RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Zygophyllum album is widely used to treat many cardiovascular diseases (CVDs) and as anti-inflammatory plant. AIM OF THE STUDY: This study aimed to investigate the mechanism of the potential protective effects of Zygophyllum album roots extract (ZARE) against myocardial damage and fibrosis induced by a chronic exposure to deltamethrin (DLM) in rats. MATERIALS AND METHODS: Bioactive compounds present in ZARE were analyzed by HPLC-DAD-ESI-QTOF-MS/MS. In vivo, DLM (4â¯mg/kg body weight), ZARE (400â¯mg/kg body weight) and DLM with ZARE were administered to rats orally for 60 days. Biochemical markers (LDH, ALT, CK, CK-MB and cTn-I) were assessed in the plasma by an auto-analyzer. Pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) were evaluated by a sandwich ELISA. NF-κB was quantified at mRNA levels by real time PCR. Heart tissue was used to determine cardiac oxidative stress markers (MDA, PC, SOD, CAT, and GPx). Masson's Trichrome (MT) and Sirius Red (SR) stainings were used for explored fibrosis statues. RESULTS: Phytochemical analysis using HPLC-DAD-ESI-QTOF-MS/MS revealed the presence of twenty six molecules including phenolic compounds and saponins. ZARE significantly improved the heart injury markers (LDH, ALT, CK, CK-MB and cTn-I), lipid peroxidation (MDA), protein oxidation (PC), antioxidant capacity (SOD, CAT, and GPx), and DNA structure, which were altered by DLM exposure. Moreover, ZARE cotreatment reduced the expressions of NF-κB, decreased plasmatic pro-inflammatory cytokines concentration (TNF-α, IL-1ß and IL-6), and suppressed the myocardial collagen deposition, as observed by Sirius Red and Masson's Trichrome staining. CONCLUSION: ZARE ameliorated the severity of DLM-induced myocardial injuries through improving the oxidative status and reducing profibrotic cytokines production. The ZARE actions could be mediated by downregulation of NF-κB mRNA.
Assuntos
Anti-Inflamatórios/farmacologia , Cardiotônicos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Extratos Vegetais/farmacologia , Zygophyllum/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/uso terapêutico , Apoptose/efeitos dos fármacos , Cardiotônicos/química , Cardiotônicos/isolamento & purificação , Cardiotônicos/uso terapêutico , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Etnofarmacologia , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Miocárdio/imunologia , Miocárdio/patologia , NF-kappa B/metabolismo , Nitrilas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Raízes de Plantas/química , Piretrinas/toxicidade , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas em Tandem , TunísiaRESUMO
BACKGROUND: The impact of gut microbiota on the regulation of host physiology has recently garnered considerable attention, particularly in key areas such as the immune system and metabolism. These areas are also crucial for the pathophysiology of and repair after myocardial infarction (MI). However, the role of the gut microbiota in the context of MI remains to be fully elucidated. METHODS: To investigate the effects of gut microbiota on cardiac repair after MI, C57BL/6J mice were treated with antibiotics 7 days before MI to deplete mouse gut microbiota. Flow cytometry was applied to examine the changes in immune cell composition in the heart. 16S rDNA sequencing was conducted as a readout for changes in gut microbial composition. Short-chain fatty acid (SCFA) species altered after antibiotic treatment were identified by high-performance liquid chromatography. Fecal reconstitution, transplantation of monocytes, or dietary SCFA or Lactobacillus probiotic supplementation was conducted to evaluate the cardioprotective effects of microbiota on the mice after MI. RESULTS: Antibiotic-treated mice displayed drastic, dose-dependent mortality after MI. We observed an association between the gut microbiota depletion and significant reductions in the proportion of myeloid cells and SCFAs, more specifically acetate, butyrate, and propionate. Infiltration of CX3CR1+ monocytes to the peri-infarct zone after MI was also reduced, suggesting impairment of repair after MI. Accordingly, the physiological status and survival of mice were significantly improved after fecal reconstitution, transplantation of monocytes, or dietary SCFA supplementation. MI was associated with a reorganization of the gut microbial community such as a reduction in Lactobacillus. Supplementing antibiotic-treated mice with a Lactobacillus probiotic before MI restored myeloid cell proportions, yielded cardioprotective effects, and shifted the balance of SCFAs toward propionate. CONCLUSIONS: Gut microbiota-derived SCFAs play an important role in maintaining host immune composition and repair capacity after MI. This suggests that manipulation of these elements may provide opportunities to modulate pathological outcome after MI and indeed human health and disease as a whole.
Assuntos
Antibacterianos/toxicidade , Bactérias/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Monócitos/imunologia , Infarto do Miocárdio/microbiologia , Miocárdio/imunologia , Animais , Bactérias/imunologia , Bactérias/metabolismo , Modelos Animais de Doenças , Disbiose , Ácidos Graxos/administração & dosagem , Ácidos Graxos/metabolismo , Transplante de Microbiota Fecal , Feminino , Interações Hospedeiro-Patógeno , Lactobacillus/imunologia , Lactobacillus/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/metabolismo , Monócitos/transplante , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Probióticos/administração & dosagem , Células RAW 264.7RESUMO
Myocardial infarction (MI) is a major cause of death in Western countries and finding new strategies for its prevention and treatment is thus of high priority. In a previous study, we have demonstrated a pathophysiologic relevance for the heterophilic interaction of CCL5 and CXCL4 in the progression of atherosclerosis. A specifically designed compound (MKEY) to block this CCL5-CXCR4 interaction is investigated as a potential therapeutic in a model of myocardial ischemia/reperfusion (I/R) damage. 8 week-old male C57BL/6 mice were intravenously treated with MKEY or scrambled control (sMKEY) from 1 day before, until up to 7 days after I/R. By using echocardiography and intraventricular pressure measurements, MKEY treatment resulted in a significant decrease in infarction size and preserved heart function as compared to sMKEY-treated animals. Moreover, MKEY treatment significantly reduced the inflammatory reaction following I/R, as revealed by specific staining for neutrophils and monocyte/macrophages. Interestingly, MKEY treatment led to a significant reduction of citrullinated histone 3 in the infarcted tissue, showing that MKEY can prevent neutrophil extracellular trap formation in vivo. Disrupting chemokine heterodimers during myocardial I/R might have clinical benefits, preserving the therapeutic benefit of blocking specific chemokines, and in addition, reducing the inflammatory side effects maintaining normal immune defence.
Assuntos
Cardiotônicos/uso terapêutico , Quimiocina CCL5/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Fator Plaquetário 4/metabolismo , Multimerização Proteica/efeitos dos fármacos , Animais , Cardiotônicos/farmacologia , Quimiocina CCL5/imunologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/imunologia , Peptídeos Cíclicos/farmacologia , Fator Plaquetário 4/imunologia , Multimerização Proteica/imunologia , Resultado do TratamentoRESUMO
Myocardial infarction is a devastating event, especially when reperfusion is not performed. The inflammatory response has been associated with the pathogenesis of left ventricular remodeling after myocardial infarction. This study focused on the anti-apoptotic and anti-inflammatory effects of sesamin on ligation of the left anterior descending artery in an experimental mouse model and the potential mechanism underlying the activation of JNK and NF-κB pathways. Mice with MI induced by surgical left anterior descending coronary artery ligation were treated with sesamin by gavage for 1 week. Results showed that after treatment with sesamin, MI-induced cardiac damage was alleviated significantly, indicated by the histopathological examination. The myocardial apoptosis in the border zone was dramatically reduced by sesamin, resulting from the altered expression of apoptosis factors. Moreover, treatment with sesamin also mitigated the inflammatory response, decreased expression of cytokines and the inactivation of NF-κB (nuclear factor κB) signaling. Sesamin decreased the levels of p-JNK protein, which in turn inactivated pro-apoptotic signaling events by restoring the balance between mitochondrial pro-apoptotic Bcl-2 and Bax proteins. Thus, our study suggests that sesamin could alleviate MI-induced cardiac dysfunction through decrease of myocardial apoptosis and inflammatory response.
Assuntos
Apoptose/efeitos dos fármacos , Dioxóis/administração & dosagem , Lignanas/administração & dosagem , MAP Quinase Quinase 4/imunologia , Infarto do Miocárdio/tratamento farmacológico , NF-kappa B/imunologia , Extratos Vegetais/administração & dosagem , Sesamum/química , Animais , Modelos Animais de Doenças , Humanos , MAP Quinase Quinase 4/genética , Masculino , Camundongos , Infarto do Miocárdio/genética , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/fisiopatologia , NF-kappa B/genética , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/imunologiaRESUMO
Few studies have examined the acute cardiovascular effects of airborne allergens. We conducted a case-crossover study to evaluate the relationship between airborne allergen concentrations and emergency room visits for myocardial infarction (MI) in Ontario, Canada. In total, 17,960 cases of MI were identified between the months of April and October during the years 2004-2011. Daily mean aeroallergen concentrations (pollen and mold spores) were assigned to case and control periods using central-site monitors in each city along with daily measurements of meteorological data and air pollution (nitrogen dioxide and ozone). Odds ratios and their 95% confidence intervals were estimated using conditional logistic regression models adjusting for time-varying covariates. Risk of MI was 5.5% higher (95% confidence interval (CI): 3.4, 7.6) on days in the highest tertile of total pollen concentrations compared with days in the lowest tertile, and a significant concentration-response trend was observed (P < 0.001). Higher MI risk was limited to same-day pollen concentrations, with the largest risks being observed during May (odds ratio = 1.16, 95% CI: 1.00, 1.35) and June (odds ratio = 1.10, 95% CI: 1.00, 1.22), when tree and grass pollen are most common. Mold spore concentrations were not associated with MI. Our findings suggest that airborne pollen might represent a previously unidentified environmental risk factor for myocardial infarction.
Assuntos
Alérgenos/efeitos adversos , Infarto do Miocárdio/imunologia , Pólen/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Cidades/epidemiologia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Ontário/epidemiologiaRESUMO
Although controversial, some data suggest that omega-3 polyunsaturated fatty acids (PUFA) are beneficial to cardiovascular diseases, and could reduce infarct size. In parallel, we have reported that the administration of Resolvin D1 (RvD1), a metabolite of docosahexaenoic acid, an omega-3 PUFA, can reduce infarct size. The present study was designed to determine if the inhibition of two important enzymes involved in the formation of RvD1 from omega-3 PUFA could reduce the cardioprotective effect of omega-3 PUFA. Sprague-Dawley rats were fed with a diet rich in omega-3 PUFA during 10 days before myocardial infarction (MI). Two days before MI, rats received a daily dose of Meloxicam, an inhibitor of cyclooxygenase-2, PD146176, an inhibitor of 15-lipoxygenase, both inhibitors or vehicle. MI was induced by the occlusion of the left coronary artery for 40min followed by reperfusion. Infarct size and neutrophil accumulation were evaluated after 24h of reperfusion while caspase-3, -8 and Akt activities were assessed at 30min of reperfusion. Rats receiving inhibitors, alone or in combination, showed a larger infarct size than those receiving omega-3 PUFA alone. Caspase-3 and -8 activities are higher in ischemic areas with inhibitors while Akt activity is diminished in groups treated with inhibitors. Moreover, the study showed that RvD1 restores cardioprotection when added to the inhibitors. Results from this study indicate that the inhibition of the metabolism of Omega-3 PUFA attenuate their cardioprotective properties. Then, resolvins seem to be an important mediator in the cardioprotection conferred by omega-3 PUFA in our experimental model of MI.
Assuntos
Cardiotônicos/metabolismo , Cardiotônicos/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Animais , Cardiotônicos/uso terapêutico , Caspase 3/metabolismo , Caspase 8/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dieta/efeitos adversos , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Relação Dose-Resposta a Droga , Ácidos Graxos Ômega-3/uso terapêutico , Inibidores de Lipoxigenase/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/metabolismo , NF-kappa B/metabolismo , Neutrófilos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVES: Despite recent advances in the understanding of the role of NLRP3 inflammasomes in coronary atherosclerosis, further work on their activation and clinical implications remains to be performed. In this study, we aimed to evaluate the effect of the dose of rosuvastatin on NLRP3 and cathepsin-B expression in peripheral blood monocytes in patients with acute coronary syndrome. METHODS: A total of 123 participants were enrolled in this study; these included acute myocardial infarction (AMI) patients (n=53), unstable angina patients (UA, n=40), and normal controls (n=30). AMI and UA patients were divided into high-dose rosuvastatin (20 mg) and low-dose rosuvastatin (5 mg) groups. NLRP3, cathepsin-B, and downstream cytokine expressions were appropriately evaluated using real-time PCR, flow cytometry, western blotting and enzyme-linked immunosorbent assay. The concentrations of serum inflammatory markers were also evaluated for correlation with NLRP3 levels. RESULTS: AMI and UA patients had higher NLRP3, cathepsin-B, interleukin-18 (IL-18), pro-IL-18, IL-1ß, and pro-IL-1ß expressions as compared with the control group (P<0.05). This corresponded with higher levels of serum total cholesterol, serum low-density lipoprotein cholesterol, and oxidized low-density lipoprotein in UA and AMI patients (P<0.05). Rosuvastatin at a concentration of 20 mg led to a significant decrease (P<0.05) in the expressions of NLRP3, cathepsin-B, and their downstream cytokines as compared with 5 mg rosuvastatin (P>0.05) from baseline to 4 weeks. This study also showed a positive correlation between NLRP3, cathepsin-B, and downstream inflammatory mediators. CONCLUSION: NLRP3 is involved in inflammation that leads to atherosclerosis. A high dose of rosuvastatin can modulate the inflammatory process of atherosclerosis by downregulating the expression of NLRP3, cathepsin-B, and their downstream mediators. These findings provide insight into the pathogenesis and management of acute coronary syndrome, with NLRP3 as the potential target.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Angina Instável/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Proteínas de Transporte/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inflamassomos/sangue , Mediadores da Inflamação/sangue , Monócitos/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Rosuvastatina Cálcica/administração & dosagem , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/genética , Síndrome Coronariana Aguda/imunologia , Adulto , Idoso , Angina Instável/sangue , Angina Instável/diagnóstico , Angina Instável/genética , Angina Instável/imunologia , Biomarcadores/sangue , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Catepsina B/sangue , China , Citocinas/sangue , Feminino , Humanos , Inflamassomos/genética , Inflamassomos/imunologia , Mediadores da Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/genética , Infarto do Miocárdio/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fatores de Tempo , Adulto JovemRESUMO
Polyunsaturated fatty acid (PUFA) intake has increased over the last 100 yr, contributing to the current obesogenic environment. Obesity and aging are prominent risk factors for myocardial infarction (MI). How obesity interacts with aging to alter the post-MI response, however, is unclear. We tested the hypothesis that obesity in aging mice would impair the resolution of post-MI inflammation. PUFA diet (PUFA aging group) feeding to 12-mo-old C57BL/6J mice for 5 mo showed higher fat mass compared with standard lab chow (LC)-fed young (LC young group; 3-5 mo old) or aging alone control mice (LC aging group). LC young, LC aging, and PUFA aging mice were subjected to coronary artery ligation to induce MI. Despite similar infarct areas post-MI, plasma proteomic profiling revealed higher VCAM-1 in the PUFA aging group compared with LC young and LC aging groups, leading to increased neutrophil infiltration in the PUFA aging group (P<0.05). Macrophage inflammatory protein-1γ and CD40 were also increased at day 1, and myeloperoxidase remained elevated at day 5, an observation consistent with delayed wound healing in the PUFA aging group. Lipidomic analysis showed higher levels of arachidonic acid and 12(S)-hydroxyeicosatetraenoic acid at day 1 post-MI in the PUFA aging group compared with the LC aging group (all P<0.05), thereby mediating neutrophil extravasation in the PUFA aging group. The inflammation-resolving enzymes 5-lipoxygenase, cyclooxygenase-2, and heme oxyegnase-1 were altered to delay wound healing post-MI in the PUFA aging group compared with LC young and LC aging groups. PUFA aging magnifies the post-MI inflammatory response and impairs the healing response by stimulating prolonged neutrophil trafficking and proinflammatory lipid mediators.
Assuntos
Envelhecimento/metabolismo , Infarto do Miocárdio/metabolismo , Obesidade/metabolismo , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Animais , Ácido Araquidônico/metabolismo , Antígenos CD40/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos Ômega-3/metabolismo , Heme Oxigenase-1/metabolismo , Inflamação/metabolismo , Lipoxigenase/metabolismo , Proteínas Inflamatórias de Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/complicações , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/fisiopatologia , Infiltração de Neutrófilos , Obesidade/etiologia , Obesidade/fisiopatologia , Função Ventricular , CicatrizaçãoRESUMO
BACKGROUND: The current study was designed to test our hypothesis that atorvastatin could reduce infarct size in intact mice by activating eNOS, specifically the eNOS in bone marrow-derived cells. C57BL/6J mice (B6) and congenic eNOS knockout (KO) mice underwent 45 min LAD occlusion and 60 min reperfusion. Chimeric mice, created by bone marrow transplantation between B6 and eNOS KO mice, underwent 40 min LAD occlusion and 60 min reperfusion. Mice were treated either with vehicle or atorvastatin in 5% ethanol at a dose of 10 mg/kg IV 5 min before initiating reperfusion. Infarct size was evaluated by TTC and Phthalo blue staining. RESULTS: Atorvastatin treatment reduced infarct size in B6 mice by 19% (p<0.05). In eNOS KO vehicle-control mice, infarct size was comparable to that of B6 vehicle-control mice (pâ=âNS). Atorvastatin treatment had no effect on infarct size in eNOS KO mice (pâ=âNS). In chimeras, atorvastatin significantly reduced infarct size in B6/B6 (donor/recipient) mice and B6/KO mice (p<0.05), but not in KO/KO mice or KO/B6 mice (pâ=âNS). CONCLUSIONS: The results demonstrate that acute administration of atorvastatin significantly reduces myocardial ischemia/reperfusion injury in an eNOS-dependent manner, probably through the post-transcriptional activation of eNOS in bone marrow-derived cells.
Assuntos
Atorvastatina/farmacologia , Cardiotônicos/farmacologia , Infarto do Miocárdio/enzimologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Óxido Nítrico Sintase Tipo III/genética , Animais , Atorvastatina/uso terapêutico , Células da Medula Óssea/enzimologia , Transplante de Medula Óssea , Cardiotônicos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/imunologia , Infiltração de Neutrófilos , Óxido Nítrico Sintase Tipo III/metabolismoRESUMO
OBJECTIVE: Therapeutic safety and efficacy are the basic prerequisites for clinical gene therapy. We investigated the effect of high-dose molecular cardiac surgery with recirculating delivery (MCARD)-mediated adeno-associated virus 9 (AAV9)/sarcoplasmic reticulum Ca(2+) adenosine triphosphatase (SERCA2a) gene delivery on clinical parameters, oxidative stress, humoral and cellular immune responses, and cardiac remodeling. METHODS: Ischemic cardiomyopathy was generated in a sheep model. The sheep were assigned to 1 of 2 groups: control (n = 10) and study (MCARD, n = 6). The control group underwent no intervention and the study group received 10(14) genome copies of AAV9/SERCA2a 4 weeks after infarction. RESULTS: Our ischemic model produced reliable infarcts leading to heart failure. The baseline ejection fraction in the MCARD group was 57.6% ± 1.6% versus 61.2% ± 1.9% in the control group (P > .05). At 12 weeks after infarction, the MCARD group had superior left ventricular function compared with the control group: stroke volume index, 46.6 ± 1.8 versus 35.8 ± 2.5 mL/m(2) (P < .05); ejection fraction, 46.2% ± 1.9% versus 38.7% ± 2.5% (P < .05); and left ventricular end-systolic and end-diastolic dimensions, 41.3 ± 1.7 versus 48.2 ± 1.4 mm and 51.2 ± 1.5 versus 57.6 ± 1.7 mm, respectively (P < .05). The markers of oxidative stress were significantly reduced in the infarct zone in the MCARD group. No positive T-cell-mediated immune response was seen in the MCARD group at any point. Myocyte hypertrophy was also significantly attenuated in the MCARD group compared with the control group. CONCLUSIONS: Cardiac overexpression of the SERCA2a gene by way of MCARD is a safe therapeutic intervention. It significantly improves left ventricular function, decreases markers of oxidative stress, abrogates myocyte hypertrophy, arrests remodeling, and does not induce a T-cell-mediated immune response.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Dependovirus/enzimologia , Técnicas de Transferência de Genes , Vetores Genéticos , Infarto do Miocárdio/terapia , Miocárdio/enzimologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Animais , Biomarcadores/metabolismo , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Cardiomegalia/enzimologia , Cardiomegalia/genética , Cardiomegalia/prevenção & controle , Dependovirus/genética , Modelos Animais de Doenças , Técnicas de Transferência de Genes/efeitos adversos , Humanos , Imunidade Celular , Imunidade Humoral , Masculino , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/imunologia , Miocárdio/patologia , Estresse Oxidativo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Ovinos , Volume Sistólico , Linfócitos T/imunologia , Fatores de Tempo , Função Ventricular Esquerda , Remodelação VentricularRESUMO
Complement C3 is an emerging risk factor in metabolic and cardiovascular diseases. It is elevated in patients with cardiovascular disease, predicts future myocardial infarction, is closely related to insulin resistance and appears to be involved in atherogenesis. C3 levels have been associated with body fat. The aim of this study was to compare C3 levels in psoriasis patients and controls and to investigate within psoriasis patients the relationship between C3 levels with several measures of body fat, markers of cardiometabolic risk and subclinical atherosclerosis. Eighty adult patients with severe plaque-type psoriasis, without psoriatic arthritis or receiving systemic therapy/phototherapy in the previous 3 months, and 95 otherwise healthy patients were enrolled. Subjects with cardiovascular disease, other systemic inflammatory diseases, use of anti-inflammatory drugs or any infectious diseases in the 4 weeks prior to study enrollment were excluded. All subjects underwent clinical and laboratory evaluation and psoriasis patients underwent multidetector computed tomography scan for coronary artery calcification, abdominal fat and epicardial adipose tissue quantification. C3 levels were increased in psoriasis patients compared to controls (129.25 ± 20.92 vs 118.24 ± 17.86, P < 0.001), even after adjustment for age, sex and waist circumference (P = 0.043), indicating that this association was not solely mediated by the adipose tissue. Within psoriasis patients, C3 levels were independently associated with abdominal visceral fat, insulin resistance, metabolic syndrome and oxidized LDL-cholesterol, while C-reactive protein did not, showing that C3 may be a better marker of cardiometabolic risk than C-reactive protein. Although more studies are needed, C3 may be a useful marker of cardiometabolic risk in psoriasis.
Assuntos
Biomarcadores/sangue , Complemento C3/imunologia , Gordura Intra-Abdominal/fisiologia , Síndrome Metabólica/sangue , Psoríase/sangue , Adulto , Aterosclerose/sangue , Aterosclerose/imunologia , Proteína C-Reativa/metabolismo , LDL-Colesterol/metabolismo , Complemento C3/metabolismo , Estudos Transversais , Feminino , Humanos , Inflamação/sangue , Inflamação/imunologia , Resistência à Insulina/imunologia , Masculino , Síndrome Metabólica/imunologia , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/imunologia , Psoríase/imunologia , Risco , Circunferência da CinturaRESUMO
CONTEXT: Magnesium lithospermate B (MLB), an active polyphenol acid of Danshen [Radix Salviae miltiorrhizae (Labiatae)], showed renoprotective, neuroprotective and myocardial salvage effects. Previous studies demonstrated that MLB could effectively suppress the production of cytokines and their associated signaling pathways in activated human T cells. OBJECTIVE: The purpose of this study was to examine the beneficial effects of MLB on myocardial ischemia/reperfusion (MI/R) injury and to explore its potential mechanisms related to anti-inflammation. MATERIALS AND METHODS: Sprague-Dawley rats were grouped as sham group, model group and MLB-treated (15, 30 and 60 mg/kg) groups. Animals were subjected to MI/R injury by the occlusion of left anterior descending artery for 30 min followed by reperfusion for 3 h. At the end of reperfusion, blood samples were collected to determine the serum levels of cardiac troponin (cTnI), creatine kinase-MB (CK-MB), tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6). Hearts were harvested to assess infarct size, histopathological changes and the activity of myeloperoxidase (MPO). The expression of phosphor-IkB-α and phosphor-nuclear factor kappa B (NF-κB) were assayed by western blot. RESULTS: MLB administration significantly (p < 0.05) reduced: (1) ST-segment elevation (0.23 mv), (2) the infarct size (22.5%), (3) histological scores of myocardial injury (1.67 score), (4) myocardial injury marker enzymes: cTnI (5.64 ng/ml) and CK-MB (49.57 ng/ml) levels, (5) pro-inflammatory cytokines: TNF-α (97.36 pg/ml), IL-1ß (93.35 pg/ml) and IL-6 (96.84 pg/ml) levels, (6) MPO activity (1.82 U/mg), (7) phosphor-NF-κB (0.87) and phosphor-IkB-α (0.96) expression. DISCUSSION AND CONCLUSION: Our study provided evidence that MLB ameliorated the inflammatory process associated with MI/R injury via NF-κB inactivation.
Assuntos
Anti-Inflamatórios/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Inflamação/prevenção & controle , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Biomarcadores/sangue , Creatina Quinase Forma MB/sangue , Citocinas/sangue , Modelos Animais de Doenças , Eletrocardiografia , Proteínas I-kappa B/metabolismo , Inflamação/sangue , Inflamação/imunologia , Mediadores da Inflamação/sangue , Masculino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologia , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Peroxidase/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Troponina I/sangueRESUMO
Myocardial infarction (MI) is the most common cause of cardiac injury in the Western world. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Inflammatory cytokines and vascular cell adhesion molecules (VCAM) promote adhesive interactions between leukocytes and endothelial cells, resulting in the transmigration of inflammatory cells into the site of injury. Low vitamin D levels are associated with higher prevalence of cardiovascular risk factors and a higher risk of MI. In this paper, we examine the effects of short-term vitamin D supplementation on inflammatory cytokine levels after an acute coronary syndrome. We recruited patients arriving to the hospital with an acute MI. All patients received optimal medical therapy and underwent a coronary catheterization. Half of the patients were randomly selected and treated with a daily supplement of vitamin D (4,000 IU) for 5 days. A short course of treatment with vitamin D effectively attenuated the increase in circulating levels of inflammatory cytokines after an acute coronary event. Control group patients had increased cytokine and cellular adhesion molecules serum concentrations after 5 days, while the vitamin D-treated group had an attenuated elevation or a reduction of these parameters. There were significant differences in VCAM-1 levels, C-reactive protein, and interleukin-6. There were trends toward significance in interleukin-8 levels. There were no significant differences in circulating levels of intercellular adhesion molecule 1, E-selectin, vascular endothelial growth factor, and tumor necrosis factor-α. These findings provide information on the anti-inflammatory effects of vitamin D on the vascular system and suggest mechanisms that mediate some of its cardioprotective properties. There is place for further studies involving prolonged vitamin D treatment in patients suffering from ischemic heart disease.
Assuntos
Síndrome Coronariana Aguda/imunologia , Síndrome Coronariana Aguda/terapia , Interleucina-6/metabolismo , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/terapia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Vitamina D/administração & dosagem , Adulto , Idoso , Proteína C-Reativa/metabolismo , Cateterismo Cardíaco , Vasos Coronários/cirurgia , Feminino , Finlândia , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-6/genética , Interleucina-8/genética , Interleucina-8/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Vitamina D/efeitos adversos , Deficiência de Vitamina DRESUMO
The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) or nucleotide-binding domain leucine-rich repeat-containing family of genes plays an important role in the development of innate immune responses. Some family members are known to form multiprotein complexes known as inflammasomes that regulate the processing and secretion of proinflammatory mediators, such as interleukin-1ß and interleukin-18. Activity of the inflammasome is triggered not only by microbial infection, but also by a wide range of both exogenous and endogenous noninfectious stimuli. Consequently, the dysregulation of inflammasome activity is associated with numerous proinflammatory, non-microbial human diseases. The discovery of NLRP3 gene mutations in autoinflammatory diseases such as Muckle-Wells syndrome has led to the association of NLRs in the pathogenesis of many non-microbial diseases that include arthritis, neurodegenerative disorders, metabolic disorders (obesity and diabetes), cardiovascular disease (atherosclerosis, myocardial infarction), inflammatory bowel disease, kidney disease and hypersensitivity dermatitis. A number of NLRs are also associated with human disease in the absence of inflammasome activity, suggesting additional roles for NLRs in the regulation of inflammation and disease. This review serves to provide a summary of NLR-associated diseases and, where possible, the mechanisms behind the associations.
Assuntos
Inflamassomos/imunologia , Mediadores da Inflamação/imunologia , Inflamação/imunologia , Receptores de Superfície Celular/imunologia , Animais , Artrite/imunologia , Artrite/metabolismo , Aterosclerose/imunologia , Aterosclerose/metabolismo , Síndromes Periódicas Associadas à Criopirina/imunologia , Síndromes Periódicas Associadas à Criopirina/metabolismo , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Humanos , Inflamação/metabolismo , Interleucina-18/imunologia , Interleucina-18/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/metabolismo , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/metabolismo , Obesidade/imunologia , Obesidade/metabolismo , Estrutura Terciária de Proteína , Receptores de Superfície Celular/metabolismoRESUMO
Proinflammatory cytokine responses might occur in elderly individuals with cardiovascular (CV) disease, cerebro-vascular (CVA) disease, and/or pulmonary disease (PD). Spiritual activation is an important coping mechanism, since psychiatric depression is an important risk factor for these individuals. Thirty-three very elderly individuals (87 ± 8 years) with previous CVD, CVA and/or PD participated in weekly 30 minute sermons by chaplains for over 20 months of chaplain liturgy (CL group). All underwent Holter ECG during the procedures and cardiac autonomic activities were assessed by maximum entropy analysis. Plasma IL-10 and IL-6 levels were compared with 26 age-matched (85 ± 10 years) individuals who did not participate in these activities (non-CL group). Both high frequency (HF) and pNN50 of heart rate variability (HRV) were higher in the CL group than in the non-CL group (HF, 190 ± 55 versus 92 ± 43 nu, P < 0.05; pNN50, 10.5 ± 16% versus 3.6 ± 3.8%, P < 0.05), whereas LF/HF was lower (1.4 ± 1.5 versus 2.2 ± 2.8, P < 0.05). Levels of IL-10/IL-6 were higher in the CL group (3.96 ± 5.0 versus 1.79 ± 1.6, P < 0.05). Hospitalization rates due to CVD and/or PD were lower in the CL group than in the non-CL group (4/33 versus 11/26, P < 0.05). We conclude that spiritual activation can modify proinflammatory cytokines and suppress CVD, CVA and/or PD via vagal modifications. Spiritual activation might be helpful for health in these very elderly individuals.
Assuntos
Eletrocardiografia Ambulatorial , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/psicologia , Frequência Cardíaca/fisiologia , Interleucina-10/sangue , Interleucina-6/sangue , Pneumopatias/imunologia , Pneumopatias/psicologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/psicologia , Religião e Medicina , Processamento de Sinais Assistido por Computador , Espiritualidade , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/psicologia , Adaptação Psicológica/fisiologia , Idoso , Idoso de 80 Anos ou mais , Sistema Nervoso Autônomo/fisiopatologia , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus/psicologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , MasculinoRESUMO
This review addresses the importance of psychoneuroimmunology (PNI) studies in understanding the role of acute and chronic psychological stressors on the immune system and development of coronary artery disease (CAD). Firstly, it illustrates how psychological stressors change endothelial function and lead to chemotaxis. Secondly, acute psychological stressors lead to leukocytosis, increased natural killer cell cytotoxicity and reduced proliferative response to mitogens while chronic psychological stressors may lead to adverse health effects. This will result in changes in cardiovascular function and development of CAD. Thirdly, acute and chronic psychological stressors will increase haemostatic factors and acute phase proteins, possibly leading to thrombus formation and myocardial infarction. The evidence for the effects of acute and chronic psychological stress on the onset and progression of CAD is consistent and convincing. This paper also highlights potential research areas and implications of early detection of immunological changes and cardiovascular risk in people under high psychological stress.
Assuntos
Doença da Artéria Coronariana/imunologia , Doença da Artéria Coronariana/psicologia , Inflamação/psicologia , Estresse Psicológico/imunologia , Proteínas de Fase Aguda , Humanos , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/psicologia , Trombose/imunologia , Trombose/psicologiaRESUMO
BACKGROUND: High-dose statin treatment improves clinical outcome of ST-elevated myocardial infarction (STEMI). However, the effect of low-dose atorvastatin treatment on inflammatory and pro-thrombotic molecules during the post-STEMI period is unclear. We investigated the effect of low-dose atorvastatin treatment on the kinetics of cytokine IL-6, vascular cell adhesion molecule (sVCAM-1) and endothelium-derived markers of thrombosis/fibrinolysis such as von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA), post STEMI. METHODS: Twenty-four normocholesterolemic patients with STEMI were randomised to receive atorvastatin 10mg/day or no statin treatment for 6 weeks after the event. Blood samples were obtained by their admission to the hospital as well as at weeks 1 and 6. Circulating levels of IL-6, sVCAM-1, vWF, PAI-1 and tPA were determined by ELISA. RESULTS: Atorvastatin induced a decrease of IL-6 at 1 week, an effect which reached significance compared to baseline at 6 weeks post STEMI (p<0.05 vs baseline). Serum sVCAM-1 was increased in controls both at 1 and 6 weeks post-STEMI (p<0.05 vs baseline), an effect prevented by atorvastatin. Plasma vWF was increased 1 week post-STEMI in controls (p<0.05 vs baseline) and returned to baseline at 6 weeks, an effect prevented by atorvastatin. Plasma PAI-1, tPA and the PAI-1/tPA ratio remained unchanged in both groups. CONCLUSION: Early initiation of low-dose atorvastatin treatment decreases the expression of IL-6 and sVCAM-1 and the release of vWF in patients with STEMI. Therefore, low-dose atorvastatin, modulates inflammatory response and decreases endothelial injury and activation in patients with recent STEMI.
Assuntos
Endotélio Vascular/lesões , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Infarto do Miocárdio/sangue , Infarto do Miocárdio/tratamento farmacológico , Pirróis/uso terapêutico , Atorvastatina , Biomarcadores/sangue , Eletrocardiografia , Feminino , Humanos , Inflamação/sangue , Inflamação/tratamento farmacológico , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/imunologia , Inibidor 1 de Ativador de Plasminogênio/sangue , Fatores de Tempo , Ativador de Plasminogênio Tecidual/sangue , Molécula 1 de Adesão de Célula Vascular/sangue , Fator de von Willebrand/análiseRESUMO
Increased oxidative stress and antioxidant deficit have been suggested to play a major role in isoproterenol-induced myocardial infarction. The present study was designed to evaluate the effect of alpha-mangostin on the antioxidant defense system and lipid peroxidation against isoproterenol-induced myocardial infarction in rats. Induction of rats with ISO (150 mg/kg body weight, ip) for 2 days resulted in a marked elevation in lipid peroxidation, serum marker enzymes (LDH, CPK, GOT, and GPT) and a significant decrease in the activities of endogenous antioxidants (SOD, CAT, GPx, GST, and GSH). Pre-treatment with alpha-mangostin (200 mg/kg of body weight per day) orally for 6 days prior to the ISO administration and 2 days along with ISO administration significantly attenuated these changes when compared to the individual treatment groups. These findings indicate the protective effect of alpha-mangostin on lipid peroxidation and antioxidant tissue defense system during ISO-induced myocardial infarction in rats.
Assuntos
Cardiotônicos/uso terapêutico , Garcinia mangostana/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/imunologia , Xantonas/uso terapêutico , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Isoproterenol , Peróxidos Lipídicos , Masculino , Infarto do Miocárdio/induzido quimicamente , Fitoterapia , Ratos , Ratos WistarRESUMO
One of the proposed mechanisms for the myocardial protective effects of heat shock (HS) treatment has been a reduction in the inflammatory response. The objective of the present study was to evaluate the impact of HS treatment in an established model of polymorphonuclear cell (PMN) migration following myocardial infarction (MI). Isolated purified PMNs (10 x 10(6) cells) labeled with (51)Cr were injected into Lewis rats following a left thoracotomy and ligation of the left anterior descending coronary artery causing MI. Two experimental groups of animals were created: MI group (n = 11) and HS+MI group (n = 7). HS treatment consisted of an elevation in core temperature to 42 degrees C for 15 min 24 h prior to MI. An additional group of control animals underwent sham thoracotomy (n = 5). All animals were euthanized at 24 h after MI, and gamma counts were obtained to estimate PMN migration. Myocardial injury was confirmed in all experimental animals (histology and echocardiography). The serum troponin I and infarct size (triphenyltetrazolium chloride) were similar in both groups. Labeled PMN migration was significantly higher in HS+MI animals (14.3 x 10(4) +/- 3.7 x 10(4) PMN) compared with MI group (9.5 x 10(4) +/- 3.6 x 10(4); P = 0.01), suggesting increased PMN migration as a result of HS treatment. HS treatment did not affect PMN migration to positive skin control sites (LPS). ICAM-1 myocardial expression was not significantly increased in HS+MI compared with MI group. In summary, HS treatment results in increased PMN migration into myocardium following MI independent of ICAM-1. These findings suggest that the proposed cardioprotective effect of HS may not be entirely due to a downregulation of myocardial inflammation as previously proposed.
Assuntos
Resposta ao Choque Térmico/imunologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Neutrófilos/imunologia , Neutrófilos/patologia , Animais , Movimento Celular/imunologia , Hipertermia Induzida/métodos , Infarto do Miocárdio/prevenção & controle , Ratos , Ratos Endogâmicos LewRESUMO
Poor subjective well-being has been associated with increased coronary heart disease (CHD) morbidity and mortality in population-based studies and with adverse outcomes in existing CHD. Little is known about the mechanisms responsible for this association, but immune activity appears to be a potential pathway. Despite the growing evidence linking immune activity to subjective feelings, very few studies have examined patients with CHD, and the results are conflicting. We examined consecutive women patients hospitalized for acute myocardial infarction, and/or underwent percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. We assessed depression, vital exhaustion, and self-rated health by questionnaires. Circulating levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1ra) concentrations were determined. After controlling for potential confounding factors there was a significant positive correlation between IL-6 levels and vital exhaustion and poor self-rated health. The association between hsCRP and vital exhaustion and self-rated health was borderline significant. In contrast, the correlations between psychological factors and IL-1ra levels were weak and non-significant, as were the correlations between inflammatory markers and depression. Similar relationships between the inflammatory markers and the measures of psychological well-being were obtained when the latter ones were categorized into tertiles. In conclusion, inflammatory activity, assessed by IL-6 and hsCRP levels, was associated with vital exhaustion and self-rated health in CHD women. These findings may provide further evidence for a possible psychoneuroimmune link between subjective well-being and CHD. Our observations also raise the possibility that a cytokine-induced sickness response in CHD may be better represented by constructs of vital exhaustion and self-rated health than of depression.