RESUMO
BACKGROUND: Oxidative stress may play an important role in the development of myocarditis. We investigated the effects of N-acetylcysteine (NAC), a potent antioxidant, on experimental autoimmune myocarditis (EAM) in rats. METHODS AND RESULTS: A rat model of porcine myosin-induced EAM was used. After the immunization with myosin, NAC (20 mg/kg/d) or saline was injected intraperitoneally on days 1 to 21. Additional myosin-immunized rats treated with NAC were orally given 25 mg/kg/d of N(G)-nitro-l-arginine methylester (l-NAME), an inhibitor of nitric oxide (NO) synthase, and N(G)-nitro-d-arginine methylester (d-NAME), an inactive enantiomer. The NAC treatment improved cardiac pathology associated with reduced superoxide production. In the EAM rats treated with NAC associated with oral l-NAME, but not with oral d-NAME, the severity of myocarditis was not reduced. Expression of intercellular adhesion molecule 1 was reduced by NAC treatment. Myocardial c-kit(+) cells were demonstrated only in the NAC-treated group. Hemodynamic study showed that the increased left ventricular mass produced by myocardial inflammation tended to be reduced by NAC treatment. CONCLUSION: Treatment with NAC ameliorated myocardial injury via NO system in a rat model of myocarditis.
Assuntos
Acetilcisteína/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Miocardite/tratamento farmacológico , Óxido Nítrico/fisiologia , Acetilcisteína/farmacologia , Animais , Doenças Autoimunes/fisiopatologia , Modelos Animais de Doenças , Molécula 1 de Adesão Intercelular/fisiologia , Miocardite/fisiopatologia , Ratos , Ratos Endogâmicos Lew , Superóxidos/metabolismoRESUMO
The in vivo mechanisms in chronic myocarditis remain unclear. The aim of the current study was to clarify the genomic difference of amyocarditic (CB3O) and myocarditic (CB3M) coxsackievirus B3 (CB3) and the pathogenesis of in vivo mechanisms in chronic myocarditis. We examined the histopathology of CB3-inoculated wild-type (WT) and severe combined immunodeficient (SCID) mice with and without adoptive transfer of lymphocytes. There were no differences in viral growth between CB3O and CB3M. There were four to six nucleotide differences in the sequence of CB3O in comparison with the known CB3M. The difference in virus sequence between CB3O and CB3M was very minimal. The changes were located in 1A, 1C, and 1D regions, which encode the structural capsid proteins. Definite myocarditis developed in WT C3H (H-2(k)) inoculated with CB3M. On the contrary, trivial or mild myocarditis occurred in WT C3H mice inoculated with CB3O. In SCID C3H and SCID C57BL/6 (H-2(b)) mice, definite myocarditis developed by inoculation with both CB3O and CB3M. Myocardial lesion was less severe in the mice infected with CB3O than in those with CB3M. After anti-CD8 antibody treatment, myocarditis was easily induced in mice originally showing resistance to infection. In addition, chronic myocarditis developed in CB3O-infected SCID C3H mice reconstituted with CB3M-sensitized splenocytes of WT C3H mice. The development of chronic myocarditis primarily depends on the presence or absence of the virus genome, and secondarily on the complex interaction between virus virulence and immunological background of the host. CB3 infection may cause chronic myocarditis with ongoing inflammation with or without viral persistence.
Assuntos
Infecções por Coxsackievirus/terapia , Enterovirus/genética , Miocardite/mortalidade , Miocardite/virologia , Miocárdio/patologia , Transferência Adotiva/veterinária , Animais , Anticorpos Monoclonais/química , Linfócitos T CD8-Positivos/citologia , Doença Crônica , Genoma Viral , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos SCID , Necrose/patologia , Nucleotídeos/classificaçãoRESUMO
Intravenous immunoglobulin (IVIG) therapy has been used to treat several autoimmune or inflammatory diseases. We conducted a clinical trial of immunoglobulin therapy for acute myocarditis. The study consisted of two projects: (1) a comparison of prognosis between patients treated with and those not treated with IVIG in a multi-center study; (2) analyses of inflammatory cytokines and blood cell profiles in a substudy. In (1), 15 patients were treated with IVIG (1-2 g/kg, over 2 days), whereas 26 were untreated. There was a statistically significant difference between the survival curves of the patients treated with IVIG and the survival curves of those not treated with IVIG. There was no significant difference between the IVIG-treated and untreated groups in terms of clinical parameters of the acute and chronic phases. In (2), 10 patients were treated with IVIG and 6 were untreated. In both groups, all of the data except for changes in the fraction of lymphocytes and the fraction of monocytes decreased due to the treatment or during the course. In patients in the IVIG group, the percentage of peripheral eosinophils was decreased and the percentage of peripheral monocytes was increased by this treatment when they were compared with the pretreatment data. Therefore, therapy with IVIG seems to be a promising treatment for acute myocarditis given that it improves the clinical course, which may be due to modulation of inflammatory cytokines and the peripheral leukocyte balance.
Assuntos
Cardiomiopatias/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Leucócitos/efeitos dos fármacos , Miocardite/tratamento farmacológico , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Cardiomiopatias/sangue , Cardiomiopatias/diagnóstico , Cardiomiopatias/imunologia , Cardiomiopatias/mortalidade , Citocinas/sangue , Feminino , Humanos , Mediadores da Inflamação/sangue , Japão , Estimativa de Kaplan-Meier , Contagem de Leucócitos , Leucócitos/imunologia , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Miocardite/sangue , Miocardite/diagnóstico , Miocardite/imunologia , Miocardite/mortalidade , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
A 32-year-old woman with anorexia nervosa showing tall P waves on electrocardiogram (ECG) was reported. Her ECG showed tall P waves (5.5mm in voltage, lead II) at 2.2mEq/L of serum potassium. After the treatment, P waves decreased in voltage with the normalization of serum potassium. Tall P waves may be considered to be the so-called pseudo-P pulmonale, and added to the criteria of hypokalemia on ECG.
Assuntos
Arritmias Cardíacas/complicações , Arritmias Cardíacas/diagnóstico , Eletrocardiografia/métodos , Hipopotassemia/complicações , Hipopotassemia/diagnóstico , Desequilíbrio Hidroeletrolítico/complicações , Desequilíbrio Hidroeletrolítico/diagnóstico , Adulto , Algoritmos , Humanos , MasculinoRESUMO
BACKGROUND: Recent evidence suggests that erythromycin (EM), a major macrolide antibiotic, has many biological functions in addition to the anti-bacterial actions, including anti-inflammatory and free radical scavenging actions. However, the effects of the drug upon inflammatory myocardial diseases are unknown. We tested the hypothesis that EM ameliorates experimental autoimmune myocarditis in rats attributing to the suppression of superoxide production. METHODS: We administered EM, 3.3mg/kg/day and 33 mg/kg/day, intraperitoneally for 3 weeks, to rats with experimental autoimmune myocarditis (EAM) produced by immunization by porcine myosin. RESULTS: EM treatment reduced the severity of myocarditis compared with the untreated group in a dose-dependent manner by comparing the heart weight/body weight ratio, pathologic scores, and myocardial macrophage, CD4(+), and CD8(+) infiltrations. Echocardiographic study showed that increased left ventricular posterior wall thickness produced by myocardial inflammation was reduced by EM treatment. Myocardial superoxide production, determined by dihydroethidium staining, was significantly reduced by the treatment. Western blotting showed that the expression of myocardial interleukin-1ß was reduced by EM treatment compared with untreated groups. The in vivo dorsal air pouch model showed that EM significantly suppressed leukocyte chemotaxis in a dose-dependent manner. CONCLUSION: Irrespective of a well-known classic antibiotic, EM attenuated EAM not only by the anti-inflammatory action but by the suppression of superoxide production.
Assuntos
Doenças Autoimunes/metabolismo , Doenças Autoimunes/prevenção & controle , Eritromicina/uso terapêutico , Miocardite/metabolismo , Miocardite/prevenção & controle , Superóxidos/metabolismo , Animais , Doenças Autoimunes/imunologia , Eritromicina/farmacologia , Miocardite/imunologia , Ratos , Ratos Endogâmicos Lew , Superóxidos/antagonistas & inibidores , Suínos , Resultado do TratamentoRESUMO
AIMS: We tested the hypothesis that immunoglobulin ameliorated experimental autoimmune myocarditis (EAM) in mice attributing to the suppression of reactive oxygen species (ROS)-mediated myocardial injury. METHODS: We intraperitoneally administered intact type of human immunoglobulin (Ig) or F(ab')2 fragments of human immunoglobulin, 1g/kg/day daily for 3 weeks, to male BALB/c mice with heart failure due to EAM. RESULTS: The results showed that intact type of Ig, but not F(ab')2 type, reduced the severity of myocarditis by comparing the heart weight/body weight and lung weight/body weight ratios, pericardial effusion score, macroscopic and microscopic scores. Tissue superoxide production was marked in untreated mice with EAM, which was suppressed by the treatment of immunoglobulins. The cytotoxic activities of lymphocytes in mice with EAM treated with Ig were reduced compared with untreated controls. The shift from Th1 toward Th2 cytokine balance was demonstrated by the treatment of immunoglobulins both in vitro and in vivo. CONCLUSION: ROS may be involved in the development of myocarditis. Intact Ig ameliorates myocardial damage in mice with myocarditis associated with suppression of ROS and cytotoxic activity of lymphocytes.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Traumatismos Cardíacos/tratamento farmacológico , Imunoglobulinas/uso terapêutico , Miocardite/tratamento farmacológico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Animais , Doenças Autoimunes/metabolismo , Traumatismos Cardíacos/metabolismo , Humanos , Imunoglobulinas/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Suínos , Resultado do TratamentoRESUMO
It has been shown that oxidative stress may play an important role in the development of atherosclerosis, and carvedilol has the capacity of reducing oxidative stress. Accordingly, we assessed the hypothesis that carvedilol may reduce the severity of atherosclerosis in apolipoprotein E (apoE)-deficient mice in addition to its hemodynamic effects. Atherosclerosis was induced in apoE-deficient mice fed a high-fat diet containing 0.3% cholesterol. Mice were orally treated with propranolol (30 mg/kg/day), metoprolol (75 mg/kg/day) and carvedilol (10 mg/kg/day) over eight weeks (each group n = 7-9). Fatty streak plaque developed in apoE-deficient mice, and was suppressed in mice treated with all three drugs. The accumulation of macrophages and expression of CD4(+) and CD8(+) cells in the lesions were decreased by the treatment of the drugs, of which carvedilol was the most effective. In addition, carvedilol reduced superoxide production in aortic walls detected by ethidium staining. There were no significant changes in blood pressure among the study groups. The heart rates in the treated groups were decreased by 4%-12% compared with the control group, with carvedilol yielding the highest suppression of heart rate. The ß-blocker treatment did not significantly modify the serum lipid profiles. Carvedilol may suppress atherosclerosis via reducing superoxide production, in addition to the hemodynamic modifications in this animal model.
Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/tratamento farmacológico , Carbazóis/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Propanolaminas/farmacologia , Superóxidos/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Aorta/efeitos dos fármacos , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carvedilol , Colesterol na Dieta/administração & dosagem , Radicais Livres/sangue , Frequência Cardíaca/efeitos dos fármacos , Lipídeos/sangue , Macrófagos/efeitos dos fármacos , Masculino , Metoprolol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/fisiopatologia , Propranolol/farmacologiaRESUMO
Atherosclerosis is widely considered to be an immune-mediated process. Fcγ receptors (Fcγ Rs) contribute to the regulation of a multitude of immune and inflammatory responses and are implicated in human atherosclerotic lesions. Major cell types involved in the pathogenesis of atherosclerosis express Fcγ Rs and their proatherogenic ligands such as immune complexes and C-reactive protein, which act to activate Fcγ R signaling pathways. This review summarizes recent significant progress addressing the multifaceted roles of Fcγ Rs in atherogenesis which comes from the studies of Fcγ R-deficient animal models, clinical investigations and in vitro molecular and cellular studies. These new findings help us appreciate the emerging role of Fcγ Rs in atherosclerosis, and suggest Fcγ Rs as a potential therapeutic target for atherosclerosis.
Assuntos
Aterosclerose/fisiopatologia , Receptores de IgG/fisiologia , Transdução de Sinais/fisiologia , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/epidemiologia , Aterosclerose/genética , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Knockout , Polimorfismo Genético/genética , Receptores de IgG/deficiência , Receptores de IgG/genética , Fatores de RiscoRESUMO
OBJECTIVE: Uremia markedly accelerates atherogenesis, but the pathogenesis remains to be elucidated and effective anti-atherogenic treatments are needed. The aim of this study was to investigate the relationship between accelerated atherosclerosis (AS) and the balance of regulatory/effector T cells (Treg/Teff) in uremic apolipoprotein E knockout (apoE-/-) mice, and the effect of pioglitazone on uremic AS and possible mechanisms. METHODS AND RESULTS: Uremia was induced surgically in 8-week-old male apoE-/- mice. Two weeks after induction of uremia, the mice were randomized to receive pioglitazone (daily oral gavage with 20mg/kg) or vehicle. Control apoE-/- mice were sham-operated and received vehicle. After 8 weeks' treatment, all mice were sacrificed. The cross-sectional area of atherosclerotic lesions at the aortic root was significantly larger and plaques were unstable in uremic mice, which was associated with a Treg/Teff imbalance (Treg down-regulated/Teff up-regulated) compared with controls. Renal function and the percentage of Treg cells in splenocytes were negatively correlated in control and uremic mice that received vehicle. Treatment with pioglitazone dramatically inhibited AS progression, stabilized plaque and modulated the Treg/Teff imbalance (up-regulated Treg/down-regulated Teff) in uremic mice, without influencing serum lipid profiles and blood glucose. In vitro, oxidized low density lipoprotein induced a Treg/Teff imbalance in splenocytes from uremic mice. Pioglitazone modulated the imbalance by upregulating Treg cells and downregulating Teff cells. The former was not abolished by the peroxisome proliferator-activated receptor (PPAR)γ antagonist GW9662, whereas the latter was completely abolished by GW9662. CONCLUSION: Pioglitazone ameliorates accelerated AS in uremic apoE-/- mice, probably through PPARγ-independent and -dependent mechanisms to modulate the Treg/Teff imbalance.
Assuntos
Apolipoproteínas E/genética , Tiazolidinedionas/farmacologia , Uremia/genética , Animais , Aorta/patologia , Aterosclerose/genética , Peso Corporal , Citocinas/metabolismo , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , PPAR gama/metabolismo , Pioglitazona , Baço/citologia , Linfócitos T/citologia , Linfócitos T Reguladores/citologia , Uremia/metabolismoRESUMO
MicroRNAs (miRNAs) are endogenous small RNAs that play an important role in various physiological processes by downregulating target genes. Recently, plasma miRNAs have been investigated as biomarkers for various diseases. In this study, miRNA array analysis in various tissues showed that miR-124 is almost exclusively expressed in the central nervous system and neuronal cells, suggesting that it might be useful as a potential biomarker for neurological diseases. We examined whether plasma concentrations of brain-specific miRNA can serve as a biomarker for cerebral infarction, where the cerebral infarction was modeled by middle cerebral artery occlusion (MCAO) in the rat. Plasma concentrations of miR-124 were significantly elevated at 6 h, and remained elevated at 48 h after MCAO introduction. Thus, plasma concentration of miR-124 provides a promising candidate biomarker for early detection of cerebral infarction.
Assuntos
Biomarcadores/sangue , Encéfalo/metabolismo , Infarto Cerebral/sangue , Infarto Cerebral/diagnóstico , MicroRNAs/sangue , Animais , Encéfalo/patologia , Células Cultivadas , Infarto Cerebral/etiologia , Infarto Cerebral/patologia , Modelos Animais de Doenças , Diagnóstico Precoce , Perfilação da Expressão Gênica , Humanos , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: We assessed the hypothesis whether behavioral stress may affect the development of atherosclerosis and whether regular exercise training may influence the composition of atherosclerotic plaques in apolipoprotein (apo) E-deficient mice. METHODS: Atherosclerosis was induced in apo E-deficient mice fed a high fat diet. Exercise training (45 min swimming, 3 times/week) was conducted, and behavioral stress was provoked by glass marble-burying procedure. Mice were treated with marble-burying, marble-burying behavior plus swimming training, and swimming alone over 8 weeks. RESULTS: Exercise training decreased the atherosclerotic lesions, but marble-burying behavior increased the lesions. The plaques containing macrophage accumulation with intercellular adhesion molecule-1 (ICAM-1) expression associated with reduced collagen contents were induced in the mice treated with marble-burying. However, ICAM-1 expression was suppressed and collagen contents were reversed in the mice that received marble-burying behavior plus exercise training. In addition, exercise alone and concomitant exercise training reduced the superoxide production in aortic walls, shown by dihydroethidium staining, compared with that in mice with marble-burying behavior alone. There were no significant differences in the serum lipids profiles among the groups. CONCLUSIONS: Behavioral stress increased the atherosclerotic lesions and induced the adhesion molecule expression with superoxide production on the lesions in apo E-deficient mice. Exercise training may stabilize plaque lesions induced by marble-burying behavior in this animal model.
Assuntos
Aterosclerose/patologia , Modelos Animais de Doenças , Condicionamento Físico Animal/fisiologia , Placa Aterosclerótica/patologia , Estresse Psicológico/patologia , Animais , Apolipoproteínas E/deficiência , Aterosclerose/etiologia , Aterosclerose/psicologia , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Condicionamento Físico Animal/métodos , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/psicologia , Estresse Psicológico/complicações , Estresse Psicológico/psicologiaRESUMO
The role of inflammation in all stages of atherosclerosis has been actively investigated, with an emphasis on the discovery of novel and innovative drugs for treatment and prevention. The anti-inflammatory and immunomodulatory capacity of cannabinoids are well established, and these agents have a broad therapeutic potential in various inflammatory diseases, including cardiovascular diseases. The aim of this study was to investigate the effect of WIN55212-2, a synthetic cannabinoid, on atherosclerosis using the apolipoprotein E-knockout (ApoE(-/-)) mouse on a cholate-containing high-fat diet. Our results showed that WIN55212-2 reduced the size of atherosclerotic lesions in the aorta root, and did not affect serum lipid levels significantly. Furthermore, alleviation of atherosclerosis by WIN55212-2 was associated with a smaller content of macrophages in plaque lesion as well as decreasing pro-inflammatory gene expression and NF-κB activation in aortic tissues. Oxidized LDL (ox-LDL) dramatically induced NF-κB activation, and enhanced pro-inflammatory mRNA and protein expression in peritoneal macrophages isolated from ApoE(-/-) mice. It is noteworthy that all of the above-mentioned effects of ox-LDL were attenuated by WIN55212-2. Moreover, WIN55212-2 also attenuated the inflammatory response that LPS induced. AM630, a cannabinoid receptor 2 (CB2) special antagonist completely abolished the protective effects of WIN55212-2 both in vivo and in vitro. Our data provide strong evidence that WIN55212-2 can potentially inhibit atherosclerosis in ApoE(-/-) mice. Importantly, all the beneficial effects of WIN55212-2 in our model were closely associated with the suppression of pro-inflammatory responses and were mediated by the CB2 receptor.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Apolipoproteínas E/metabolismo , Aterosclerose/tratamento farmacológico , Benzoxazinas/farmacologia , Benzoxazinas/uso terapêutico , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Receptor CB2 de Canabinoide/agonistas , Animais , Anti-Inflamatórios não Esteroides/antagonistas & inibidores , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Benzoxazinas/antagonistas & inibidores , Citocinas/genética , Citocinas/metabolismo , Dieta Aterogênica , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Morfolinas/antagonistas & inibidores , NF-kappa B/metabolismo , Naftalenos/antagonistas & inibidores , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , RNA Mensageiro/metabolismo , Distribuição Aleatória , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismoRESUMO
We systematically investigated serial efficacy of granulocyte colony-stimulating factor (G-CSF) therapy upon experimental autoimmune myocarditis (EAM) in rats treated with and without the inhibition of nitric oxide (NO) with the analyses of tissue regeneration. G-CSF could mobilize multipotent progenitor cells of bone marrow into the peripheral blood and may improve ventricular function. A rat model of porcine myosin-induced EAM was used. After the immunization of myosin, G-CSF (10 microg/kg/day) or saline was injected intraperitoneally on days 0-21 in experiment 1 and on days 21-42 in experiment 2. Additional myosin-immunized rats were orally given 25 mg/kg/day of N(G)-nitro-L-arginine methylester (L-NAME), an inhibitor of nitric oxide synthase (NOS), in each experiment (each group; n=8-21). Serum cytokines and peripheral blood cell counts were measured in each group. In experiment 1, G-CSF treatment aggravated cardiac pathology associated with increased macrophage inflammatory protein-2 (MIP-2) and interleukin-6 (IL-6) levels and enhanced superoxide production. In experiment 2, G-CSF treatment reduced the severity of myocarditis with increased capillary density and improved left ventricular ejection fraction. In the rats with EAM treated with G-CSF associated with oral L-NAME treatment in experiment 2, the severity of myocarditis was not reduced. Myocardial c-kit(+) cells were demonstrated only in G-CSF-treated group in experiment 2 but not in other groups. G-CSF has differential effects on EAM in rats associated with the modulation of cytokine network. The overwhelming superoxide production by G-CSF administration in the acute stage may worsen the disease. G-CSF therapy improved cardiac function via NO system in a rat model of myocarditis in the chronic stage, but not in the acute stage, possibly through the myocardial regeneration and acceleration of healing process.
Assuntos
Doenças Autoimunes/terapia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Miocardite/terapia , Óxido Nítrico/metabolismo , Doença Aguda , Animais , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Miosinas Cardíacas/metabolismo , Doença Crônica , Citocinas/metabolismo , Ecocardiografia , Inibidores Enzimáticos/farmacologia , Humanos , Imunização , Técnicas Imunoenzimáticas , Miocardite/metabolismo , Miocardite/patologia , NG-Nitroarginina Metil Éster/farmacologia , Neovascularização Patológica , Ratos , Ratos Endogâmicos Lew , Proteínas Recombinantes , Superóxidos/metabolismo , SuínosRESUMO
AIMS: High glucose promotes macrophage-derived foam cell formation involved in increased influx or reduced efflux of lipids. The aim of this study is to investigate the influence of hyperglycaemia on foam cell transformation of vascular smooth muscle cells (VSMCs) and possible mechanisms contributing to these effects. METHODS AND RESULTS: The results showed that high glucose increased the expression of CD36, a regulator of lipid influx, and suppressed the expression and activity of the adenosine triphosphate-binding cassette (ABC) transporter ABCG1, a regulator of cholesterol efflux to high-density lipoprotein, in a dose- and time-dependent manner. However, cholesterol efflux to lipid-free apoAI was not impaired. VSMCs exposed to high glucose readily developed into lipid-loaded cells, as demonstrated by Oil Red O staining and cholesterol content analysis. In addition, high glucose-induced down-regulation of ABCG1 was reversed by nuclear factor-kappaB (NF-kappaB) inhibitors BAY 11-7085 and tosyl-phenylalanine chloromethyl ketone and by the antioxidant N-acetyl-L-cysteine (NAC). This reversal was accompanied by reduced cellular lipid content. Also, NAC and NF-kappaB inhibitors can effectively block the high glucose-induced activity of NF-kappaB binding to DNA and/or peroxide production. CONCLUSION: These results suggested that hyperglycaemia-induced foam cell formation in VSMCs was related to the imbalanced lipid flux by increasing CD36-mediated modified low-density lipoprotein uptake and reducing ABCG1-regulated cellular cholesterol efflux. Moreover, this effect was associated with increased oxidative stress and activated NF-kappaB pathway signalling.
Assuntos
Colesterol/metabolismo , Células Espumosas/metabolismo , Glucose/farmacologia , Hiperglicemia/metabolismo , Músculo Liso Vascular/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antioxidantes/farmacologia , Aorta/citologia , Apolipoproteína A-I/metabolismo , Antígenos CD36/metabolismo , Células Cultivadas , Ésteres do Colesterol/metabolismo , HDL-Colesterol/metabolismo , Células Espumosas/citologia , Células Espumosas/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Hiperglicemia/patologia , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Nitrilas/farmacologia , Peróxidos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Sulfonas/farmacologia , Tosilfenilalanil Clorometil Cetona/farmacologiaRESUMO
BACKGROUND: Oxidative stress may play an important role in the development of atherosclerosis. Because N-acetylcysteine (NAC) is able to reduce oxidative stress, the present study assessed the hypothesis that NAC may reduce the severity of atherosclerosis in apolipoprotein (apo) E-deficient mice. METHODS AND RESULTS: Atherosclerosis was induced in apoE-deficient mice fed a high-fat diet containing 0.3% cholesterol. Mice were injected intraperitoneally with NAC (20 mg . kg(-1) . day(-1)) 3 times per week over 8 weeks. Fatty streak plaque developed in the apoE-deficient mice, but not in mice treated with NAC. In addition, NAC reduced superoxide production in the aortic walls, as detected by ethidium staining. NAC treatment did not significantly modify the serum lipid profiles. CONCLUSIONS: In this animal model NAC may suppress atherosclerosis via reducing superoxide production.
Assuntos
Acetilcisteína/uso terapêutico , Apolipoproteínas E/deficiência , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Sequestradores de Radicais Livres/uso terapêutico , Índice de Gravidade de Doença , Superóxidos/metabolismo , Acetilcisteína/farmacologia , Animais , Aterosclerose/etiologia , Gorduras na Dieta/efeitos adversos , Modelos Animais de Doenças , Sequestradores de Radicais Livres/farmacologia , Molécula 1 de Adesão Intercelular/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Estresse Oxidativo/efeitos dos fármacosRESUMO
Little is known about effects of naloxone, an opiate receptor antagonist, upon experimental autoimmune myocarditis (EAM) in mice. The aim of the present study was to test the effects of naloxone upon EAM in mice. Four-week-old C57BL/6 mice were injected with porcine cardiac myosin. Naloxone 1 mg/kg/day was given intraperitoneally daily on days 0 to 21 in experiment I (acute stage) and on days 21 to 42 in experiment II (chronic stage). For the analysis of endogenous opiate and neurohumoral system, plasma beta-endorphin and cytokines were measured. The cytotoxic activity of lymphocytes was determined by Cr-release assay. Naloxone reversed hypotension produced by massive myocardial injury in experiment I. In experiment I, the severity of cardiac pathology and inflammatory cytokines were decreased in the naloxone-treated group associated with higher beta-endorphin level compared with the untreated group. In addition, naloxone induced a shift from Th1 cytokine toward Th2 cytokine balance. Thus, cytotoxic activities of lymphocytes against EL-4 tumor cells were lower in the treated group than in the untreated group in experiment I, but not in experiment II. Naloxone is beneficial for heart failure caused by EAM in the acute stage, but not in the chronic stage, due to decreasing cytotoxic activities of lymphocytes and to its neurohumoral modulating effects.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Citotoxicidade Imunológica/efeitos dos fármacos , Miocardite/tratamento farmacológico , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Doença Aguda , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Linhagem Celular Tumoral , Citocinas/sangue , Citocinas/imunologia , Testes Imunológicos de Citotoxicidade , Modelos Animais de Doenças , Eritrócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Miocardite/imunologia , Miocardite/patologia , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologia , Naloxona/administração & dosagem , Naloxona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/farmacologia , Radioimunoensaio , beta-Endorfina/sangueRESUMO
It was previously shown that administration of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) aggravated murine viral myocarditis by increasing myocardial virus titres. Experimental autoimmune myocarditis in mice and rats mimics human fulminant myocarditis. The effects of L-arginine, a precursor of nitric oxide, upon heart failure in experimental autoimmune myocarditis were evaluated. Dietary L-arginine (L-arginine group) and L-arginine plus N(G)-nitro-L-arginine methyl ester (L-arginine + l-NAME group) were administered to C57BL/6 mice immunized with porcine cardiac myosin over 3 weeks. An untreated myocarditis group was prepared. Cardiac damage was less in the L-arginine group compared with the other two groups, as was incidence of heart failure. In addition, extracellular matrix change was less prominent in the L-arginine group. Plasma concentrations of nitric oxide were elevated in the L-arginine group. Cytotoxic activities of lymphocytes were lower in L-arginine group than in other two groups. L-arginine treatment may be effective in preventing the development of heart failure in experimental myocarditis by maintaining extracellular matrix and reducing the cytotoxic activity of lymphocytes.
Assuntos
Arginina/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Miocardite/tratamento farmacológico , Miocardite/imunologia , Miocárdio/imunologia , Animais , Doenças Autoimunes/patologia , Testes Imunológicos de Citotoxicidade , Matriz Extracelular/patologia , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Miocardite/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miosinas , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/sangue , SuínosRESUMO
BACKGROUND: There are few reports on the precise electrocardiographic characteristics of acute myocarditis. The present study was focused on QRS voltage changes at the superacute stage of murine myocarditis. METHODS: Serial electrocardiograms were recorded during the acute stage of viral myocarditis in mice, and then the cardiac pathology was examined. After recording baseline electrocardiograms, mice (n=235) were inoculated intraperitoneally with the encephalomyocarditis virus, resulting in severe myocarditis. Electrocardiograms were serially recorded until nine days after virus inoculation (superacute stage, days 3 to 6; acute stage, days 7 to 9). Changes in heart rate and QRS voltages were analyzed. RESULTS: Serial electrocardiograms revealed that heart rates began to increase after day 3, and that the sum of the QRS voltages increased on day 3 and then decreased on days 7 to 9. Trivial mononuclear cell infiltrations and interstitial edema were most frequently found in mice at the superacute stage. CONCLUSIONS: Transient increase of the QRS voltages at the superacute stage of myocarditis was demonstrated, which may be due to an increase in ventricular mass caused by interstitial edema at this stage.
RESUMO
BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARgamma) is a transcription factor implicated in the expression of proinflammatory cytokines in atheroma-associated cells, and the expression of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha) and matrix metalloproteinases (MMPs), represents a critical step in atherogenesis and atherosclerosis. In this study, we test the hypothesis of whether a polymorphism corresponding to C161T substitution in exon 6 of the PPARgamma gene may affect the expression of proinflammatory cytokines and the onset of coronary artery diseases (CADs) in a Chinese population. METHODS: We have studied distribution of the PPARgamma C161T substitution at exon 6 in 247 patients with CAD and 214 patients with chest pain syndrome. The plasma concentrations of MMP-9 and TNF-alpha were measured by enzyme-linked immunosorbent assay. RESULTS: The results showed that the frequencies of the CC, CT, and TT genotypes were 61.9%, 34.0%, and 4.1% in CAD, and 51.4%, 45.3%, and 3.3% in chest pain syndrome, respectively. There was a significant association between the PPARgamma C161T polymorphism and CAD. The T allele carriers (CT + TT) had significantly reduced CAD risk compared with the CC homozygotes (odds ratio 0.547, 95% CI 0.327-0.831, P = .012) in a logistic regression model after controlling known independent factors for CAD. The CC homozygotes also had increased MMP-9 and TNF-alpha levels compared with T allele carriers. Moreover, the CC homozygotes were more susceptible to acute coronary syndrome than T allele carriers. CONCLUSIONS: PPARgamma C161T polymorphism was associated with angiographically documented CAD in a Chinese population. The T allele of the PPARgamma gene might have a protective effect on the progression of CAD and reduce the onset of acute coronary syndrome, which might be associated with the decreased expression of MMP-9 and TNF-alpha in patients with CAD.