Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 730
Filtrar
Filtros adicionais











Intervalo de ano
1.
Virchows Arch ; 475(3): 279-301, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31297595

RESUMO

Myocarditis is an inflammatory disease of the myocardium, which may occur in isolation or as part of systemic infectious/immune/autoimmune conditions, characterized by vast aetiologic, clinical and histopathologic heterogeneity. The broad spectrum of myocarditis can be categorized according to the prevalent histopathologic pattern including lymphocytic, lympho-histiocytic, eosinophilic and neutrophilic forms, giant cell myocarditis and myocarditis with granulomata. Diverse histopathologic substrates generally reflect different aetiologies and pathogenetic mechanisms and may be critical to clinical decision-making. Active vasculitis, when present, completes the inflammatory spectrum. Unfortunately, the correlation of histopathologic patterns, clinical presentation and disease course in myocarditis is still largely unresolved, due to limited availability of bioptic samples at specific stages of disease and impracticality of serial sampling. We here review the elements supporting an aetiology-driven diagnostic work-up in myocarditis, emphasizing the importance of integrating pathologic studies with clinical features and information derived from multimodality imaging. Furthermore, we explore myocardial inflammation in genetic cardiomyopathies, its role in driving clinical variability and the potential of transcriptomic and proteomic analysis in our understanding of these complex interrelations.


Assuntos
Miocardite/etiologia , Miocardite/metabolismo , Miocardite/patologia , Biópsia , Eosinófilos/patologia , Humanos , Miocárdio/patologia , Proteômica
2.
Life Sci ; 230: 141-149, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129142

RESUMO

When administered alone, preinfection exercise training and benznidazole-based chemotherapy induce cardioprotection in Chagas disease. However, the effect of concomitant exercise and benznidazole treatment is unknown. We investigated whether exercise and specific chemotherapy could interact to modulate parasitemia, inflammation, redox status and heart damage in a murine model of T. cruzi infection. Wistar rats were randomized into an uninfected control group (CNT) and four groups infected with T. cruzi: sedentary untreated (SUN) and treated (STR), and trained untreated (TUN) and treated (TTR). Running training was administered 5 days/week for 4 weeks. Treated animals concomitantly received 100 mg/kg/day benznidazole. Heart inflammation and reactive damage were not detected in CNT animals. Compared to SUN, TUN animals presented increased levels of parasitemia, myocarditis, nitric oxide, hydrogen peroxide, protein carbonyl, malondialdehyde, cytokines (IFN-γ, TNF-α, IL-4, IL-6, IL-10 and IL-17), catalase, superoxide dismutase and glutathione reductase activity, as well as reduced heart non-protein antioxidant levels (P < 0.05). TTR animals exhibited higher levels of parasitemia, myocarditis, hydrogen peroxide, malondialdehyde, IFN-γ, TNF-α and IL-6 than STR animals (P < 0.05), which showed the lowest levels of all analyzed parameters compared to the other groups (P < 0.05). Our findings indicate that exercise aggravates acute infection. When concomitantly administered with benznidazole, exercise training impaired parasitic control and chemotherapy-induced cardioprotection in T. cruzi-infected rats. Considering that exercise training and T. cruzi infection constitute independent metabolic challenges, the negative effects of concomitant treatment are potentially related to the overlapping oxidative and immunoinflammatory demands of exercise and the infection itself.


Assuntos
Doença de Chagas/tratamento farmacológico , Doença de Chagas/fisiopatologia , Condicionamento Físico Animal/fisiologia , Animais , Antioxidantes/farmacologia , Cardiotônicos/metabolismo , Catalase/metabolismo , Cardiomiopatia Chagásica/fisiopatologia , Cardiomiopatia Chagásica/terapia , Citocinas/metabolismo , Modelos Animais de Doenças , Coração/fisiologia , Inflamação/metabolismo , Interleucina-10/metabolismo , Masculino , Miocardite/metabolismo , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Nitroimidazóis/farmacologia , Parasitemia/parasitologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Trypanosoma cruzi/patogenicidade , Fator de Necrose Tumoral alfa/metabolismo
3.
PLoS Pathog ; 15(4): e1007674, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30958867

RESUMO

Viral myocarditis is a serious disease, commonly caused by type B coxsackieviruses (CVB). Here we show that innate immune protection against CVB3 myocarditis requires the IFIT (IFN-induced with tetratricopeptide) locus, which acts in a biphasic manner. Using IFIT locus knockout (IFITKO) cardiomyocytes we show that, in the absence of the IFIT locus, viral replication is dramatically increased, indicating that constitutive IFIT expression suppresses CVB replication in this cell type. IFNß pre-treatment strongly suppresses CVB3 replication in wild type (wt) cardiomyocytes, but not in IFITKO cardiomyocytes, indicating that other interferon-stimulated genes (ISGs) cannot compensate for the loss of IFITs in this cell type. Thus, in isolated wt cardiomyocytes, the anti-CVB3 activity of IFITs is biphasic, being required for protection both before and after T1IFN signaling. These in vitro findings are replicated in vivo. Using novel IFITKO mice we demonstrate accelerated CVB3 replication in pancreas, liver and heart in the hours following infection. This early increase in virus load in IFITKO animals accelerates the induction of other ISGs in several tissues, enhancing virus clearance from some tissues, indicating that-in contrast to cardiomyocytes-other ISGs can offset the loss of IFITs from those cell types. In contrast, CVB3 persists in IFITKO hearts, and myocarditis occurs. Thus, cardiomyocytes have a specific, biphasic, and near-absolute requirement for IFITs to control CVB infection.


Assuntos
Proteínas de Transporte/fisiologia , Infecções por Coxsackievirus/prevenção & controle , Enterovirus Humano B/patogenicidade , Miocardite/prevenção & controle , Miócitos Cardíacos/enzimologia , Animais , Células Cultivadas , Infecções por Coxsackievirus/metabolismo , Infecções por Coxsackievirus/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/metabolismo , Miocardite/virologia , Replicação Viral
4.
BMJ Case Rep ; 12(4)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975785

RESUMO

Mesalazine (5-aminosalicylic acid)-based products are a widely used treatment for inflammatory bowel disease in children and adults. Associated myopericarditis is an uncommon but recorded phenomenon related to drug hypersensitivity. Unless recognised, this important complication may culminate in the development of dilated cardiomyopathy and severe heart failure. We report the case of a boy with Crohn's disease who developed myopericarditis 14 days after starting treatment with mesalazine. Discontinuation of the drug rapidly led to normalisation of left ventricular structure and function, and a parallel improvement in the levels of plasma N-terminal pro-B-type natriuretic peptide and other markers of myocardial damage. Clinicians should be aware of this potentially life-threatening adverse effect of mesalazine therapy, which is quickly and fully reversible on cessation of the agent.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Doença de Crohn/tratamento farmacológico , Mesalamina/efeitos adversos , Miocardite/diagnóstico , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/metabolismo , Adolescente , Diagnóstico Diferencial , Humanos , Masculino , Miocardite/induzido quimicamente , Miocardite/metabolismo
5.
Basic Res Cardiol ; 114(2): 11, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30673858

RESUMO

Coxsackieviruses of group B (CVB) are well-known causes of acute and chronic myocarditis. Chronic myocarditis can evolve into dilated cardiomyopathy (DCM) characterized by fibrosis and cardiac remodeling. Interleukin-1ß (IL-1ß) plays a decisive role in the induction of the inflammatory response as a consequence of viral replication. In this study, we analyzed the effects of IL-1ß neutralization on the transition of acute to chronic myocarditis in a mouse model of CVB3 myocarditis. Mice were treated with an anti-murine IL-1ß antibody as a surrogate for Canakinumab at different time points post CVB3 infection. Treatment was performed in the early phase (day 1-14 pi, day 3-14 pi) or at a later stage of myocarditis (day 14-28 pi). Subsequently, the hearts were examined histologically, immunohistochemically and by molecular biology. A significant reduction of viral replication, cardiac damage and inflammation was found after administration of the antibody in the early phase and in the later phase of infection. Furthermore, less collagen I deposition and a considerable reduction of fibrosis were found in antibody-treated mice. Using microarray analysis, a significant upregulation of various extracellular matrix and fibrosis-associated molecules was found in CVB3-infected mice, including TGF-ß, TIMP-1 and MMP12, as well as diverse matricellular proteins, whereas, these molecules were significantly downregulated in all IL-1ß antibody-treated infected mice. Neutralization of IL-1ß at different stages of enteroviral infection prevents the development of chronic viral myocarditis by reducing inflammation, interstitial fibrosis and adverse cardiac remodeling. These findings are relevant for the treatment of patients with acute and chronic myocarditis.


Assuntos
Interleucina-1beta/antagonistas & inibidores , Miocardite/patologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Anticorpos Monoclonais/farmacologia , Doença Crônica , Infecções por Coxsackievirus/metabolismo , Infecções por Coxsackievirus/patologia , Enterovirus Humano B , Camundongos , Miocardite/metabolismo , Miocardite/virologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
6.
Int J Mol Sci ; 20(2)2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30669342

RESUMO

Adenosine deaminases acting on RNA (ADAR) are enzymes that regulate RNA metabolism through post-transcriptional mechanisms. ADAR1 is involved in a variety of pathological conditions including inflammation, cancer, and the host defense against viral infections. However, the role of ADAR1p150 in vascular disease remains unclear. In this study, we examined the expression of ADAR1p150 and its role in viral myocarditis (VMC) in a mouse model. VMC mouse cardiomyocytes showed significantly higher expression of ADAR1p150 compared to the control samples. Coimmunoprecipitation verified that ADAR1p150 forms a complex with Dicer in VMC. miRNA-222, which is involved in many cardiac diseases, is highly expressed in cardiomyocytes in VMC. In addition, the expression of miRNA-222 was promoted by ADAR1p150/Dicer. Among the target genes of miRNA-222, the expression of phosphatase-and-tensin (PTEN) protein was significantly reduced in VMC. By using a bioinformatics tool, we found a potential binding site of miRNA-222 on the PTEN gene's 3'-UTR, suggesting that miRNA-222 might play a regulatory role. In cultured cells, miR-222 suppressed PTEN expression. Our findings suggest that ADAR1p150 plays a key role in complexing with Dicer and promoting the expression of miRNA-222, the latter of which suppresses the expression of the target gene PTEN during VMC. Our work reveals a previously unknown role of ADAR1p150 in gene expression in VMC.


Assuntos
Adenosina Desaminase/metabolismo , Infecções por Coxsackievirus/complicações , Enterovirus Humano B , MicroRNAs/genética , Miocardite/etiologia , Miocardite/metabolismo , PTEN Fosfo-Hidrolase/genética , Ribonuclease III/metabolismo , Animais , Sobrevivência Celular/genética , Células Cultivadas , Infecções por Coxsackievirus/patologia , Infecções por Coxsackievirus/virologia , Modelos Animais de Doenças , Enterovirus Humano B/fisiologia , Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Imuno-Histoquímica , Masculino , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/virologia , Ligação Proteica , Interferência de RNA
7.
Exp Mol Pathol ; 107: 43-50, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30695715

RESUMO

BACKGROUND: Cardiac hypertrophy related factor (CHRF), a newly recognized long non-coding RNA (lncRNA), is a central regulator in cardiac hypertrophy responses. This study attempted to show the potential role of lncRNA CHRF in bacterial infection caused myocarditis. METHODS: H9c2 cells were transfected with small interfering RNAs (siRNAs) specific for lncRNA CHRF alone or in combination with miR-221 inhibitor, and then subjected to lipopolysaccharide (LPS). The following parameters were measured: cell viability, apoptosis, reactive oxygen species (ROS) generation, pro-inflammatory cytokines release, microRNA (miR)-221 expression and the activation of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways. RESULTS: Silence of lncRNA CHRF impeded the LPS injury to H9c2 cells, as cell viability was increased (p < .05), apoptosis was inhibited (p < .05), ROS generation was decreased (p < .01), and the expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α was suppressed (p < .05). However, silence of lncRNA CHRF had no impacts on normal H9c2 cells growth (p > .05). miR-221 was negatively regulated by lncRNA CHRF (p < .01). LncRNA CHRF silence did not protect H9c2 cells against LPS when miR-221 was suppressed (p < .05 or p < .01). Also, the inhibitory effects of lncRNA CHRF silence on the activation of NF-κB and JNK pathways were flattened by miR-221 suppression (p < .05 or p < .01). CONCLUSION: These in vitro data collectively demonstrated that lncRNA CHRF silence protected H9c2 cells against LPS-induced injury via up-regulating miR-221 and modulating NF-κB and JNK pathways.


Assuntos
MicroRNAs/metabolismo , Miocardite/metabolismo , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/genética , Animais , Linhagem Celular , Técnicas de Silenciamento de Genes , Lipopolissacarídeos/toxicidade , Mioblastos , Miócitos Cardíacos/patologia , Ratos , Regulação para Cima
8.
Int J Cardiol ; 275: 114-119, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30384979

RESUMO

BACKGROUND: Myocarditis may be self-limited but has been identified as an important contributor to downstream cardiomyopathy. Aldosterone mediates myocardial damage in various conditions, but has not been considered specifically as a therapeutic target for inflammatory damage in acute myocarditis. We sought to demonstrate local aldosterone synthesis in human myocardium affected by acute myocarditis. METHODS: We evaluated myocardial samples obtained via endomyocardial biopsy (EMB) for expression of CYP11B2, the final and key enzyme for aldosterone synthesis, from patients with acute myocarditis and from stable heart transplant recipients with no evidence of rejection as negative controls. Excised adrenal glands from patients with aldosterone-secreting adenomas were used as positive controls. An experienced cardiovascular pathologist blinded to clinical information rated CYP11B2 stains as negative, positive, or borderline, also recording location of any CYP11B2-positivity. RESULTS: Sixteen patients' EMB samples showing definite acute myocarditis were identified (50% female). CYP11B2 was positive in 13/16 cases (81%), typically showing diffuse intracardiomyocyte cytoplasmic staining, vs. 2/16 borderline stains in transplant controls (p < 0.001 myocarditis vs. negative controls). All 3 adrenalectomy samples stained positive for CYP11B2 (diffuse intracellular staining). Importantly, no myocarditis or transplant patients were on aldosterone antagonist therapy at the time of biopsy. CONCLUSIONS: In this proof-of-concept study, myocardium from patients with acute myocarditis demonstrates evidence and high prevalence of local aldosterone synthesis by immunohistochemistry that showed high accuracy, specificity, and sensitivity. Aldosterone warrants consideration as a specific target for therapy in patients with myocardial damage due to inflammation towards strategies that reduce downstream complications.


Assuntos
Aldosterona/biossíntese , Miocardite/metabolismo , Miocárdio/metabolismo , Doença Aguda , Adulto , Biomarcadores/metabolismo , Biópsia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Miocardite/patologia , Miocárdio/patologia
9.
Biochim Biophys Acta Mol Basis Dis ; 1864(8): 2579-2589, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29730342

RESUMO

Acute viral myocarditis (VM), characterised by leukocyte infiltration and dysfunction of the heart, is an important cause of sudden cardiac death in young adults. Unfortunately, to date, the pathological mechanisms underlying cardiac failure in VM remain incompletely understood. In the current study, we investigated if acute VM leads to cardiac metabolic rewiring and if this process is driven by local inflammation. Transcriptomic analysis of cardiac biopsies from myocarditis patients and a mouse model of VM revealed prominent reductions in the expression of a multitude of genes involved in mitochondrial oxidative energy metabolism. In mice, this coincided with reductions in high-energy phosphate and NAD levels, as determined by Imaging Mass Spectrometry, as well as marked decreases in the activity, protein abundance and mRNA levels of various enzymes and key regulators of cardiac oxidative metabolism. Indicative of fulminant cardiac inflammation, NF-κB signalling and inflammatory cytokine expression were potently induced in the heart during human and mouse VM. In cultured cardiomyocytes, cytokine-mediated NF-κB activation impaired cardiomyocyte oxidative gene expression, likely by interfering with the PGC-1 (peroxisome proliferator-activated receptor (PPAR)-γ co-activator) signalling network, the key regulatory pathway controlling cardiomyocyte oxidative metabolism. In conclusion, we provide evidence that acute VM is associated with extensive cardiac metabolic remodelling and our data support a mechanism whereby cytokines secreted primarily from infiltrating leukocytes activate NF-κB signalling in cardiomyocytes thereby inhibiting the transcriptional activity of the PGC-1 network and consequently modulating myocardial energy metabolism.


Assuntos
Infecções por Coxsackievirus/metabolismo , Enterovirus Humano B , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Proteínas Musculares/metabolismo , Miocardite/metabolismo , NF-kappa B/metabolismo , Doença Aguda , Animais , Infecções por Coxsackievirus/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Miocardite/patologia , Miocardite/virologia , PPAR gama/metabolismo , Fatores de Transcrição/metabolismo
10.
PLoS One ; 13(3): e0193844, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29538462

RESUMO

Heart failure (HF) is a leading cause of morbidity and mortality in the western world. Although optimal medical care and treatment is widely available, the prognosis of patients with HF is still poor. Toll-like receptors (TLRs) are important compartments of the innate immunity. Current studies have identified TLRs as critical mediators in cardiovascular diseases. In the present study, we investigated the involvement of TLRs and interferon (IFN) regulatory factors (IRFs) in different experimental HF models including viral myocarditis, myocardial ischemia, diabetes mellitus, and cardiac hypertrophy. In addition, we investigated for the first time comprehensive TLR and IRF gene and protein expression under basal conditions in murine and human cardiac tissue. We found that Tlr4, Tlr9 and Irf7 displayed highest gene expression under basal conditions, indicating their significant role in first-line defense in the murine and human heart. Moreover, induction of TLRs and IRFs clearly differs between the various experimental HF models of diverse etiology and the concomitant inflammatory status. In the HF model of acute viral-induced myocarditis, TLR and IRF activation displayed the uppermost gene expression in comparison to the remaining experimental HF models, indicating the highest amount of myocardial inflammation in myocarditis. In detail, Irf7 displayed by far the highest gene expression during acute viral infection. Interestingly, post myocardial infarction TLR and IRF gene expression was almost exclusively increased in the infarct zone after myocardial ischemia (Tlr2, Tlr3, Tlr6, Tlr7, Tlr9, Irf3, Irf7). With one exception, Irf3 showed a decreased gene expression in the remote zone post infarction. Finally, we identified Irf7 as novel cardiovascular stress-inducible factor in the pathologically stressed heart. These findings on TLR and IRF function in the inflamed heart highlight the complexity of inflammatory immune response and raise more interesting questions for future investigation.


Assuntos
Insuficiência Cardíaca/metabolismo , Fatores Reguladores de Interferon/metabolismo , Miocárdio/metabolismo , Receptores Toll-Like/metabolismo , Animais , Cardiomegalia/metabolismo , Membrana Celular/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Insuficiência Cardíaca/etiologia , Humanos , Inflamação/metabolismo , Espaço Intracelular/metabolismo , Camundongos Endogâmicos C57BL , Isquemia Miocárdica/metabolismo , Miocardite/metabolismo , Proteoma , Distribuição Aleatória
11.
Can J Cardiol ; 34(4): 492-501, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29455951

RESUMO

BACKGROUND: Viral myocarditis is a widespread cardiac disease associated with inflammation and myocardial injury and is predominantly caused by coxsackievirus B3 (CVB3) infection in humans as well as in mice. CVB3-induced myocarditis shows sexually dimorphic sensitivity and is more prevalent in male mice. Our previous studies showed that natural killer (NK) cells played an indispensable role in CVB3-induced myocarditis, and female mice exhibited less pathological cardiac interferon gamma (IFN-γ)+ NK cell infiltration than did male mice. However, the precise mechanisms were not well elucidated. METHODS: We investigated the influence of estrogen on cardiac IFN-γ+ NK cell enrichment in CVB3-induced myocarditis and explored the underlying molecular mechanism. RESULTS: In this study, we found that CVB3 stimulation could clearly induce IFN-γ expression by NK cells; however, this trend could be blunted by estrogen treatment. Consistently, ovariectomized female mice with decreased estrogen levels exhibited substantially increased enrichment of cardiac IFN-γ+ NK cells and displayed significantly aggravated myocarditis. Similarly, estrogen-treated male mice showed less cardiac IFN-γ+ NK cell infiltration, accompanied by significantly alleviated viral myocarditis. In sharp contrast, sexually immature female and male mice (with similar estrogen levels) showed comparable levels of cardiac IFN-γ+ NK cell infiltration and similar levels of myocarditis severity. Upon further exploration of the underlying mechanisms, we found that estrogen could downregulate expression of Th1-specific T box transcription factor (T-bet), the key transcription factor associated with IFN-γ production, in CVB3-stimulated NK cells. CONCLUSIONS: Overall, this study might help us understand the mechanism of increased cardiac infiltration by IFN-γ+ NK cells in CVB3-infected male mice compared with that in female mice and might provide new clues for the sex bias in CVB3-induced myocarditis.


Assuntos
Infecções por Coxsackievirus , Enterovirus Humano B/patogenicidade , Estrogênios/análise , Interferon gama , Células Matadoras Naturais/imunologia , Miocardite , Animais , Infecções por Coxsackievirus/complicações , Infecções por Coxsackievirus/imunologia , Regulação para Baixo , Feminino , Interferon gama/análise , Interferon gama/imunologia , Masculino , Camundongos , Miocardite/imunologia , Miocardite/metabolismo , Miocardite/virologia , Estatística como Assunto , Proteínas com Domínio T/metabolismo
12.
Biochim Biophys Acta Mol Basis Dis ; 1864(1): 11-23, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28987763

RESUMO

Cardiac dysfunction with progressive inflammation and fibrosis is a hallmark of Chagas disease caused by persistent Trypanosoma cruzi infection. Osteopontin (OPN) is a pro-inflammatory cytokine that orchestrates mechanisms controlling cell recruitment and cardiac architecture. Our main goal was to study the role of endogenous OPN as a modulator of myocardial CCL5 chemokine and MMP-2 metalloproteinase, and its pathological impact in a murine model of Chagas heart disease. Wild-type (WT) and OPN-deficient (spp1 -/-) mice were parasite-infected (Brazil strain) for 100days. Both groups developed chronic myocarditis with similar parasite burden and survival rates. However, spp1 -/- infection showed lower heart-to-body ratio (P<0.01) as well as reduced inflammatory pathology (P<0.05), CCL5 expression (P<0.05), myocyte size (P<0.05) and fibrosis (P<0.01) in cardiac tissues. Intense OPN labeling was observed in inflammatory cells recruited to infected heart (P<0.05). Plasma concentration of MMP-2 was higher (P<0.05) in infected WT than in spp1 -/- mice. Coincidently, specific immunostaining revealed increased gelatinase expression (P<0.01) and activity (P<0.05) in the inflamed hearts from T. cruzi WT mice, but not in their spp1 -/- littermates. CCL5 and MMP-2 induction occurred preferentially (P<0.01) in WT heart-invading CD8+ T cells and was mediated via phospho-JNK MAPK signaling. Heart levels of OPN, CCL5 and MMP-2 correlated (P<0.01) with collagen accumulation in the infected WT group only. Endogenous OPN emerges as a key player in the pathogenesis of chronic Chagas heart disease, through the upregulation of myocardial CCL5/MMP-2 expression and activities resulting in pro-inflammatory and pro-hypertrophic events, cardiac remodeling and interstitial fibrosis.


Assuntos
Remodelamento Atrial , Cardiomiopatia Chagásica , Quimiocina CCL5/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Miocardite , Osteopontina/fisiologia , Remodelação Ventricular , Animais , Remodelamento Atrial/genética , Remodelamento Atrial/imunologia , Células Cultivadas , Cardiomiopatia Chagásica/genética , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/patologia , Modelos Animais de Doenças , Fibrose Endomiocárdica/genética , Fibrose Endomiocárdica/metabolismo , Fibrose Endomiocárdica/patologia , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/genética , Miocardite/imunologia , Miocardite/metabolismo , Miocardite/patologia , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologia , Osteopontina/genética , Remodelação Ventricular/genética , Remodelação Ventricular/imunologia
13.
Mol Cell Biochem ; 442(1-2): 11-18, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28887702

RESUMO

In this study, we investigated the roles of RIP1/RIP3 mediated cardiomyocyte necroptosis in CVB3-induced acute myocarditis. Serum concentrations of creatinine kinase (CK), CK-MB, and cardiac troponin I were detected using a Hitachi Automatic Biochemical Analyzer in a mouse model of acute VMC. Histological changes in cardiac tissue were observed by light microscope and expression levels of RIP1/RIP3 in the cardiac tissue were detected via Western blot and immunohistochemistry. The data showed that RIP1/RIP3 was highly expressed in cardiomyocytes in the acute VMC mouse model and that the necroptosis pathway specific blocker, Nec-1, dramatically reduced the myocardial damage by downregulating the expression of RIP1/RIP3. These findings provide evidence that necroptosis plays a significant role in cardiomyocyte death and it is a major pathway for cell death in acute VMC. Blocking the necroptosis pathway may serve as a new therapeutic option for the treatment of acute viral myocarditis.


Assuntos
Miocardite/metabolismo , Miócitos Cardíacos/metabolismo , Doença Aguda , Animais , Morte Celular , Infecções por Coxsackievirus/metabolismo , Infecções por Coxsackievirus/patologia , Enterovirus Humano B/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/patologia , Miocardite/virologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/virologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
14.
Inflammation ; 41(1): 221-231, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29047036

RESUMO

Luteolin is a major component of many medicinal plants and traditional medicines. The current study aims at testing its protective effect against high-carbohydrate/high-fat (HCHF) diet-induced cardiac dysfunction in rats. Male Wistar rats were divided into six groups as follows: control group that received standard rat chow, group received HCHF diet (~ 30% carbohydrate and 42% fat) daily for 16 weeks, and four groups received HCHF diet concurrently with luteolin (10, 25, 50 or 100 mg/kg; 10% w/v suspension in 0.9% NaCl) daily from the first week by oral gavage. Body weight was measured weekly. At the end of the study, histopathological examinations of stained heart sections were carried out. Lipid profile, oxidative stress, and cardiac function biomarkers were measured. Furthermore, neurohumoral mediators and inflammatory cytokines (TNF-α, IL-18) were assigned. Results showed a significant improvement in cardiac function, tissue integrity, and a decrease in the compensatory neurohumoral mediators by luteolin 50 and 100 mg/kg. In addition, a significant (P < 0.05) decrease in collagen deposition, fibrosis percentage, lipid peroxidation, and inflammatory cells (macrophages and lymphocytes) infiltration was observed. Tested doses of luteolin decreased lipid peroxidation and elevated the endogenous antioxidant biomarkers (reduced glutathione and superoxide dismutase) significantly (P < 0.05). Finally, luteolin decreased TNF-α and IL-18 (P < 0.001) in a dose-dependent manner. It can be concluded that luteolin has a cardioprotective effect against HCHF diet-induced myocardial inflammation through antioxidant anti-inflammatory mechanisms.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cardiomiopatias/prevenção & controle , Dieta Hiperlipídica , Carboidratos da Dieta , Luteolina/farmacologia , Miocardite/prevenção & controle , Miocárdio/metabolismo , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/imunologia , Cardiomiopatias/metabolismo , Colágeno/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fibrose , Glutationa/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-18/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Miocardite/etiologia , Miocardite/imunologia , Miocardite/metabolismo , Miocárdio/imunologia , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Superóxido Dismutase/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo
15.
Inflammation ; 41(1): 232-239, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29039143

RESUMO

The cluster of differentiation protein complex, CD80/CD86, regulates Th1/Th2 differentiation in autoimmune disease. In order to establish the effects of CD80/CD86 on Th17 cell differentiation in acute viral myocarditis (VMC), we infected C57BL/6 mice with Coxsackie virus B3 (CVB3) and examined the effects of the treatment with anti-CD80/CD86 monoclonal antibodies (mAbs) on Th17 cell differentiation in vivo. The effects of anti-CD80/CD86 mAbs on Th17 cell differentiation were further evaluated in vitro. The treatment with anti-CD80 mAb induced marked suppression of Th17 cell differentiation and ROR-γt mRNA expression, whereas anti-CD86 mAb alone had no effect, both in vivo and in vitro. Our finding that CD80 regulates Th17 differentiation supports the potential utility of anti-CD80 mAb as an effective new immunotherapeutic target in acute VMC.


Assuntos
Antígeno B7-1/imunologia , Diferenciação Celular , Infecções por Coxsackievirus/imunologia , Enterovirus Humano B/imunologia , Miocardite/imunologia , Miocárdio/imunologia , Baço/imunologia , Células Th17/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Antígeno B7-1/antagonistas & inibidores , Antígeno B7-1/metabolismo , Antígeno B7-2/imunologia , Antígeno B7-2/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Infecções por Coxsackievirus/tratamento farmacológico , Infecções por Coxsackievirus/metabolismo , Infecções por Coxsackievirus/virologia , Modelos Animais de Doenças , Enterovirus Humano B/patogenicidade , Interações Hospedeiro-Patógeno , Masculino , Camundongos Endogâmicos C57BL , Miocardite/tratamento farmacológico , Miocardite/metabolismo , Miocardite/virologia , Miocárdio/metabolismo , Miocárdio/patologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Transdução de Sinais , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/virologia , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Células Th17/virologia
16.
Biochim Biophys Acta Mol Basis Dis ; 1864(1): 238-251, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28982613

RESUMO

Cardiac inflammation and oxidative stress play a key role in the pathogenesis of diabetic cardiomyopathy (DCM). The anti-aging protein Klotho has been found to protect cells from inflammation and oxidative stress. The current study aimed to explore the cardioprotective effects of Klotho on DCM and the underlying mechanisms. H9c2 cells and neonatal cardiomyocytes were incubated with 33mM glucose in the presence or absence of Klotho. Klotho pretreatment effectively inhibited high glucose-induced inflammation, ROS generation, apoptosis, mitochondrial dysfunction, fibrosis and hypertrophy in both H9c2 cells and neonatal cardiomyocytes. In STZ-induced type 1 diabetic mice, intraperitoneal injection of Klotho at 0.01mg/kg per 48h for 3months completely suppressed cardiac inflammatory cytokines and oxidative stress and prevented cardiac cell death and remodeling, which subsequently improved cardiac dysfunction without affecting hyperglycemia. This study revealed that Klotho may exert its protective effects by augmenting nuclear factor erythroid 2-related factor 2 (Nrf2) expression and inactivating nuclear factor κB (NF-κB) activation both in vitro and in vivo. Thus, this work demonstrated for the first time that the anti-aging protein Klotho may be a potential therapeutic agent to treat DCM by inhibiting oxidative stress and inflammation. We also demonstrated the critical roles of the Nrf2 and NF-κB pathways in diabetes-stimulated cardiac injuries and indicated that they may be key therapeutic targets for diabetic complications.


Assuntos
Cardiotônicos/farmacologia , Cardiomiopatias Diabéticas/prevenção & controle , Glucose/efeitos adversos , Glucuronidase/farmacologia , Coração/efeitos dos fármacos , Miocardite/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Animais , Células Cultivadas , Citoproteção/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Hiperglicemia/complicações , Hiperglicemia/imunologia , Hiperglicemia/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocardite/metabolismo , Miocardite/patologia , Miócitos Cardíacos/fisiologia , NF-kappa B/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo
17.
J Physiol Pharmacol ; 69(6)2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30898985

RESUMO

Myocarditis, a life threatening disease, is still not adequately treated. Histamine plays an important role in physiology and pathophysiology of cardiovascular system. All four histamine receptors (H1R - H4R), are present in the heart. Experimental autoimmune myocarditis (EAM) was used to investigate which histamine receptor had a greater impact on the disease's progression. EAM was evoked in Lewis rats by porcine myosin immunization. Mepyramine, ranitidine and ciproxifan were used to inhibit H1R, H2R and H3R receptors, respectively, and 2,4-diaminopyrimidines: ST994, ST1012, ST1006 were ligands of H4R. Quinapril, an ACE inhibitor, served as a reference drug. Drugs were administered daily, either from 0 - 2 weeks or from 2 to 4 weeks post EAM induction. Cardiac dysfunction developed with significant decreases in left ventricular ejection fraction and fractional shortening due to dilatation and wall thickening. EAM rats treated with mepyramine and ST994 in weeks 0 - 2 had the lowest decreases. These treated with ST994, ST1012 or quinapril performed much better the following 2 weeks without therapy than did the other groups. On autopsy their hearts were smaller, less fibrotic, histopathological changes in them of a lower grade. When the treatment started with 2 weeks' delay, the ST994-treated EAM rats showed the highest median survival. H4 receptor antagonism inhibits heart remodelling, preserves heart contractility, improves survival and may be of potent therapeutic relevance in human clinics. The blockade of H1 receptor inhibits heart dilatation but does not prolong the life.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Antagonistas dos Receptores Histamínicos/farmacologia , Miocardite/tratamento farmacológico , Receptores Histamínicos/metabolismo , Disfunção Ventricular Esquerda/tratamento farmacológico , Animais , Doenças Autoimunes/metabolismo , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Histamina/metabolismo , Ligantes , Masculino , Miocardite/metabolismo , Ratos , Ratos Endogâmicos Lew , Disfunção Ventricular Esquerda/metabolismo
18.
Physiol Rep ; 5(24)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29263115

RESUMO

Adiponectin (APN) is a multifunctional adipocytokine that inhibits myocardial fibrosis, dilatation, and left ventricular (LV) dysfunction after myocardial infarction (MI). Coxsackievirus B3 (CVB3) myocarditis is associated with intense extracellular matrix (ECM) remodeling which might progress to dilated cardiomyopathy. Here, we investigated in experimental CVB3 myocarditis whether APN inhibits adverse ECM remodeling following cardiac injury by affecting matrix metalloproteinase (MMP) expression. Cardiac injury was induced by CVB3 infection in APN knockout (APN-KO) and wild-type (WT) mice. Expression and activity of MMPs was quantified by qRT-PCR and zymography, respectively. Activation of protein kinases was assessed by immunoblot. In cardiac myocytes and fibroblasts APN up-regulates MMP-9 expression via activation of 5' adenosine monophosphate-activated protein kinase (AMPK) and extracellular signal-regulated kinase (ERK)1/2 which function as master regulators of inflammation-induced MMP-9 expression. Correspondingly, APN further increased up-regulation of MMP-9 expression triggered by tumor necrosis factor (TNF)α, lipopolysaccharide (LPS) and R-848 in cardiac fibroblasts. In vivo, compared to WT mice cardiac MMP-9 activity and serum levels of carboxy-terminal telopeptide of type I collagen (ICTP) were attenuated in APN-KO mice in subacute (day 7 p.i.) CVB3 myocarditis. Moreover, on day 3 and day 7 post CVB3 infection splenic MMP-9 expression was diminished in APN-KO mice correlating with attenuated myocardial immune cell infiltration in subacute CVB3 myocarditis. These results indicate that APN attenuates adverse cardiac remodeling following cardiac injury by up-regulating MMP-9 expression in cardiac and immune cells. Thus, APN mediates intensified collagen cleavage that might explain inhibition of LV fibrosis and dysfunction.


Assuntos
Adiponectina/metabolismo , Matriz Extracelular/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Miocardite/metabolismo , Animais , Células Cultivadas , Colágeno Tipo I/metabolismo , Matriz Extracelular/patologia , Feminino , Fibrose , Masculino , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miocardite/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas Quinases/metabolismo , Regulação para Cima
19.
PLoS Pathog ; 13(12): e1006744, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29220410

RESUMO

Nuclear factor of activated T cells 5 (NFAT5)/Tonicity enhancer binding protein (TonEBP) is a transcription factor induced by hypertonic stress in the kidney. However, the function of NFAT5 in other organs has rarely been studied, even though it is ubiquitously expressed. Indeed, although NFAT5 was reported to be critical for heart development and function, its role in infectious heart diseases has remained obscure. In this study, we aimed to understand the mechanism by which NFAT5 interferes with infection of Coxsackievirus B3 (CVB3), a major cause of viral myocarditis. Our initial results demonstrated that although the mRNA level of NFAT5 remained constant during CVB3 infection, NFAT5 protein level decreased because the protein was cleaved. Bioinformatic prediction and verification of the predicted site by site-directed mutagenesis experiments determined that the NFAT5 protein was cleaved by CVB3 protease 2A at Glycine 503. Such cleavage led to the inactivation of NFAT5, and the 70-kDa N-terminal cleavage product (p70-NFAT5) exerted a dominant negative effect on the full-length NFAT5 protein. We further showed that elevated expression of NFAT5 to counteract viral protease cleavage, especially overexpression of a non-cleavable mutant of NFAT5, significantly inhibited CVB3 replication. Ectopic expression of NFAT5 resulted in elevated expression of inducible nitric oxide synthase (iNOS), a factor reported to inhibit CVB3 replication. The necessity of iNOS for the anti-CVB3 effect of NFAT5 was supported by the observation that inhibition of iNOS blocked the anti-CVB3 effect of NFAT5. In a murine model of viral myocarditis, we observed that treatment with hypertonic saline or mannitol solution upregulated NFAT5 and iNOS expression, inhibited CVB3 replication and reduced tissue damage in the heart. Taken together, our data demonstrate that the anti-CVB3 activity of NFAT5 is impaired during CVB3 infection due to 2A-mediated cleavage of NFAT5. Thus induction of NFAT5 by hypertonic agents may be a promising strategy for the development of anti-CVB3 therapeutics.


Assuntos
Infecções por Coxsackievirus/virologia , Cisteína Endopeptidases/metabolismo , Enterovirus Humano B/enzimologia , Miocardite/virologia , Miócitos Cardíacos/virologia , Fatores de Transcrição/metabolismo , Proteínas Virais/metabolismo , Substituição de Aminoácidos , Animais , Linhagem Celular , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/metabolismo , Infecções por Coxsackievirus/patologia , Enterovirus Humano B/imunologia , Enterovirus Humano B/fisiologia , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos A , Mutação , Miocardite/imunologia , Miocardite/metabolismo , Miocardite/patologia , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/química , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Proteólise , Interferência de RNA , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Especificidade por Substrato , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/química , Fatores de Transcrição/genética , Replicação Viral
20.
Circ Heart Fail ; 10(11)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29158436

RESUMO

BACKGROUND: The alarmins S100A8 and S100A9 are damage-associated molecular patterns, which play a pivotal role in cardiovascular diseases, inflammation, and viral infections. We aimed to investigate their role in Coxsackievirus B3 (CVB3)-induced myocarditis. METHODS AND RESULTS: S100A8 and S100A9 mRNA expression was 13.0-fold (P=0.012) and 5.1-fold (P=0.038) higher in endomyocardial biopsies from patients with CVB3-positive myocarditis compared with controls, respectively. Elimination of CVB3 led to a downregulation of these alarmins. CVB3-infected mice developed an impaired left ventricular function and displayed an increased left ventricular S100A8 and S100A9 protein expression versus controls. In contrast, CVB3-infected S100A9 knockout mice, which are also a complete knockout for S100A8 on protein level, showed an improved left ventricular function, which was associated with a reduced cardiac inflammatory and oxidative response, and lower CVB3 copy number compared with wild-type CVB3 mice. Exogenous application of S100A8 to S100A9 knockout CVB3 mice induced a severe myocarditis similar to wild-type CVB3 mice. In CVB3-infected HL-1 cells, S100A8 and S100A9 enhanced oxidative stress and CVB3 copy number compared with unstimulated infected cells. In CVB3-infected RAW macrophages, both alarmins increased MIP-2 (macrophage inflammatory protein-2) chemokine expression, which was reduced in CVB3 S100A8 knockdown versus scrambled siRNA CVB3 cells. CONCLUSIONS: S100A8 and S100A9 aggravate CVB3-induced myocarditis and might serve as therapeutic targets in inflammatory cardiomyopathies.


Assuntos
Calgranulina A/metabolismo , Calgranulina B/metabolismo , Infecções por Coxsackievirus/metabolismo , Enterovirus Humano B/patogenicidade , Miocardite/metabolismo , Miócitos Cardíacos/metabolismo , Adulto , Animais , Calgranulina A/deficiência , Calgranulina A/genética , Calgranulina B/genética , Estudos de Casos e Controles , Quimiocina CXCL2/metabolismo , Infecções por Coxsackievirus/diagnóstico , Infecções por Coxsackievirus/genética , Infecções por Coxsackievirus/virologia , Modelos Animais de Doenças , Enterovirus Humano B/genética , Feminino , Fibrose , Interações Hospedeiro-Patógeno , Humanos , Macrófagos/metabolismo , Macrófagos/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Miocardite/diagnóstico , Miocardite/genética , Miocardite/virologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/virologia , Infiltração de Neutrófilos , Estresse Oxidativo , Células RAW 264.7 , Interferência de RNA , RNA Mensageiro/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais , Transfecção , Função Ventricular Esquerda
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA