relaxation were improved in Gp2-O17 and Gp5-AR-O17. O(2)(-) release was decreased in Gp2-O17 and Gp7-LN-O17. CONCLUSION: ONO1714 retards the progression of atherosclerosis in rabbits. Although the up-regulation of endothelial nitric oxide synthase (eNOS) and the decrease of O(2)(-) may play roles in this retardation, the inhibition of iNOS may be the principal factor, alone was not sufficient.
Assuntos
Amidinas/farmacologia , Aterosclerose/prevenção & controle , Colesterol na Dieta/farmacologia , Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Animais , Aorta Torácica/enzimologia , Aorta Torácica/patologia , Arginina/farmacologia , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Western Blotting , Colesterol na Dieta/sangue , GMP Cíclico/metabolismo , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Imuno-Histoquímica , Macrófagos/patologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , RNA Mensageiro/metabolismo , Coelhos , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
The objective of this study was to evaluate the influence of ingested l-arginine, l-citrulline, and antioxidants (vitamins C and E) on the progression of atherosclerosis in rabbits fed a high-cholesterol diet. The fatty diet caused a marked impairment of endothelium-dependent vasorelaxation in isolated thoracic aorta and blood flow in rabbit ear artery in vivo, the development of atheromatous lesions and increased superoxide anion production in thoracic aorta, and increased oxidation-sensitive gene expression [Elk-1 and phosphorylated cAMP response element-binding protein]. Rabbits were treated orally for 12 weeks with l-arginine, l-citrulline, and/or antioxidants. l-arginine plus l-citrulline, either alone or in combination with antioxidants, caused a marked improvement in endothelium-dependent vasorelaxation and blood flow, dramatic regression in atheromatous lesions, and decrease in superoxide production and oxidation-sensitive gene expression. These therapeutic effects were associated with concomitant increases in aortic endothelial NO synthase expression and plasma NO(2)(-)+NO(3)(-) and cGMP levels. These observations indicate that ingestion of certain NO-boosting substances, including l-arginine, l-citrulline, and antioxidants, can abrogate the state of oxidative stress and reverse the progression of atherosclerosis. This approach may have clinical utility in the treatment of atherosclerosis in humans.
Assuntos
Arginina/administração & dosagem , Arteriosclerose/metabolismo , Citrulina/administração & dosagem , Dieta Aterogênica , Endotélio Vascular/metabolismo , Animais , Antioxidantes/administração & dosagem , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Arteriosclerose/tratamento farmacológico , Arteriosclerose/patologia , Ácido Ascórbico/administração & dosagem , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/biossíntese , GMP Cíclico/metabolismo , Proteínas de Ligação a DNA/biossíntese , Endotélio Vascular/patologia , Humanos , Masculino , Nitratos/metabolismo , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase Tipo III , Nitritos/metabolismo , Oxirredução/efeitos dos fármacos , Proteínas Proto-Oncogênicas/biossíntese , Coelhos , Superóxidos/metabolismo , Fatores de Transcrição/biossíntese , Vasodilatação/efeitos dos fármacos , Vitamina E/administração & dosagem , Proteínas Elk-1 do Domínio etsRESUMO
Although endothelial dysfunction deteriorates diabetic angiopathy, the mechanisms are obscure. We revealed that high glucose augmented eNOS through stimulation of eNOS mRNA in cultured BAECs. NO was decreased and O2- was increased simultaneously. NOS inhibitor, inhibited O2- release, so did NADPH oxidase inhibitor. The effects were synergistic. Both intracellular BH4 level and GTPCH1 activity were decreased by high glucose, in line with decrease of GTPCH1 mRNA. HMG-CoA reductase inhibitor, atorvastatin increased GTPCH1 mRNA and activity, and BH4 level. Conclusively, high glucose leads to eNOS dysfunction by inhibiting BH4 synthesis and atorvastatin stimulate BH4 synthesis directly, and it may work as atherogenic process.
Assuntos
Biopterinas/análogos & derivados , Células Endoteliais/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Óxido Nítrico Sintase/metabolismo , RNA Mensageiro/metabolismo , Animais , Atorvastatina , Biopterinas/metabolismo , Western Blotting , Bovinos , Citometria de Fluxo , GTP Cicloidrolase/metabolismo , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , NADPH Oxidases/antagonistas & inibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III , Oxigênio/metabolismo , Pirróis/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não ParamétricasRESUMO
Human inducible nitric oxide synthase (iNOS) is most readily observed in macrophages from patients with inflammatory diseases like atherosclerosis. The aim of the present study was to find out the combined effect of male sex hormone; testosterone and apocynin (NADPH oxidase inhibitor) on cytokine-induced iNOS production. THP-1 cells were differentiated into macrophages by phorbol myristate acetate (PMA). Expression of iNOS was induced by the addition of cytokine mixture? Testosterone was added at different concentrations (10(-6)-10(-12) M) with apocynin (1 mM). Testosterone (10(-8), 10(-10) M) inhibited NOx production in cytokine-added THP-1 cells which was further confirmed by quantikine assay of iNOS protein and RT-PCR analysis. Testosterone treatment decreased 40% of superoxide anion production. Testosterone showed inhibition of NADPH oxidase, especially expression of p67phox and p47phox (cytosol subunits). Addition of testosterone with apocynin further decreased the expression of p67phox and p47phox subunits of NADPH oxidase. The findings of the present study suggest that, testosterone; the male androgen plays an important role in the prevention of atherogenesis. Even though apocynin does not have any role on NO production, addition of apocynin together with testosterone is effective in suppressing iNOS activity.
Assuntos
Acetofenonas/farmacologia , Macrófagos/metabolismo , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico/metabolismo , Superóxidos/metabolismo , Testosterona/farmacologia , Acetofenonas/administração & dosagem , Inibidores da Aromatase , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Fadrozol/farmacologia , Humanos , Macrófagos/efeitos dos fármacos , Masculino , NADPH Oxidases/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II , Fosfoproteínas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Testosterona/administração & dosagem , Acetato de TetradecanoilforbolRESUMO
BACKGROUND: The remarkable anti-atherosclerotic effects of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor have not been demonstrated in diet induced severe hyperlipidemia in rabbit model. OBJECTIVE: We have investigated the effect of pitavastatin, a newly developed statin, on atherosclerosis in rabbits. METHODS AND RESULTS: Oophorectomized female NZW rabbits were fed 0.3% cholesterol chow for 12 weeks with or without pitavastatin (0.1mg/kg per day) (Gp.NK and HCD). The level of serum cholesterol was decreased in Gp.NK compared with Gp.HCD (772.8 +/- 70.2 versus 1056.9 +/- 108.3 mg/d), whereas no significant alterations were observed in triglyceride and HDL-cholesterol. NO dependent response stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N(G)-monomethyl-l-arginine acetate were all improved by pitavastatin treatment. Pitavastatin treatment increased the level of cyclic GMP in the aorta of cholesterol fed rabbits. In the aorta, the expression of eNOS mRNA was significantly up regulated and O(2)(-) production was slightly reduced in Gp.NK animals. Atherosclerotic area was significantly decreased in aortic arch and thoracic aorta from Gp.NK compared with those from Gp.HCD ( 15.1 +/- 5.3 versus 41.9 +/- 10.2%, 3.1 +/- 1.1versus 7.9 +/- 1.2% in Gp.NK and Gp.HCD aortic arch and thoracic aorta). Anti-macrophage staining area, the MMP1 or 2 and the nitrotyrosine positive area were decreased in Gp.NK. CONCLUSION: Pitavastatin retards the progression of atherosclerosis formation and it improves NO bioavailability by eNOS up-regulation and decrease of O(2)(-).
Assuntos
Arteriosclerose/tratamento farmacológico , Arteriosclerose/fisiopatologia , Inibidores Enzimáticos/farmacologia , Quinolinas/farmacologia , Administração Oral , Animais , Arteriosclerose/veterinária , Disponibilidade Biológica , HDL-Colesterol/sangue , Modelos Animais de Doenças , Progressão da Doença , Feminino , Óxido Nítrico/farmacologia , Coelhos , Triglicerídeos/sangue , Regulação para CimaRESUMO
The effects of in vivo gene transfer of endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) genes on severe atherosclerosis were investigated in rabbits. The recombinant adenoviruses, Ad.eNOS and Ad.iNOS, which respectively express eNOS and iNOS, were constructed. Atherosclerosis was induced by a balloon injury followed by a high cholesterol diet for 12 weeks. The rabbits were divided into six groups: Gp cont (no treatment); Gp null (adenovirus sham-infected); Gp eNOS (Ad.eNOS); Gp iNOS (Ad.iNOS); Gp e+i (Ad.eNOS plus Ad.iNOS); and Gp heNOS (a high dose of Ad.eNOS). Examinations were carried out 7 days after gene transfer. Plasma lipid levels were not significantly changed, but transfection with Ad.eNOS (Gp eNOS and Gp heNOS) decreased the tissue cholesterol concentration and regressed atherosclerotic lesions. Vessels treated with Ad.iNOS (Gp iNOS and Gp e+i) showed iNOS staining in the atheroma, and slight staining at other parts of the vessels; those treated with Ad.eNOS showed eNOS staining in the endothelium and subintima, and slight staining at other parts. Ad.eNOS transfection, but not Ad.iNOS or Ad.eNOS+Ad.iNOS transfection, improved the impaired aortic endothelium-dependent relaxation (EDR) and basal NO-dependent response, increased tissue cyclic GMP (cGMP), and decreased the release of O2- from vessels. eNOS treatment showed a decreasing tendency in regions with peroxynitrite staining, MMP1 staining, and suspected apoptosis. In conclusion, in vivo gene transfer of eNOS, but not iNOS or eNOS plus iNOS, regressed atherosclerosis. The relations among NO, O2-, and peroxynitrite may be critical, and lipid resorption from the lesions may be responsible for the regression.
Assuntos
Arteriosclerose/terapia , Terapia Genética/métodos , Óxido Nítrico Sintase/genética , Transdução Genética/métodos , Acetilcolina , Adenoviridae/genética , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Colesterol/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Vetores Genéticos/administração & dosagem , Infusões Intra-Arteriais , Metabolismo dos Lipídeos , Masculino , Modelos Animais , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Nitroglicerina , Oxigênio/metabolismo , Ácido Peroxinitroso/metabolismo , Coelhos , Vasodilatadores , ômega-N-Metilarginina/farmacologiaRESUMO
Although sarpogrelate HCl is widely used for the prevention of arterial thrombosis, its effect on atherosclerosis is unknown. Accordingly, we here investigated the effects of sarpogrelate HCl on a rabbit model of atherosclerosis. Male rabbits were fed a 0.5% cholesterol diet (HCD) (Gp 1), HCD with vitamin E (Gp 2), HCD with vitamin E and sarpogrelate (Gp 3), or HCD with sarpogrelate alone (Gp 4) for 8 weeks. The atherosclerotic area was decreased by feeding of vitamin E and sarpogrelate (16.9+/-2.0% in Gp 1 vs. 8.2+/-2.0% in Gp 3). Tone-related basal NO release was higher in Gps 3 and 4. Acetylcholine-induced relaxation tended to be improved in Gp 3. The amount of eNOS mRNA was increased in Gp 4, and aortic cyclic GMP concentration showed the same tendency. O(2)(-) release tended to be decreased in Gps 2 and 3. The matrix metalloproteinase-1 (MMP-1)-positive area was decreased, and the percentage ratio of cell numbers of smooth muscle cells/macrophages in the plaque was increased in Gp 3. The results demonstrated that sarpogrelate HCl retards the progression of atherosclerosis in rabbits, and that this effect is enhanced by concomitant administration of vitamin E. Although upregulation of eNOS may play a role as one of the underlying mechanisms, our results suggest that an additional mechanism-possibly involving the antiproliferative effects of sarpogrelate HCl on smooth muscle cells and macrophages-may also play an important role.
Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Antagonistas da Serotonina/uso terapêutico , Succinatos/uso terapêutico , Acetilcolina/administração & dosagem , Animais , Antioxidantes/uso terapêutico , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Biomarcadores/sangue , Proteínas Sanguíneas/metabolismo , HDL-Colesterol/sangue , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Masculino , Metaloproteinase 1 da Matriz/efeitos dos fármacos , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Modelos Cardiovasculares , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/fisiologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico Sintase/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Coelhos , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Vitamina E/uso terapêuticoRESUMO
OBJECTIVE: We investigated the effect of glimepiride, a third-generation sulfonylurea hypoglycemic agent, on insulin resistance in elderly patients with type 2 diabetes, in connection with plasma adiponectin and 8-epi-prostagrandin F2alpha (8-epi-PGF2alpha), an oxidative stress marker. RESEARCH DESIGN AND METHODS: A total of 17 elderly patients with type 2 diabetes received 12 weeks of treatment with glimepiride. Homeostasis assessment model of insulin resistance (HOMA-IR), homeostasis assessment model of beta-cell function, HbA(1c), C-peptide in 24-h pooled urine (urine CPR), and plasma concentrations of 8-epi-PGF2alpha, tumor necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor type 1, and adiponectin were measured at various times. The metabolic clearance rate of glucose (MCR-g) was also assessed by a hyperinsulinemic-euglycemic clamp. RESULTS: After 8 weeks of glimepiride treatment, significant reductions were observed in HbA(1c) (from 8.4 +/- 1.9 to 6.9 +/- 1.0%), HOMA-IR (from 2.54 +/- 2.25 to 1.69 +/- 0.95%), and plasma TNF-alpha concentrations (from 4.0 +/- 2.0 to 2.6 +/- 2.5 pg/ml). MCR-g was significantly increased from 3.92 +/- 1.09 to 5.73 +/- 1.47 mg. kg(-1). min(-1). Plasma adiponectin increased from 6.61 +/- 3.06 to 10.2 +/- 7.14 micro g/ml. In control subjects, who maintained conventional treatment, no significant changes were observed in any of these markers. CONCLUSIONS: Glimepiride remarkably improved insulin resistance, suggested by a significant reduction in HOMA-IR, an increase in MCR-g, and a reduction in HbA(1c) without changing extrapancreatic beta-cell function and urine CPR. Increased plasma adiponectin and decreased plasma TNF-alpha may underlie the improvement of insulin resistance with glimepiride.