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1.
Front Immunol ; 12: 666594, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630378

RESUMO

Coxsackievirus B3 (CVB3)-induced viral myocarditis is a common clinical cardiovascular disease without effective available vaccine. In this study, we tried to potentiate the immunoprotection efficacy of our previous CVB3-specific VP1 protein vaccine by introducing a streptococcal protein G-derived, draining lymph nodes (dLNs)-targeting albumin-binding domain (ABD) peptide. We found that compared with the original VP1 vaccine, ABD-fused VP1 (ABD-VP1) vaccine gained the new ability to efficiently bind murine albumin both in vitro and in vivo, possessed a much longer serum half-life in serum and exhibited more abundance in the dLNs after immunization. Accordingly, ABD-VP1 immunization not only significantly facilitated the enrichment and maturation of dendritic cells (DCs), induced higher percentages of IFN-γ+ CD8 + cells in the dLNs, but also robustly promoted VP1-induced T cell proliferation and cytotoxic T lymphocyte (CTL) responses in the spleens. More importantly, ABD-VP1 also elicited higher percentages of protective CD44hi CD62Lhi memory T cells in dLNs and spleens. Consequently, obvious protective effect against viral myocarditis was conferred by ABD-VP1 vaccine compared to the VP1 vaccine, reflected by the less body weight loss, improved cardiac function, alleviated cardiac histomorphological changes and an increased 28-day survival rate. Our results indicated that the ABD might be a promising immune-enhancing regime for vaccine design and development.


Assuntos
Proteínas de Bactérias/administração & dosagem , Proteínas do Capsídeo/administração & dosagem , Infecções por Coxsackievirus/prevenção & controle , Enterovirus Humano B/imunologia , Imunogenicidade da Vacina , Miocardite/prevenção & controle , Fragmentos de Peptídeos/administração & dosagem , Albumina Sérica/metabolismo , Vacinas Virais/administração & dosagem , Animais , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/metabolismo , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/metabolismo , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/metabolismo , Infecções por Coxsackievirus/virologia , Modelos Animais de Doenças , Células HeLa , Humanos , Imunização , Masculino , Camundongos Endogâmicos BALB C , Miocardite/imunologia , Miocardite/metabolismo , Miocardite/virologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/metabolismo , Vacinas Virais/imunologia , Vacinas Virais/metabolismo
2.
J Oleo Sci ; 70(8): 1115-1124, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34349088

RESUMO

Previous research has proven that coxsackievirus B3 (CVB3) is broadly considered virus used in the experimental model of animals, which causes myocarditis in humans. To investigate whether there exists a cardio-protective effect of crocetin in an experimental murine model of acute viral myocarditis (AVM). Male BALB/c mice were randomly assigned to three groups: control, myocarditis treated with placebo and myocarditis treated with crocetin (n = 40 animals per group). Myocarditis was established by intraperitoneal injection with CVB3. Twenty-four hours after infection, crocetin was intraperitoneally administered for 14 consecutive days. Twenty mice were randomly selected from each group to monitor a 14-day survival rate. On day 7 and day 14, eight surviving mice from each group were sacrificed and their hearts and blood were obtained to perform serological and histological examinations. Expression of ROCKs, interleukin-17 (IL-17), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNFα), RORγt, and Foxp3 was quantified by RT-PCR. Plasma levels of TNFα, IL-1ß and IL-17 were measured by ELISA. In addition, protein levels of IL-17 and ROCK2 in cardiac tissues were analyzed by Western blot. Crocetin treatment significantly increased survival, attenuated myocardial necrotic lesions, reduced CVB3 replication and expression of ROCK2 and IL-17 in the infected hearts. ROCK pathway inhibition was cardio-protective in viral myocarditis with increased survival, decreased viral replication, and inflammatory response. These findings suggest that crocetin is a potential therapeutic agent for patients with viral myocarditis.


Assuntos
Antivirais/uso terapêutico , Cardiotônicos/uso terapêutico , Carotenoides/uso terapêutico , Enterovirus Humano B/patogenicidade , Miocardite/tratamento farmacológico , Vitamina A/análogos & derivados , Doença Aguda , Animais , Fatores de Transcrição Forkhead/metabolismo , Coração/efeitos dos fármacos , Coração/virologia , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Miocardite/metabolismo , Miocardite/virologia , Miocárdio/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Vitamina A/uso terapêutico , Quinases Associadas a rho/metabolismo
3.
Int Heart J ; 62(4): 900-909, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34234076

RESUMO

Virus myocarditis (VMC) is a common cardiovascular disease and a major cause of sudden death in young adults. However, there is still a lack of effective treatments. Our previous studies found that calpain activation was involved in VMC pathogenesis. This study aims to explore the underlying mechanisms further. Neonatal rat cardiomyocytes (NRCMs) and transgenic mice overexpressing calpastatin (Tg-CAST), the endogenous calpain inhibitor, were used to establish VMC model. Hematoxylin and eosin and Masson staining revealed inflammatory cell infiltration and fibrosis. An ELISA array detected myocardial injury. Cardiac function was measured using echocardiography. CVB3 replication was assessed by capsid protein VP1. Apoptosis was measured by TUNEL staining, flow cytometry, and western blot. The endoplasmic reticulum (ER) stress-related proteins were detected by western blot. Our data showed that CVB3 infection resulted in cardiac injury, as evidenced by increased inflammatory responses and fibrosis, which induced myocardial apoptosis. Inhibiting calpain, both by PD150606 and calpastatin overexpression, could attenuate these effects. Furthermore, ER stress was activated during CVB3 infection. However, calpain inhibition could downregulate some ER stress-associated protein levels such as GRP78, pancreatic ER kinase-like ER kinase (PERK), and inositol-requiring enzyme-1α (IRE-1α), and ER stress-related apoptotic factors, during CVB3 infection. In conclusion, calpain inhibition attenuated CVB3-induced myocarditis by suppressing ER stress, thereby inhibiting cardiomyocyte apoptosis.


Assuntos
Acrilatos/uso terapêutico , Calpaína/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Miocardite/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Acrilatos/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Calpaína/antagonistas & inibidores , Infecções por Coxsackievirus/tratamento farmacológico , Infecções por Coxsackievirus/metabolismo , Avaliação Pré-Clínica de Medicamentos , Enterovirus Humano B , Camundongos Transgênicos , Miocardite/tratamento farmacológico , Miocardite/virologia , Ratos Sprague-Dawley
4.
PLoS Pathog ; 17(7): e1009494, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34237110

RESUMO

The mammalian orthoreovirus double-stranded (ds) RNA-binding protein σ3 is a multifunctional protein that promotes viral protein synthesis and facilitates viral entry and assembly. The dsRNA-binding capacity of σ3 correlates with its capacity to prevent dsRNA-mediated activation of protein kinase R (PKR). However, the effect of σ3 binding to dsRNA during viral infection is largely unknown. To identify functions of σ3 dsRNA-binding activity during reovirus infection, we engineered a panel of thirteen σ3 mutants and screened them for the capacity to bind dsRNA. Six mutants were defective in dsRNA binding, and mutations in these constructs cluster in a putative dsRNA-binding region on the surface of σ3. Two recombinant viruses expressing these σ3 dsRNA-binding mutants, K287T and R296T, display strikingly different phenotypes. In a cell-type dependent manner, K287T, but not R296T, replicates less efficiently than wild-type (WT) virus. In cells in which K287T virus demonstrates a replication deficit, PKR activation occurs and abundant stress granules (SGs) are formed at late times post-infection. In contrast, the R296T virus retains the capacity to suppress activation of PKR and does not mediate formation of SGs at late times post-infection. These findings indicate that σ3 inhibits PKR independently of its capacity to bind dsRNA. In infected mice, K287T produces lower viral titers in the spleen, liver, lungs, and heart relative to WT or R296T. Moreover, mice inoculated with WT or R296T viruses develop myocarditis, whereas those inoculated with K287T do not. Overall, our results indicate that σ3 functions to suppress PKR activation and subsequent SG formation during viral infection and that these functions correlate with virulence in mice.


Assuntos
Miocardite/virologia , Proteínas de Ligação a RNA/metabolismo , Infecções por Reoviridae/metabolismo , Proteínas Virais/metabolismo , Fatores de Virulência/metabolismo , Células A549 , Animais , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Miocardite/metabolismo , eIF-2 Quinase/metabolismo
5.
J Exp Med ; 218(9)2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34325467

RESUMO

Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic insult, including myocardial infarction (MI). HIFs are also activated within macrophages, which orchestrate the tissue repair response. Although isoform-specific therapeutics are in development for cardiac ischemic injury, surprisingly, the unique role of myeloid HIFs, and particularly HIF-2α, is unknown. Using a murine model of myocardial infarction and mice with conditional genetic loss and gain of function, we uncovered unique proinflammatory roles for myeloid cell expression of HIF-1α and HIF-2α during MI. We found that HIF-2α suppressed anti-inflammatory macrophage mitochondrial metabolism, while HIF-1α promoted cleavage of cardioprotective MerTK through glycolytic reprogramming of macrophages. Unexpectedly, combinatorial loss of both myeloid HIF-1α and HIF-2α was catastrophic and led to macrophage necroptosis, impaired fibrogenesis, and cardiac rupture. These findings support a strategy for selective inhibition of macrophage HIF isoforms and promotion of anti-inflammatory mitochondrial metabolism during ischemic tissue repair.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células Mieloides/metabolismo , Idoso , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cardiomiopatias/fisiopatologia , Modelos Animais de Doenças , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Células Mieloides/patologia , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Miocardite/metabolismo , Miocardite/patologia
6.
JAMA Neurol ; 78(8): 948-960, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34115106

RESUMO

Importance: Myalgia, increased levels of creatine kinase, and persistent muscle weakness have been reported in patients with COVID-19. Objective: To study skeletal muscle and myocardial inflammation in patients with COVID-19 who had died. Design, Setting, and Participants: This case-control autopsy series was conducted in a university hospital as a multidisciplinary postmortem investigation. Patients with COVID-19 or other critical illnesses who had died between March 2020 and February 2021 and on whom an autopsy was performed were included. Individuals for whom informed consent to autopsy was available and the postmortem interval was less than 6 days were randomly selected. Individuals who were infected with SARS-CoV-2 per polymerase chain reaction test results and had clinical features suggestive of COVID-19 were compared with individuals with negative SARS-CoV-2 polymerase chain reaction test results and an absence of clinical features suggestive of COVID-19. Main Outcomes and Measures: Inflammation of skeletal muscle tissue was assessed by quantification of immune cell infiltrates, expression of major histocompatibility complex (MHC) class I and class II antigens on the sarcolemma, and a blinded evaluation on a visual analog scale ranging from absence of pathology to the most pronounced pathology. Inflammation of cardiac muscles was assessed by quantification of immune cell infiltrates. Results: Forty-three patients with COVID-19 (median [interquartile range] age, 72 [16] years; 31 men [72%]) and 11 patients with diseases other than COVID-19 (median [interquartile range] age, 71 [5] years; 7 men [64%]) were included. Skeletal muscle samples from the patients who died with COVID-19 showed a higher overall pathology score (mean [SD], 3.4 [1.8] vs 1.5 [1.0]; 95% CI, 0-3; P < .001) and a higher inflammation score (mean [SD], 3.5 [2.1] vs 1.0 [0.6]; 95% CI, 0-4; P < .001). Relevant expression of MHC class I antigens on the sarcolemma was present in 23 of 42 specimens from patients with COVID-19 (55%) and upregulation of MHC class II antigens in 7 of 42 specimens from patients with COVID-19 (17%), but neither were found in any of the controls. Increased numbers of natural killer cells (median [interquartile range], 8 [8] vs 3 [4] cells per 10 high-power fields; 95% CI, 1-10 cells per 10 high-power fields; P < .001) were found. Skeletal muscles showed more inflammatory features than cardiac muscles, and inflammation was most pronounced in patients with COVID-19 with chronic courses. In some muscle specimens, SARS-CoV-2 RNA was detected by reverse transcription-polymerase chain reaction, but no evidence for a direct viral infection of myofibers was found by immunohistochemistry and electron microscopy. Conclusions and Relevance: In this case-control study of patients who had died with and without COVID-19, most individuals with severe COVID-19 showed signs of myositis ranging from mild to severe. Inflammation of skeletal muscles was associated with the duration of illness and was more pronounced than cardiac inflammation. Detection of viral load was low or negative in most skeletal and cardiac muscles and probably attributable to circulating viral RNA rather than genuine infection of myocytes. This suggests that SARS-CoV-2 may be associated with a postinfectious, immune-mediated myopathy.


Assuntos
COVID-19/patologia , Músculo Esquelético/patologia , Miocardite/patologia , Miocárdio/patologia , Miosite/patologia , Idoso , Idoso de 80 Anos ou mais , Autopsia , Linfócitos T CD8-Positivos/patologia , COVID-19/metabolismo , Teste de Ácido Nucleico para COVID-19 , Teste Sorológico para COVID-19 , Estudos de Casos e Controles , Feminino , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Células Matadoras Naturais/patologia , Leucócitos/patologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Miocardite/metabolismo , Miocárdio/metabolismo , Miosite/metabolismo , RNA Viral/metabolismo , SARS-CoV-2 , Sarcolema/metabolismo , Fatores de Tempo
7.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072423

RESUMO

Tenascin-C (TNC) is a large extracellular matrix (ECM) glycoprotein and an original member of the matricellular protein family. TNC is transiently expressed in the heart during embryonic development, but is rarely detected in normal adults; however, its expression is strongly up-regulated with inflammation. Although neither TNC-knockout nor -overexpressing mice show a distinct phenotype, disease models using genetically engineered mice combined with in vitro experiments have revealed multiple significant roles for TNC in responses to injury and myocardial repair, particularly in the regulation of inflammation. In most cases, TNC appears to deteriorate adverse ventricular remodeling by aggravating inflammation/fibrosis. Furthermore, accumulating clinical evidence has shown that high TNC levels predict adverse ventricular remodeling and a poor prognosis in patients with various heart diseases. Since the importance of inflammation has attracted attention in the pathophysiology of heart diseases, this review will focus on the roles of TNC in various types of inflammatory reactions, such as myocardial infarction, hypertensive fibrosis, myocarditis caused by viral infection or autoimmunity, and dilated cardiomyopathy. The utility of TNC as a biomarker for the stratification of myocardial disease conditions and the selection of appropriate therapies will also be discussed from a clinical viewpoint.


Assuntos
Suscetibilidade a Doenças , Cardiopatias/etiologia , Cardiopatias/metabolismo , Tenascina/genética , Tenascina/metabolismo , Animais , Biomarcadores , Biópsia , Gerenciamento Clínico , Fibrose , Expressão Gênica , Regulação da Expressão Gênica , Cardiopatias/diagnóstico , Humanos , Miocardite/diagnóstico , Miocardite/etiologia , Miocardite/metabolismo , Organogênese/genética , Prognóstico , Transdução de Sinais , Remodelação Ventricular/genética
8.
Cells ; 10(5)2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064728

RESUMO

Th17 cells are recognized as indispensable in inducing protective immunity against bacteria and fungi, as they promote the integrity of mucosal epithelial barriers. It is believed that Th17 cells also play a central role in the induction of autoimmune diseases. Recent advances have evaluated Th17 effector functions during viral infections, including their critical role in the production and induction of pro-inflammatory cytokines and in the recruitment and activation of other immune cells. Thus, Th17 is involved in the induction both of pathogenicity and immunoprotective mechanisms seen in the host's immune response against viruses. However, certain Th17 cells can also modulate immune responses, since they can secrete immunosuppressive factors, such as IL-10; these cells are called non-pathogenic Th17 cells. Here, we present a brief review of Th17 cells and highlight their involvement in some virus infections. We cover these notions by highlighting the role of Th17 cells in regulating the protective and pathogenic immune response in the context of viral infections. In addition, we will be describing myocarditis and multiple sclerosis as examples of immune diseases triggered by viral infections, in which we will discuss further the roles of Th17 cells in the induction of tissue damage.


Assuntos
Miocardite/imunologia , Células Th17/metabolismo , Viroses/imunologia , Adenoviridae , Animais , Doenças Autoimunes/imunologia , Vírus Chikungunya , Citocinas/imunologia , Vírus da Dengue , Humanos , Sistema Imunitário , Imunossupressores/farmacologia , Inflamação , Interleucina-10/biossíntese , Linfócitos/citologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/virologia , Miocardite/metabolismo , Miocardite/virologia , Orthomyxoviridae , SARS-CoV-2 , Simplexvirus , Células Th1/citologia , Células Th2/citologia , Viroses/tratamento farmacológico , Viroses/metabolismo , Zika virus
9.
Cell Death Dis ; 12(5): 487, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33986259

RESUMO

Myocarditis (MC) is a common, potentially life-threatening inflammatory disease of the myocardium. A growing body of evidence has shown that mitogen-activated protein kinase 14 (MAPK14) participates in the pathogenesis of MC. However, the upstream regulators of MAPK14 remain enigmatic. Circular RNAs (circRNAs) have been identified to play vital roles in the pathophysiology of cardiovascular diseases. Nevertheless, the clinical significance, biological function, and regulatory mechanisms of circRNAs in MC remain poorly understood. In this study, we determined a novel circRNA, circACSL1 (ID: hsa_circ_0071542), which was significantly upregulated in the acute phase of MC, and its dynamic change in expression was related to the progression of MC. We used lipopolysaccharide (LPS) to induce the inflammatory responses in the human cardiomyocytes (HCM) line for in vitro and in cellulo experiments. The pro-inflammatory factors (IL-1ß, IL-6, and TNF-α), myocardial injury markers (cTnT, CKMB, and BNP), cell viability, and cell apoptosis were measured to evaluate the extent of myocardial inflammation and myocardial injury level. Functional experiments, including gain-of-function and loss-of-function, were then performed to investigate the pro-inflammatory roles of circACSL1. The results revealed that circACSL1 could aggravate inflammation, myocardial injury, and apoptosis in HCM. Mechanistically, circACSL1 acted as a sponge for miR-8055-binding sites to regulate the downstream target MAPK14 expression. Furthermore, overexpression of miR-8055 rescued the pro-inflammatory effects of circACSL1 on HCM, and the upregulation of MAPK14 induced by circACSL1 was attenuated by miR-8055 overexpression. Knockdown of circACSL1 or overexpression of miR-8055 reduced myocardial inflammation and myocardial injury level and these effects were rescued by overexpression of MAPK14. In summary, our study demonstrated that circACSL1 could aggravate myocardial inflammation and myocardial injury through competitive absorption of miR-8055, thereby upregulating MAPK14 expression. Moreover, circACSL1 may represent a potential novel biomarker for the precise diagnosis of MC and offer a promising therapeutic target for MC treatment.


Assuntos
Coenzima A Ligases/genética , MicroRNAs/genética , Miocardite/metabolismo , RNA Circular/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Humanos , Pessoa de Meia-Idade , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Miocardite/genética , RNA Circular/genética , Regulação para Cima
10.
Biochim Biophys Acta Mol Basis Dis ; 1867(9): 166170, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34000374

RESUMO

The vascular cellular adhesion molecule-1 (VCAM-1) is a protein that canonically participates in the adhesion and transmigration of leukocytes to the interstitium during inflammation. VCAM-1 expression, together with soluble VCAM-1 (sVCAM-1) induced by the shedding of VCAM-1 by metalloproteinases, have been proposed as biomarkers in immunological diseases, cancer, autoimmune myocarditis, and as predictors of mortality and morbidity in patients with chronic heart failure (HF), endothelial injury in patients with coronary artery disease, and arrhythmias. This revision aims to discuss the role of sVCAM-1 as a biomarker to predict the occurrence, development, and preservation of cardiovascular disease.


Assuntos
Biomarcadores/metabolismo , Doenças Cardiovasculares/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Humanos , Miocardite/metabolismo
11.
PLoS Negl Trop Dis ; 15(4): e0008964, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33826636

RESUMO

Chronic Chagas cardiomyopathy (CCC) caused by a parasite Trypanosoma cruzi is a life-threatening disease in Latin America, for which there is no effective drug or vaccine. The pathogenesis of CCC is complex and multifactorial. Previously, we demonstrated T. cruzi infected mice lose a significant amount of fat tissue which correlates with progression of CCC. Based on this an investigation was undertaken during both acute and chronic T. cruzi infection utilizing the FAT-ATTAC murine model (that allows modulation of fat mass) to understand the consequences of the loss of adipocytes in the regulation of cardiac parasite load, parasite persistence, inflammation, mitochondrial stress, ER stress, survival, CCC progression and CCC severity. Mice were infected intraperitoneally with 5x104 and 103 trypomastigotes to generate acute and chronic Chagas models, respectively. Ablation of adipocytes was carried out in uninfected and infected mice by treatment with AP21087 for 10 days starting at 15DPI (acute infection) and at 65DPI (indeterminate infection). During acute infection, cardiac ultrasound imaging, histological, and biochemical analyses demonstrated that fat ablation increased cardiac parasite load, cardiac pathology and right ventricular dilation and decreased survival. During chronic indeterminate infection ablation of fat cells increased cardiac pathology and caused bi-ventricular dilation. These data demonstrate that dysfunctional adipose tissue not only affects cardiac metabolism but also the inflammatory status, morphology and physiology of the myocardium and increases the risk of progression and severity of CCC in murine Chagas disease.


Assuntos
Cardiomiopatia Chagásica/metabolismo , Miocardite/metabolismo , Adipogenia , Tecido Adiposo Branco/metabolismo , Animais , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , LDL-Colesterol/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Miocardite/parasitologia , Miocardite/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Carga Parasitária , Ultrassonografia Doppler
12.
Med Sci Monit ; 27: e929512, 2021 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-33866323

RESUMO

BACKGROUND Sepsis is a serious clinical problem that results from the systemic response of the body to infection. Left ventricular (LV) diastolic dysfunction is increasingly appreciated as a contributor to morbidity and mortality in sepsis. Animal models may offer a method of studying diastolic dysfunction while controlling for many potential clinical confounders, such as sepsis duration, premorbid condition, and therapeutic interventions. This study sought to evaluate an endotoxemia (LPS) rodent model of sepsis, with regard to echocardiographic evidence, including tissue Doppler, of LV diastolic dysfunction and histopathology findings. MATERIAL AND METHODS Fourteen male Sprague-Dawley rats were randomly allocated (1: 1) to LPS or saline (control). Mean arterial blood pressure (MAP) was measured through cannulation of the carotid artery. After a 30-min stabilization, baseline assessment with echocardiography and blood collection was performed. Rats were administered 0.9% saline or LPS (10 mg/mL). Follow-up echocardiography and blood collection were performed after 2 h. Hearts were removed post-mortem and pathology studied using histology and immunohistochemistry. RESULTS LPS was associated with hypotension (MAP 81.86±31.67 mmHg; 124.29±20.16; p=0.02) and LV impaired relaxation (myocardial early diastolic velocity [e'] 0.06±0.02 m/s; 0.09±0.02; P=0.008). Histopathology and immunohistochemistry demonstrated evidence of interstitial myocarditis (hydropic changes and inflammation). CONCLUSIONS LPS was associated with both diastolic dysfunction (impaired relaxation) and interstitial myocarditis. These features may offer a link between the structural and functional changes that have previously been described separately in clinical sepsis. This may facilitate further studies focused upon the mechanism and potential benefit treatment of sepsis-associated cardiac dysfunction.


Assuntos
Ventrículos do Coração/metabolismo , Miocardite/metabolismo , Miocárdio/metabolismo , Sepse/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Animais , Diástole , Modelos Animais de Doenças , Ecocardiografia Doppler , Ventrículos do Coração/patologia , Humanos , Imuno-Histoquímica , Masculino , Miocardite/patologia , Ratos , Ratos Sprague-Dawley , Sepse/patologia , Disfunção Ventricular Esquerda/patologia
13.
Pediatr Infect Dis J ; 40(5): e173-e178, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33847291

RESUMO

BACKGROUND: Acute myocarditis (AM) is defined as inflammation of the myocardium. The aim of our study is a comparative analysis of the differences between AM related and unrelated to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: The retrospective study included children with AM treated from January 2018 to November 2020. RESULTS: The study included 24 patients; 7 of 24 had AM related to SARS-CoV-2 and they were older than 7. They were more likely to have abdominal pain (P = 0.014), headache (P = 0.003), cutaneous rash (P = 0.003), and conjunctivitis (P = 0.003), while fulminant myocarditis was commonly registered in AM unrelated to SARS-CoV-2 (P = 0.04). A multisystem inflammatory syndrome in children associated with COVID-19 was diagnosed in six adolescents. Patients with AM related SARS-CoV-2 had lower serum cardiac troponin I (cTnI) (P = 0.012), and platelets (P < 0.001), but had a higher C-reactive protein (CRP) value (P = 0.04), and N-terminal-pro hormone BNP in comparison to patients with AM unrelated to SARS-CoV-2. The patients with AM related to SARS-CoV-2 had significant reduction of CRP (P = 0.007). Inotropic drug support was used for shorter durations in patients with AM related to SARS-CoV-2, than in others (P = 0.02). Children with AM related to SARS-CoV-2 had significant improvement of left ventricle systolic function on the third day in hospital (P = 0.001). Patients with AM unrelated to SARS-CoV-2 AM had more frequent adverse outcomes (P = 0.04; three died and four dilated cardiomyopathy). CONCLUSIONS: In contrast to patients with AM unrelated to SARS-CoV-2, patients with AM related to SARS-CoV-2 had a higher CRP value, polymorphic clinical presentation, shorter durations of inotropic drugs use as well as prompt recovery of left ventricle systolic function.


Assuntos
COVID-19/patologia , Miocardite/virologia , Adolescente , Proteína C-Reativa/metabolismo , COVID-19/metabolismo , COVID-19/fisiopatologia , COVID-19/virologia , Criança , Pré-Escolar , Exantema , Feminino , Humanos , Inflamação/virologia , Masculino , Miocardite/metabolismo , Miocardite/patologia , Miocardite/fisiopatologia , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/patologia , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia , Síndrome de Resposta Inflamatória Sistêmica/virologia , Função Ventricular Esquerda
14.
Front Immunol ; 12: 624703, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33692798

RESUMO

Accumulating evidence suggests that the breakdown of immune tolerance plays an important role in the development of myocarditis triggered by cardiotropic microbial infections. Genetic deletion of immune checkpoint molecules that are crucial for maintaining self-tolerance causes spontaneous myocarditis in mice, and cancer treatment with immune checkpoint inhibitors can induce myocarditis in humans. These results suggest that the loss of immune tolerance results in myocarditis. The tissue microenvironment influences the local immune dysregulation in autoimmunity. Recently, tenascin-C (TN-C) has been found to play a role as a local regulator of inflammation through various molecular mechanisms. TN-C is a nonstructural extracellular matrix glycoprotein expressed in the heart during early embryonic development, as well as during tissue injury or active tissue remodeling, in a spatiotemporally restricted manner. In a mouse model of autoimmune myocarditis, TN-C was detectable before inflammatory cell infiltration and myocytolysis became histologically evident; it was strongly expressed during active inflammation and disappeared with healing. TN-C activates dendritic cells to generate pathogenic autoreactive T cells and forms an important link between innate and acquired immunity.


Assuntos
Doenças Autoimunes/metabolismo , Autoimunidade , Cardiomiopatias/metabolismo , Mediadores da Inflamação/metabolismo , Miocardite/metabolismo , Miocárdio/metabolismo , Tenascina/metabolismo , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Cardiomiopatias/imunologia , Cardiomiopatias/patologia , Microambiente Celular , Humanos , Miocardite/imunologia , Miocardite/patologia , Miocárdio/imunologia , Miocárdio/patologia , Tolerância a Antígenos Próprios , Transdução de Sinais
15.
J Clin Invest ; 131(6)2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33529176

RESUMO

Tyro3, AXL, and MerTK (TAM) receptors are activated in macrophages in response to tissue injury and as such have been proposed as therapeutic targets to promote inflammation resolution during sterile wound healing, including myocardial infarction. Although the role of MerTK in cardioprotection is well characterized, the unique role of the other structurally similar TAMs, and particularly AXL, in clinically relevant models of myocardial ischemia/reperfusion infarction (IRI) is comparatively unknown. Utilizing complementary approaches, validated by flow cytometric analysis of human and murine macrophage subsets and conditional genetic loss and gain of function, we uncover a maladaptive role for myeloid AXL during IRI in the heart. Cross signaling between AXL and TLR4 in cardiac macrophages directed a switch to glycolytic metabolism and secretion of proinflammatory IL-1ß, leading to increased intramyocardial inflammation, adverse ventricular remodeling, and impaired contractile function. AXL functioned independently of cardioprotective MerTK to reduce the efficacy of cardiac repair, but like MerTK, was proteolytically cleaved. Administration of a selective small molecule AXL inhibitor alone improved cardiac healing, which was further enhanced in combination with blockade of MerTK cleavage. These data support further exploration of macrophage TAM receptors as therapeutic targets for myocardial infarction.


Assuntos
Macrófagos/metabolismo , Infarto do Miocárdio/complicações , Infarto do Miocárdio/metabolismo , Miocardite/etiologia , Miocardite/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Humanos , Inflamassomos/metabolismo , Ativação de Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Receptor Cross-Talk , Receptores Proteína Tirosina Quinases/deficiência , Receptores Proteína Tirosina Quinases/genética , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , c-Mer Tirosina Quinase/deficiência , c-Mer Tirosina Quinase/genética , c-Mer Tirosina Quinase/metabolismo
16.
Int J Mol Med ; 47(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33448307

RESUMO

Heart failure (HF) is a serious threat to human health. Long noncoding RNAs (lncRNAs) are critical regulators of HF. The aim of the study was to investigate the molecular mechanism of MALAT1 in HF rats. MALAT1 expression was detected in serum of normal volunteers and HF patients, HF rats and isoproterenol (ISO)­induced H9C2 cells, and its diagnostic value was evaluated in HF patients. Indexes related to cardiac functions and hemodynamics, myocardial injury, lipid metabolism, lipid oxidation, and inflammation were detected. Moreover, the downstream mechanism of MALAT1 was predicted and verified and in vivo experiments were further performed in ISO­induced H9C2 cells to verify the effects of MALAT1 in HF. MALAT1 was highly expressed in serum of HF patients, HF rats and ISO­induced H9C2 cells and was valuable in predicting HF. Inhibition of MALAT1 increased cardiac function and anti­inflammation and alleviated myocardial injury, lipid metabolism, lipid oxidation and apoptosis rates. Inhibition of MALAT1 reduced H9C2 cell injury. MALAT1 competitively bound to microRNA (miR)­532­3p to upregulate LDLR protein. Inhibition of miR­532­3p weakened the protective effect of downregulated MALAT1 against H9C2 cell injury. We concluded that MALAT1 upregulated LDLR expression by competitively binding to miR­532­3p, thereby increasing pathological injury in HF.


Assuntos
Insuficiência Cardíaca/metabolismo , Metabolismo dos Lipídeos , Miocardite/metabolismo , Miocárdio/metabolismo , RNA Longo não Codificante/metabolismo , Idoso , Animais , Linhagem Celular , Feminino , Insuficiência Cardíaca/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Miocardite/patologia , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley
17.
Am J Physiol Heart Circ Physiol ; 320(4): H1348-H1360, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33416455

RESUMO

Viral myocarditis (VMC) is a life-threatening disease characterized by severe cardiac inflammation generally caused by coxsackievirus B3 (CVB3) infection. Several microRNAs (miRNAs or miRs) are known to play crucial roles in the pathogenesis of VMC. The study aimed to decipher the role of miR-30a-5p in the underlying mechanisms of VMC pathogenesis. We first quantified miR-30a-5p expression in a CVB3-induced mouse VMC model. The physiological characteristics of mouse cardiac tissues were then detected by hematoxylin and eosin (HE) and Picrosirius red staining. We established the correlation between miR-30a-5p and SOCS1, using dual-luciferase gene assay and Pearson's correlation coefficient. The expression of inflammatory factors (IFN-γ, IL-6, IL-10, and IL-13), M1 polarization markers [TNF-α, inducible nitric oxide synthase (iNOS)], M2 polarization markers (Arg-1, IL-10), and myocardial hypertrophy markers [atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)] was detected by RT-qPCR and Western blot analysis. miR-30a-5p was found to be highly expressed in VMC mice. Silencing of miR-30a-5p improved the cardiac function index and reduced heart weight-to-body weight ratio, myocardial tissue pathological changes and fibrosis degree, serological indexes, as well as proinflammatory factor levels, while enhancing anti-inflammatory factor levels in VMC mice. Furthermore, silencing of miR-30a-5p inhibited M1 polarization of macrophages while promoting M2 polarization in vivo and in vitro. SOCS1 was a target gene of miR-30a-5p, and the aforementioned cardioprotective effects of miR-30a-5p silencing were reversed upon silencing of SOCS1. Overall, this study shows that silencing of miR-30a-5p may promote M2 polarization of macrophages and improve cardiac injury following VMC via SOCS1 upregulation, constituting a potential therapeutic target for VMC treatment.NEW & NOTEWORTHY We found in this study that microRNA (miR)-30a-5p inhibition might improve cardiac injury following viral myocarditis (VMC) by accelerating M2 polarization of macrophages via SOCS1 upregulation. Furthermore, the anti-inflammatory mechanisms of miR-30a-5p inhibition may contribute to the development of new therapeutic strategies for VMC.


Assuntos
Infecções por Coxsackievirus/terapia , Inativação Gênica , Terapia Genética , Macrófagos/metabolismo , MicroRNAs/genética , Miocardite/terapia , Miócitos Cardíacos/metabolismo , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Animais , Antagomirs/genética , Antagomirs/metabolismo , Células Cultivadas , Infecções por Coxsackievirus/genética , Infecções por Coxsackievirus/metabolismo , Infecções por Coxsackievirus/virologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Enterovirus Humano B/patogenicidade , Mediadores da Inflamação/metabolismo , Macrófagos/virologia , Masculino , Camundongos Endogâmicos BALB C , MicroRNAs/metabolismo , Miocardite/genética , Miocardite/metabolismo , Miocardite/virologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/virologia , Fenótipo , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina/genética
18.
Oxid Med Cell Longev ; 2021: 8845607, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33510843

RESUMO

Chronic kidney disease (CKD) is known to be associated with cardiovascular dysfunction. Dietary adenine intake in mice is also known to induce CKD. However, in this experimental model, the mechanisms underlying the cardiotoxicity and coagulation disturbances are not fully understood. Here, we evaluated cardiac inflammation, oxidative stress, DNA damage, and coagulation events in mice with adenine (0.2% w/w in feed for 4 weeks)-induced CKD. Control mice were fed with normal chow for the same duration. Adenine increased water intake, urine output, relative kidney weight, the plasma concentrations of urea and creatinine, and the urinary concentrations of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. It also decreased the body weight and creatinine clearance, and caused kidney DNA damage. Renal histological analysis showed tubular dilation and damage and neutrophilic influx. Adenine induced a significant increase in systolic blood pressure and the concentrations of troponin I, tumor necrosis factor-α, and interleukin-1ß in heart homogenates. It also augmented the levels of markers of lipid peroxidation measured by malondialdehyde production and 8-isoprostane, as well as the antioxidants superoxide dismutase and catalase. Immunohistochemical analysis of the hearts showed that adenine increased the expression of nuclear factor erythroid-derived 2-like 2 by cardiomyocytes. It also caused cardiac DNA damage. Moreover, compared with the control group, adenine induced a significant increase in the number of circulating platelet and shortened the thrombotic occlusion time in pial arterioles and venules in vivo, and induced a significant reduction in the prothrombin time and activated partial thromboplastin time. In conclusion, the administration of adenine in mice induced CKD-associated cardiac inflammation, oxidative stress, Nrf2 expression, and DNA damage. It also induced prothrombotic events in vivo. Therefore, this model can be satisfactorily used to study the cardiac pathophysiological events in subjects with CKD and the effect of drug treatment thereon.


Assuntos
Coagulação Sanguínea , Regulação da Expressão Gênica , Miocardite/metabolismo , Fator 2 Relacionado a NF-E2/biossíntese , Estresse Oxidativo , Insuficiência Renal Crônica/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Miocardite/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Insuficiência Renal Crônica/patologia
19.
Eur J Pharmacol ; 890: 173645, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33098837

RESUMO

Clozapine (CLZ) represents an effective treatment for resistant schizophrenia. However, myocarditis, recently reported in about 66% of the psychiatric patients treated with CLZ, has raised concerns about its safety. ß-blocking agents have shown to be helpful in the management of myocarditis. Moreover, Vimentin (VIM) and Connexin-43 (CX43) are important structural proteins play key roles in cytoskeletal functions and cellular communication and have complex implications in pathophysiology. The present work aimed to study the mechanisms behind the protective effect of propranolol (PRO) against CLZ-induced myocarditis and the possible involvement of VIM and CX43. The effect of PRO (5 and 10 mg/kg, oral) on the myocarditis induced by CLZ (25 mg/kg/d, i. p.) treatment for 21 days in rats, was assessed biochemically, and immunohistochemically. CLZ treatment increased the serum levels of cardiac injury (CK-MP, LDH and cTn-I) and cardiac levels of oxidative stress (TBARS and NO) markers, proinflammatory cytokines (IL-1ß and TNF-α), and mRNA expression of VIM and CX43 with decreased the antioxidant defenses (GSH and GSH-Px). Immunohistochemical study showed increased cardiac expression of VIM, CX43 and caspase-3 proteins. Coadministration of PRO with CLZ, dose-dependently decreased the biochemical and immunohistochemical hallmarks of CLZ-induced myocardial injury and significantly decreased mRNA expression of VIM and CX43. Taken together, our results demonstrate that the cardioprotective effects of PRO on CLZ-induced myocarditis are related in addition to its ß-blocking activity to protection of myocardial VIM and CX43 proteins through antagonizing the CLZ-induced oxidative stress and inflammatory response, and preventing cell apoptosis.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Cardiotônicos/farmacologia , Conexina 43/metabolismo , Miocardite/prevenção & controle , Propranolol/farmacologia , Vimentina/metabolismo , Antagonistas Adrenérgicos beta/uso terapêutico , Animais , Antipsicóticos/toxicidade , Apoptose/efeitos dos fármacos , Cardiotônicos/uso terapêutico , Caspase 3/metabolismo , Clozapina/toxicidade , Conexina 43/efeitos dos fármacos , Conexina 43/genética , Creatina Quinase/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , L-Lactato Desidrogenase/sangue , Masculino , Miocardite/induzido quimicamente , Miocardite/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Propranolol/uso terapêutico , Ratos Wistar , Troponina I/sangue , Vimentina/efeitos dos fármacos , Vimentina/genética
20.
J Card Fail ; 27(1): 92-96, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33166657

RESUMO

Cardiac complications, including clinically suspected myocarditis, have been described in novel coronavirus disease 2019. Here, we review current data on suspected myocarditis in the course of severe acute respiratory syndrome novel coronavirus-2 (SARS-CoV-2) infection. Hypothetical mechanisms to explain the pathogenesis of troponin release in patients with novel coronavirus disease 2019 include direct virus-induced myocardial injury (ie, viral myocarditis), systemic hyperinflammatory response (ie, cytokine storm), hypoxemia, downregulation of angiotensin-converting enzyme 2, systemic virus-induced endothelialitis, and type 1 and type 2 myocardial infarction. To date, despite the fact that millions of SARS-CoV-2 infections have been diagnosed worldwide, there is no definitive proof that SARS-CoV-2 is a novel cardiotropic virus causing direct cardiomyocyte damage. Diagnosis of viral myocarditis should be based on the molecular assessment of endomyocardial biopsy or autopsy by polymerase chain reaction or in-situ hybridization. Blood, sputum, or nasal and throat swab virology testing are insufficient and do not correlate with the myocardial involvement of a given pathogen. Data from endomyocardial biopsies and autopsies in clinically suspected SARS-CoV-2 myocarditis are scarce. Overall, current clinical epidemiologic data do not support the hypothesis that viral myocarditis is caused by SARS-CoV-2, or that it is common. More endomyocardial biopsy and autopsy data are also needed for a better understanding of pathogenesis of clinically suspected myocarditis in the course of SARS-CoV-2 infection, which may include virus-negative immune-mediated or already established subclinical autoimmune forms, triggered or accelerated by the hyperinflammatory state of severe novel coronavirus disease 2019.


Assuntos
COVID-19/complicações , COVID-19/diagnóstico , Miocardite/diagnóstico , Miocardite/etiologia , SARS-CoV-2 , COVID-19/metabolismo , Europa (Continente)/epidemiologia , Humanos , Mediadores da Inflamação/metabolismo , Miocardite/metabolismo
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