Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 785
Filtrar
1.
Cardiovasc Pathol ; 49: 107261, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32771878

RESUMO

Cardiac inflammation in Coxsackievirus B3 (CVB3)-induced myocarditis is a consequence of viral-related cardiac injury and immune response. Caspase-associated recruitment domain 9 (CARD9) is a critical adaptor protein involved in transduction of signals from various innate pattern recognition receptors. In this study, the role of CARD9 in acute viral myocarditis was evaluated. CARD9-/- and C57BL/6 mice were infected with CVB3. On day 7 postinfection, myocardial tissue and blood samples were collected and examined. After CARD9 knockout, mRNA and protein levels of transforming growth factor-ß(TGF-ß), interleukin-17A(IL-17A), and CARD domain of B-cell CLL/lymphoma 10(BCL-10) in the myocardium were markedly lower in CARD9-/- mice than in C57BL/6 mice with CVB3-induced viral myocarditis. This trend was similar for the pathological scores for inflammation and serum levels of cytokines interleukin-6(IL-6), interleukin-10(IL-10), interferon -γ(IFN-γ), TGF-ß, and IL-17A. These results suggest that the CARD9-mediated secretion of pro-inflammatory cytokines plays an important role in the immune response to acute viral myocarditis.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Infecções por Coxsackievirus/metabolismo , Enterovirus Humano B/imunologia , Miocardite/metabolismo , Miocárdio/metabolismo , Linfócitos T/metabolismo , Animais , Proteínas Adaptadoras de Sinalização CARD/deficiência , Proteínas Adaptadoras de Sinalização CARD/genética , Infecções por Coxsackievirus/genética , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/virologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Mediadores da Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/genética , Miocardite/imunologia , Miocardite/virologia , Miocárdio/imunologia , Miocárdio/patologia , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/virologia
2.
Int J Mol Med ; 45(2): 634-646, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894309

RESUMO

The aim of the present study was to investigate the expression levels and roles of microRNA (miR)­217 and miR­543 in viral myocarditis, and to examine their underlying mechanisms. Coxsackievirus B3 (CVB3) was used to establish in vivo and in vitro models of viral myocarditis. The levels of miR­217 and miR­543 were detected using reverse transcription­quantitative PCR. The association between miR­217 and miR­543 and sirtuin­1 (SIRT1) was predicted and confirmed by TargetScan and dual­luciferase reporter assay. Cell viability was detected using Cell Counting Kit­8 assay, and cell apoptosis was measured by analyzing the expression levels of Bcl­2 and Bax, and by flow cytometry. In addition, the synthesis of various pro­inflammatory factors was determined by ELISA. In addition, superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels were measured in cardiomyocytes following transfection and CVB infection. miR­217 and miR­543 were found to be highly expressed in the peripheral blood of pediatric patients with viral myocarditis, in the peripheral blood and myocardial tissues of viral myocarditis mice and in CVB3­infected cardiomyocytes. SIRT1 was found to be a target of both miR­217 and miR­543, and SIRT1 expression level was downregulated in viral myocarditis. Further analysis indicated that the reduced cell viability, increased cell apoptosis, enhanced synthesis of inflammatory factors, increased MDA content and decreased SOD activity associated with myocarditis were significantly reversed after inhibition of miR­217 or miR­543. Importantly, the present results showed that all the effects of miR­217 and miR­543 inhibition on cardiomyocytes were significantly suppressed following SIRT1 knockdown. Collectively, the present data indicated that miR­217 and miR­543 were significantly upregulated in viral myocarditis, and downregulation of miR­217 and miR­543 attenuated CVB3 infection­induced cardiomyocyte injury by targeting SIRT1. miR­217 and miR­543 may be potential therapeutic targets for developing novel viral myocarditis treatments in the future.


Assuntos
Infecções por Coxsackievirus/complicações , MicroRNAs/genética , Miocardite/genética , Miocardite/virologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linhagem Celular , Criança , Pré-Escolar , Infecções por Coxsackievirus/genética , Infecções por Coxsackievirus/metabolismo , Infecções por Coxsackievirus/virologia , Regulação para Baixo , Enterovirus Humano B/isolamento & purificação , Feminino , Humanos , Lactente , Masculino , Camundongos Endogâmicos BALB C , Miocardite/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais , Sirtuína 1/genética , Sirtuína 1/metabolismo , Regulação para Cima
3.
J Biochem Mol Toxicol ; 34(2): e22426, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31777165

RESUMO

The purpose of this study was to investigate the biological effect of miR-16 on myocarditis and the underlying molecular mechanism. H9c2 cells were treated with 10 µg/mL lipopolysaccharide (LPS) for 12 hours to form a myocarditis injury model. We observed that LPS treatment distinctly decreased the level of miR-16 in H9c2 cells. Upregulation of miR-16 increased cell proliferation and reduced cell apoptosis. Then, CD40 was predicted and verified as a target gene of miR-16 by TargetScan and luciferase reporter assay, respectively. Furthermore, the messenger RNA and protein expression of CD40 are negatively regulated by miR-16. The relative expression of inflammatory factors was dramatically decreased by the miR-16 mimic. Cells cotransfected with miR-16 mimic and si-CD40 could significantly abolish the injury of cardiomyocytes caused by myocarditis. Our study illustrated that the upregulation of miR-16 has a protective effect on LPS-damaged H9c2 cells, which may be achieved by regulating CD40 and the nuclear factor kappa B pathway.


Assuntos
Antígenos CD40/metabolismo , Lipopolissacarídeos/farmacologia , MicroRNAs/metabolismo , Miocardite/induzido quimicamente , Miocardite/metabolismo , NF-kappa B/metabolismo , Regulação para Cima/genética , Regiões 3' não Traduzidas/genética , Animais , Apoptose/genética , Sítios de Ligação , Biomarcadores/metabolismo , Antígenos CD40/genética , Linhagem Celular , Técnicas de Silenciamento de Genes , Lipopolissacarídeos/efeitos adversos , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Ratos , Transdução de Sinais/genética , Transfecção
4.
Int Immunopharmacol ; 77: 105961, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31685438

RESUMO

We investigated the immunomodulatory, antiparasitic and cardioprotective effects of a sesquiterpene lactone (SL) administered alone or combined with benznidazole (Bz), in a murine model of Chagas' disease by in vitro and in vivo assays. Antiparasitic and cytotoxic potential of tagitinin C (SL) and Bz were tested in vitro against T. cruzi epimastigotes and cardiomyocytes. Swiss mice challenged with T. cruzi were also treated for 20 days with tagitinin C (10 mg/kg) alone and combined with Bz (100 mg/kg). Tagitinin C exhibited a higher antiparasitic (IC50: 1.15 µM) and cytotoxic (CC50 at 6.54 µM) potential than Bz (IC50: 35.81 µM and CC50: 713.5 µM, respectively). When combined, these drugs presented an addictive interaction, determining complete suppression of parasitemia and parasitological cure in all infected mice (100%) compared to those receiving Bz alone (70%). Anti-T. cruzi immunoglobulin G, and pro-inflammatory cytokines IFN-γ and TNF-α levels were reduced in animals treated with tagitinin C combined with Bz, while IL-10 production was unaffected. Heart inflammation was undetectable in 90% of the animals receiving this combination, while only 50% of the animals receiving Bz alone showed no evidence of myocarditis. Together, our findings indicated that the combination of tagitinin C and Bz exerts potent antiparasitic, immunomodulatory and cardioprotective effects. Due to the remarkable suppression of parasitemia and high parasitological cure, this combination was superior to Bz monotherapy, indicating a high potential for the treatment of Chagas's disease.


Assuntos
Antiparasitários/farmacologia , Cardiotônicos/farmacocinética , Fatores Imunológicos/farmacologia , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Cardiotônicos/farmacologia , Linhagem Celular , Doença de Chagas/tratamento farmacológico , Doença de Chagas/metabolismo , Doença de Chagas/parasitologia , Citocinas/metabolismo , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/parasitologia , Camundongos , Miocardite/metabolismo , Miocardite/parasitologia , Nitroimidazóis/farmacologia , Parasitemia/tratamento farmacológico , Parasitemia/metabolismo , Parasitemia/parasitologia , Ratos , Fator de Necrose Tumoral alfa/metabolismo
5.
EBioMedicine ; 47: 329-340, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31474552

RESUMO

BACKGROUND: The objective of the current study was to study the molecular mechanism(s) underlying cardiac troponin I autoantibody (cTnIAAb) binding to cardiomyocyte and resultant myocardial damage/dysfunction. METHODS: cTnIAAb was purified from serum of 10 acute myocardial infarction (AMI) patients with left ventricular remodeling. Recombinant human cTnI was used to generate three mouse-derived monoclonal anti-cTnI antibodies (cTnImAb1, cTnImAb2, and cTnImAb3). The target proteins in cardiac myocyte membrane bound to cTnImAb and effect of cTnIAAb and cTnImAb on apoptosis and myocardial function were determined. FINDINGS: We found that cTnIAAb/cTnImAb1 directly bound to the cardiomyocyte membraneα-Enolase (ENO1) and triggered cell apoptosis via increased expression of ENO1 and Bax, decreased expression of Bcl2, subsequently activating Caspase8, Caspase 3, phosphatase and tensin homolog (PTEN) while inhibiting Akt activity. This cTnIAAb-ENO1-PTEN-Akt signaling axis contributed to increased myocardial apoptosis, myocardial collagen deposition, and impaired systolic dysfunction. INTERPRETATION: Results obtained in this study indicate that cTnIAAb is involved in the process of ventricular remodeling after myocardial injury. FUND: The National Natural Science Foundation of China (Grant#: 81260026).


Assuntos
Autoanticorpos/imunologia , Miocardite/etiologia , Miocardite/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Transdução de Sinais , Troponina I/imunologia , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Autoanticorpos/efeitos adversos , Biomarcadores , Membrana Celular/imunologia , Membrana Celular/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Feminino , Testes de Função Cardíaca , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Miocardite/diagnóstico , Miocardite/fisiopatologia , Miocárdio/imunologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo
6.
Life Sci ; 235: 116838, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31493482

RESUMO

AIMS: This work aimed to evaluate the regulatory function of IL-10-producing B cells in viral myocarditis (VMC). MAIN METHODS: We adoptively transferred purified IL-10-producing B cells to VMC mice via the tail vein. We observed the inflammatory responses and cardiac lesions by histological analysis, examined the proportions of spleen Th1 and T17 cells by flow cytometry and expression levels of related transcription factors (T-bet and RORγt) by reverse transcription polymerase chain reaction (RT-PCR), and calculated the cardiac pathological scores and the mean survival times. KEY FINDINGS: IL-10-producing B cells were found to be T cell-dependent in the pathogenesis of VMC. They mainly downregulated T-bet and RORγt mRNA levels to decrease the proportions of Th1 and Th17 cells, thereby restraining the inflammation and damage in the myocardium in B cell-deficient VMC mice. Adoptive transfer of IL-10-producing B cells before VMC induction also normalized the inflammatory responses and prolonged the survival time in wild-type (WT) VMC mice. While the transfer of IL-10-producing B cells on day 3 of VMC alleviated the severity of disease, it did not extend the mean survival time of VMC mice. By contrast, IL-10-producing B cells showed no effect on day 7 of VMC. In conclusion, IL-10-producing B cells downregulate the proportion of Th1 and Th17 cells to alleviate inflammatory damage in the myocardium during VMC before the induction or the early phase of disease. SIGNIFICANCE: These findings suggest that IL-10-producing B cells may be a new therapeutic target for modulating the immune response in VMC.


Assuntos
Linfócitos B/metabolismo , Enterovirus Humano B/imunologia , Inflamação/fisiopatologia , Interleucina-10/fisiologia , Miocardite/fisiopatologia , Células Th1/imunologia , Células Th17/imunologia , Transferência Adotiva , Animais , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/virologia , Regulação para Baixo , Interleucina-10/biossíntese , Masculino , Camundongos , Miocardite/metabolismo , Miocardite/patologia , Miocardite/virologia , Miocárdio/patologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/biossíntese , Taxa de Sobrevida , Proteínas com Domínio T/biossíntese
7.
Int J Mol Sci ; 20(18)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31489895

RESUMO

Inflammation is a physiological process by which the body responds to external insults and stress conditions, and it is characterized by the production of pro-inflammatory mediators such as cytokines. The acute inflammatory response is solved by removing the threat. Conversely, a chronic inflammatory state is established due to a prolonged inflammatory response and may lead to tissue damage. Based on the evidence of a reciprocal regulation between inflammation process and calcium unbalance, here we described the involvement of a calcium sensor in cardiac diseases with inflammatory drift. Indeed, the Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated in several diseases with an inflammatory component, such as myocardial infarction, ischemia/reperfusion injury, pressure overload/hypertrophy, and arrhythmic syndromes, in which it actively regulates pro-inflammatory signaling, among which includes nuclear factor kappa-B (NF-κB), thus contributing to pathological cardiac remodeling. Thus, CaMKII may represent a key target to modulate the severity of the inflammatory-driven degeneration.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiopatias/metabolismo , Miocardite/metabolismo , Miocárdio/metabolismo , Animais , Biomarcadores , Cálcio/metabolismo , Suscetibilidade a Doenças , Cardiopatias/diagnóstico , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Sistema Imunitário/patologia , Miocardite/diagnóstico , Miocardite/etiologia , Miocárdio/patologia , Estresse Oxidativo , Transdução de Sinais
8.
Environ Sci Pollut Res Int ; 26(29): 30444-30451, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31440970

RESUMO

Heavily chromium-polluted areas, where people are prohibited from entering, are paradises for stray dogs. In this study, stray dogs were used to study the effects of chromium exposure on the heart of dogs in severely Cr(VI)-contaminated rural areas of China. The dogs were given water (control), low dose (L, 0.92 mg/kg), medium dose (M, 1.15 mg/kg), and high dose (H, 1.38 mg/kg) of Cr(VI). The changes of electrocardiogram (ECG), myocardial enzyme parameters, inflammatory factors, oxidative kinase, and ATPase were measured to determine the toxicity of chromium on the heart of dogs. Results showed that the ST segment of ECG increased significantly, and the amplitude of T wave increased in the experimental group. The myocardial enzyme (CK-MB, AST, CK, and LDH) content in groups M and H increased significantly over time. The values of CAT, T-SOD, IL-10, and ATPase (K+-Na+-ATPase and Ca2+-Mg2+-ATPase) decreased with the increase of Cr(VI) dose, and the content of MDA, IL-1ß, IL-8, and TNF-α increased with the increase of Cr(VI) dose. Our study suggested that the heart of Chinese rural dog was damaged by Cr(VI), and Cr(VI) could cause oxidative damage and alteration of ATPase content in dogs.


Assuntos
Adenosina Trifosfatases/metabolismo , Cromo/toxicidade , Exposição Dietética/efeitos adversos , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Animais , Animais Selvagens , Antioxidantes/metabolismo , China , Cães , Eletrocardiografia , Poluentes Ambientais/toxicidade , Interleucinas/metabolismo , Miocardite/metabolismo , Miocárdio/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo
9.
Int J Biol Sci ; 15(7): 1345-1357, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31337966

RESUMO

Pyroptotic cell death or pyroptosis is characterized by caspase-1-dependent formation of plasma membrane pores, leading to the release of pro-inflammatory cytokines and cell lysis. Pyroptosis tightly controls the inflammatory responses and coordinates antimicrobial host defenses by releasing pro-inflammatory cellular contents, such as interleukin (IL)-1ß and IL-18, and consequently expands or sustains inflammation. It is recognized as an important innate immune effector mechanism against intracellular pathogens. The induction of pyroptosis is closely associated with the activation of the NOD-like receptor 3 (NLRP3) inflammasome which has been linked to key cardiovascular risk factors including hyperlipidemia, diabetes, hypertension, obesity, and hyperhomocysteinemia. Emerging evidence has indicated pyroptosis as an important trigger and endogenous regulator of cardiovascular inflammation. Thus, pyroptosis may play an important role in the pathogenesis of cardiovascular diseases. Design of therapeutic strategies targeting the activation of NLRP3 inflammasome and pyroptosis holds promise for the treatment of cardiovascular diseases.


Assuntos
Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/terapia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Animais , Autofagia , Proteínas de Transporte/metabolismo , Caspase 1/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Insuficiência Cardíaca/metabolismo , Humanos , Inflamação , Interleucinas/metabolismo , Macrófagos/metabolismo , Miocardite/metabolismo , Miocardite/virologia , Fatores de Risco
10.
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
11.
Clin Immunol ; 207: 24-35, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31279856

RESUMO

Since toll-like receptor 9 (TLR9) or interferon regulatory factor 5 (IRF5) was reported to be associated with the development of myocarditis, we wondered if the TLR9-IRF5 pathway could contribute to the development of coxsackievirus B3 (CVB3)-induced myocarditis. We detected signaling molecules of TLR9-IRF5 pathway in CVB3-infected patients and mice. The results showed that TLR9, IRF5 and its downstream molecules such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were significantly increased, and the increase was correlated with the severity of heart injury during CVB3 infection. In addition, we demonstrated that an AAAG ODN with IRF5 interfering activities significantly decreased the levels of the TLR9-IRF5 pathway molecules in hearts, spleens as well as white blood cells, and alleviated the myocarditis in CVB3-infected mice. The data suggest that interfering TLR9-IRF5 pathway could be an approach to treat CVB3-induced myocarditis.


Assuntos
Infecções por Coxsackievirus/metabolismo , Fatores Reguladores de Interferon/metabolismo , Miocardite/metabolismo , Miocardite/virologia , Animais , Criança , Pré-Escolar , Citocinas/genética , Citocinas/metabolismo , Enterovirus , Feminino , Regulação da Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocárdio/patologia , Oligodesoxirribonucleotídeos/metabolismo , Transdução de Sinais , Receptor Toll-Like 9
13.
Am J Physiol Heart Circ Physiol ; 317(3): H531-H540, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31225989

RESUMO

As an inflammatory disease afflicting the heart muscle, autoimmune myocarditis (AM) represents one of the foremost causes of heart failure. Accumulating evidence has implicated microRNAs (miRNAs) in the process of inflammation and autoimmunity. Hence, the current study aimed to investigate the mechanism by which miR-141-3p influences experimental AM (EAM). An EAM mouse model was established using 6-wk old male BALB/c mice, after which the expression of miR-141-3p and STAT4 was measured. Gain-of-function and loss-of-function investigations were performed to identify the functional role of miR-141-3p and STAT4 in EAM. Heart weight-to-body weight ratio, cardiac function, and degree of inflammation, as well as the levels of inflammation factors (IFN-γ, TNF-α, IL-2, IL-6, and IL-17) in the serum were detected. STAT4 was subsequently verified to be upregulated, and miR-141-3p was downregulated in the EAM mice. Furthermore, the overexpression of miR-141-3p or silencing of STAT4 was observed to reduce the heart weight-to-body weight ratio of EAM mice and improve cardiac function, while alleviating the degree of inflammatory cell infiltration in the myocardial tissue. Meanwhile, the overexpression of miR-141-3p was identified to diminish serum inflammatory factor levels by downregulating STAT4. Additionally, miR-141-3p could bind to STAT4 to downregulate its expression, ultimately mitigating inflammation and inducing an anti-inflammatory effect in EAM mice. Taken together, upregulation of miR-141-3p alleviates the inflammatory response in EAM mice by inhibiting STAT4, providing a promising intervention target for the molecular treatment of AM.NEW & NOTEWORTHY miR-141-3p is poorly expressed, and STAT4 is upregulated in experimental autoimmune myocarditis (EAM) mice. Overexpressing miR-141-3p inhibits EAM. miR-141-3p binds to and suppresses STAT4 expression. miR-141-3p overexpression inhibits inflammatory factors by downregulating STAT4. This study provides new insights into the treatment of autoimmune myocarditis.


Assuntos
Doenças Autoimunes/prevenção & controle , MicroRNAs/metabolismo , Miocardite/prevenção & controle , Miocárdio/metabolismo , RNA Interferente Pequeno/administração & dosagem , Terapêutica com RNAi , Fator de Transcrição STAT4/metabolismo , Animais , Antagomirs/administração & dosagem , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Citocinas/sangue , Citocinas/genética , Modelos Animais de Doenças , Redes Reguladoras de Genes , Mediadores da Inflamação/sangue , Masculino , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Miocardite/genética , Miocardite/imunologia , Miocardite/metabolismo , Miocárdio/imunologia , Miosinas , Interferência de RNA , Fator de Transcrição STAT4/genética
14.
Am J Physiol Heart Circ Physiol ; 317(2): H405-H414, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31199184

RESUMO

Hypereosinophilic syndrome is characterized by sustained and marked eosinophilia leading to tissue damage and organ dysfunction. Morbidity and mortality occur primarily due to cardiac and thromboembolic complications. Understanding the cause and mechanism of disease would aid in the development of targeted therapies with greater efficacy and fewer side effects. We discovered a spontaneous mouse mutant in our colony with a hypereosinophilic phenotype. Mice develop peripheral blood eosinophilia; infiltration of lungs, spleen, and heart by eosinophils; and extensive myocardial damage and remodeling. This ultimately leads to heart failure and premature death. Histopathological assessment of the hearts revealed a robust inflammatory infiltrate composed primarily of eosinophils and B-lymphocytes, associated with myocardial damage and replacement fibrosis, consistent with eosinophilic myocarditis. In many cases, hearts showed dilatation and thinning of the right ventricular wall, suggestive of an inflammatory dilated cardiomyopathy. Most mice showed atrial thrombi, which often filled the chamber. Protein expression analysis revealed overexpression of chemokines and cytokines involved in innate and adaptive immunity including IL-4, eotaxin, and RANTES. Disease could be transferred to wild-type mice by adoptive transfer of splenocytes from affected mice, suggesting a role for the immune system. In summary, the pathologies observed in the mutant lines are reminiscent of those seen in patients with hypereosinophilia, where cardiac-related morbidities, like congestive heart failure and thrombi, are the most common causes of death. As such, our model provides an opportunity to test mechanistic hypotheses and develop targeted therapies.NEW & NOTEWORTHY This article describes a new model of heart disease in hypereosinophilia. The model developed as a spontaneous mouse mutant in the colony and is characterized by peripheral blood eosinophilia and infiltration of lungs, spleen, and heart by eosinophils. In the heart, there is extensive myocardial damage, remodeling, fibrosis, and thrombosis, leading to heart failure and death. The immune microenvironment is one of increased innate and adaptive immunity, including Th1 and Th2 cytokines/chemokines. Finally, adoptive transfer of splenocytes transfers disease to recipient mice. In summary, this model provides an opportunity to test mechanistic hypotheses and develop targeted therapies for this rare but devastating disease.


Assuntos
Cardiomiopatia Dilatada/etiologia , Insuficiência Cardíaca/etiologia , Síndrome Hipereosinofílica/complicações , Miocardite/etiologia , Miocárdio , Imunidade Adaptativa , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Cardiomiopatia Dilatada/imunologia , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Eosinófilos/imunologia , Eosinófilos/metabolismo , Fibrose , Predisposição Genética para Doença , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Síndrome Hipereosinofílica/imunologia , Síndrome Hipereosinofílica/metabolismo , Síndrome Hipereosinofílica/patologia , Imunidade Inata , Camundongos Mutantes , Miocardite/imunologia , Miocardite/metabolismo , Miocardite/patologia , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologia , Fenótipo , Transdução de Sinais , Fatores de Tempo , Remodelação Ventricular
15.
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
16.
Am J Physiol Heart Circ Physiol ; 317(2): H213-H225, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125258

RESUMO

Ischemic heart disease is a growing worldwide epidemic. Improvements in medical and surgical therapies have reduced early mortality after acute myocardial infarction and increased the number of patients living with chronic heart failure. The irreversible loss of functional cardiomyocytes puts these patients at significant risk of ongoing morbidity and mortality after their index event. Recent evidence suggests that inflammation is a key mediator of postinfarction adverse remodeling in the heart. In this review, we discuss the cardioprotective and deleterious effects of inflammation and its mediators during acute myocardial infarction. We also explore the role of mesenchymal stem cell therapy to limit secondary injury and promote myocardial healing after myocardial infarction.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Infarto do Miocárdio/cirurgia , Miocardite/cirurgia , Miócitos Cardíacos/imunologia , Regeneração , Animais , Humanos , Células-Tronco Mesenquimais/metabolismo , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocardite/imunologia , Miocardite/metabolismo , Miocardite/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Recuperação de Função Fisiológica , Cicatrização
17.
PLoS One ; 14(4): e0209534, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30933983

RESUMO

Secreted protein acidic and rich in cysteine (SPARC) is a non-structural extracellular matrix protein that regulates interactions between the matrix and neighboring cells. In the cardiovascular system, it is expressed by cardiac fibroblasts, endothelial cells, and at lower levels by ventricular cardiomyocytes. SPARC expression levels are increased upon myocardial injury and also during hypertrophy and fibrosis. We have previously shown that SPARC improves cardiac function after myocardial infarction by regulating post-synthetic procollagen processing, however whether SPARC directly affects cardiomyocyte contraction is still unknown. In this study we demonstrate a novel inotropic function for extracellular SPARC in the healthy heart as well as in the diseased state after myocarditis-induced cardiac dysfunction. We demonstrate SPARC presence on the cardiomyocyte membrane where it is co-localized with the integrin-beta1 and the integrin-linked kinase. Moreover, extracellular SPARC directly increases cardiomyocyte cell shortening ex vivo and cardiac function in vivo, both in healthy myocardium and during coxsackie virus-induced cardiac dysfunction. In conclusion, we demonstrate a novel inotropic function for SPARC in the heart, with a potential therapeutic application when myocyte contractile function is diminished such as that caused by a myocarditis-related cardiac injury.


Assuntos
Miocardite/patologia , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Osteonectina/metabolismo , Animais , Células Cultivadas , Infecções por Coxsackievirus/complicações , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/virologia , Masculino , Camundongos , Contração Miocárdica , Miocardite/metabolismo , Miocardite/virologia , Miocárdio/citologia , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/virologia , Osteonectina/análise , Ratos Wistar
18.
Toxicology ; 422: 1-13, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31005592

RESUMO

Myocarditis is a serious hazard to human life and is difficult to treat due to the proliferation of inflammatory lesions in the myocardium. Leonurine (LE) is a plant phenolic alkaloid extracted from Herba leonuri that has demonstrated cardioprotective effects in many preclinical experiments. However, whether LE can be used for myocarditis therapy has not been reported. We aimed to investigate the cardioprotective effects of LE on lipopolysaccharide (LPS)-induced myocarditis in vivo and vitro. The possible mechanism involved was also further elucidated. In vivo, C57BL/6 mice were exposed to LPS with or without LE. We found out that LE effectively improved cardiac function and attenuated cardiomyocyte apoptosis in mice with myocarditis. In addition, LPS-induced inflammatory and oxidative injuries in the myocardium were also reduced by LE administration. In vitro, LPS simultaneously induced apoptosis and reduced the H9c2 cells viability, followed by elevation of intracellular reactive oxygen species (ROS) generation. However, the abnormalities mentioned were preventable by LE pretreatment in a dose-dependent manner. Both in vivo and in vitro, LPS activated the nuclear factor kappa B (NF-кB) signaling pathway in myocarditis, and LE inhibited the increased expression of phosphorylated iκBα and p65 (p-iκBα, p-p65). Furthermore, the nuclear translocalization and nuclear protein expression of p65 in LPS-injured H9c2 cells were also suppressed by LE. Our results demonstrated that LE exerts potent cardioprotective effects against myocarditis via anti-inflammatory and antioxidative mechanisms, possibly through blocking the activation of NF-кB pathway.


Assuntos
Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Ácido Gálico/análogos & derivados , Miocardite/tratamento farmacológico , NF-kappa B/metabolismo , Animais , Linhagem Celular , Ácido Gálico/farmacologia , Ácido Gálico/uso terapêutico , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos C57BL , Miocardite/induzido quimicamente , Miocardite/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos
19.
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 , Proteínas de Ligação a RNA , Replicação Viral
20.
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
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA