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2.
Int J Cardiol ; 359: 108-112, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35395284

RESUMO

BACKGROUND: Early detection and initiation of treatment in cardiac sarcoidosis (CS) is believed to be crucial to reduce morbidity and mortality. The diagnosis of CS is challenging, especially in isolated CS (ICS). Certain human leukocyte antigen (HLA-DRB1) alleles associate with different phenotypes of sarcoidosis. Phenotypic and genotypic characterization of patients with CS may improve our ability to identify patients being at risk for developing CS. METHODS: 87 patients with CS, identified at two Swedish university hospitals were included. Phenotypic characteristics were extracted from the medical records and the patients were HLA-DRB1 typed. RESULTS: Median age at diagnosis was 55 years, 37% were women. HLA-DRB1 distribution was similar to a general sarcoidosis population. A majority of patients (51/87) had CS as the first sarcoidosis presentation. They were younger (p = 0.04), more often presenting with ventricular tachycardia (VT) or atrioventricular block (AVB) grade II or III (p < 0.001), had lower left ventricular ejection fraction (LVEF) (p = 0.002), lower serum angiotensin converting enzyme (s-ACE) (p = 0.025), and fewer extra cardiac manifestations (ECM) (p = 0.02) than those presenting with CS later. CONCLUSIONS: Of Swedish CS patients, 59% presented with cardiac involvement as first manifestation. They had more severe cardiac symptoms than patients presenting with CS later. This phenotype disclosed less ECM and lower s-ACE thus diagnosis can be missed or delayed. We did not observe significant differences in HLA-DRB1 allele frequency between patients with CS compared to sarcoidosis in general. Awareness of CS as a primary manifestation can enable early detection and adequate intervention.


Assuntos
Cadeias HLA-DRB1 , Miocardite , Sarcoidose , Alelos , Feminino , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Humanos , Masculino , Miocardite/genética , Miocardite/imunologia , Fenótipo , Sarcoidose/genética , Sarcoidose/imunologia , Volume Sistólico , Suécia , Função Ventricular Esquerda
3.
Int J Mol Sci ; 23(3)2022 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-35163412

RESUMO

Protein kinase B2 (AKT2) is involved in various cardiomyocyte signaling processes, including those important for survival and metabolism. Coxsackievirus B3 (CVB3) is one of the most common pathogens that cause myocarditis in humans. The role of AKT2 in CVB3 infection is not yet well understood. We used a cardiac-specific AKT2 knockout (KO) mouse to determine the role of AKT2 in CVB3-mediated myocarditis. CVB3 was injected intraperitoneally into wild-type (WT) and KO mice. The mice's survival rate was recorded: survival in KO mice was significantly decreased compared with WT mice (WT vs. KO: 73.3 vs. 27.1%). Myocardial damage and inflammation were significantly increased in the hearts of KO mice compared with those of WT mice. Moreover, from surface ECG, AKT2 KO mice showed a prolonged atria and ventricle conduction time (PR interval, WT vs. KO: 47.27 ± 1.17 vs. 64.79 ± 7.17 ms). AKT2 deletion induced severe myocarditis and cardiac dysfunction due to CVB3 infection. According to real-time PCR, the mRNA level of IL-1, IL-6, and TNF-α decreased significantly in KO mice compared with WT mice on Days 5 after infection. In addition, innate immune response antiviral effectors, Type I interferon (interferon-α and ß), and p62, were dramatically suppressed in the heart of KO mice. In particular, the adult cardiac myocytes isolated from the heart showed high induction of TLR4 protein in KO mice in comparison with WT. AKT2 deletion suppressed the activation of Type I interferon and p62 transcription in CVB3 infection. In cardiac myocytes, AKT2 is a key signaling molecule for the heart from damage through the activation of innate immunity during acute myocarditis.


Assuntos
Enterovirus Humano B/imunologia , Infecções por Enterovirus/imunologia , Imunidade Inata , Miocardite/imunologia , Miocárdio/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Doença Aguda , Animais , Enterovirus Humano B/genética , Infecções por Enterovirus/genética , Células HeLa , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/virologia , Camundongos , Camundongos Knockout , Miocardite/genética , Miocardite/virologia , Proteínas Proto-Oncogênicas c-akt/genética
4.
Viruses ; 14(2)2022 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-35215893

RESUMO

INTRODUCTION: This study investigated the spontaneous clinical course of patients with endomyocardial biopsy (EMB)-proven lymphocytic myocarditis and cardiac human herpesvirus 6 (HHV6) DNA presence, and the effectiveness of steroid-based intervention in HHV6-positive patients. RESULTS: 756 heart failure (HF) patients underwent an EMB procedure to determine the underlying cause of unexplained HF. Low levels of HHV6 DNA, detectable by nested PCR only, were found in 10.4% of the cases (n = 79) of which 62% (n = 49) showed myocardial inflammation. The spontaneous course of patients with EMB-proven HHV6 DNA-associated lymphocytic myocarditis (n = 26) showed significant improvements in the left ventricular ejection fraction (LVEF) and clinical symptoms, respectively, in 15/26 (60%) patients, 3-12 months after disease onset. EMB mRNA expression of components of the NLRP3 inflammasome pathway and protein analysis of cardiac remodeling markers, analyzed by real-time PCR and MALDI mass spectrometry, respectively, did not differ between HHV6-positive and -negative patients. In another cohort of patients with ongoing symptoms related to lymphocytic myocarditis associated with cardiac levels of HHV6-DNA copy numbers <500 copies/µg cardiac DNA, quantified by real-time PCR, the efficacy and safety of steroid-based immunosuppression for six months was investigated. Steroid-based immunosuppression improved the LVEF (≥5%) in 8/10 patients and reduced cardiac inflammation in 7/10 patients, without an increase in cardiac HHV6 DNA levels in follow-up EMBs. CONCLUSION: Low HHV6 DNA levels are frequently detected in the myocardium, independent of inflammation. In patients with lymphocytic myocarditis with low levels of HHV6 DNA, the spontaneous clinical improvement is nearby 60%. In selected symptomatic patients with cardiac HHV6 DNA copy numbers less than 500 copies/µg cardiac DNA and without signs of an active systemic HHV6 infection, steroid-based therapy was found to be effective and safe. This finding needs to be further confirmed in large, randomized trials.


Assuntos
Herpesvirus Humano 6/fisiologia , Imunossupressores/administração & dosagem , Miocardite/tratamento farmacológico , Miocardite/virologia , Infecções por Roseolovirus/tratamento farmacológico , Infecções por Roseolovirus/virologia , Esteroides/administração & dosagem , Adulto , Idoso , Biópsia , Estudos de Coortes , DNA Viral/genética , Feminino , Dosagem de Genes , Herpesvirus Humano 6/genética , Herpesvirus Humano 6/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Miocardite/imunologia , Miocardite/fisiopatologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Infecções por Roseolovirus/imunologia , Infecções por Roseolovirus/fisiopatologia , Volume Sistólico
5.
Signal Transduct Target Ther ; 7(1): 57, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35197452

RESUMO

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.


Assuntos
Injúria Renal Aguda/complicações , COVID-19/complicações , Síndrome da Liberação de Citocina/complicações , Coagulação Intravascular Disseminada/complicações , Linfopenia/complicações , Miocardite/complicações , Embolia Pulmonar/complicações , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/virologia , Anticoagulantes/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/virologia , Ensaios Clínicos como Assunto , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/imunologia , Coagulação Intravascular Disseminada/virologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Células Endoteliais/virologia , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Linfopenia/tratamento farmacológico , Linfopenia/imunologia , Linfopenia/virologia , Miocardite/tratamento farmacológico , Miocardite/imunologia , Miocardite/virologia , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/imunologia , Embolia Pulmonar/virologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/imunologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/patogenicidade
6.
EBioMedicine ; 75: 103807, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34998242

RESUMO

BACKGROUND: COVID-19 mRNA vaccines have proven to be highly safe and effective. Myocarditis is an adverse event associated with mRNA vaccination, especially in young male subjects. These events are rare and, in the majority of cases, resolve quickly. As myocarditis can be driven by autoimmune responses, we wanted to determine if the SARS-CoV-2 spike protein antigen encoded in the mRNA COVID vaccines had potential cross-reactivity with auto-antigens previously associated with myocarditis. METHODS: We performed a sequence identity comparison between SARS-CoV-2 spike protein-derived peptides and myocarditis-associated antigens. We also performed a structural analysis of these antigens and the SARS-CoV-2 spike protein to identify potential discontinuous 3-D epitope similarities. FINDINGS: We found no significant enrichment in the frequency of spike-derived peptides similar to myocarditis-associated antigens as compared to several controls. INTERPRETATION: Our results do not support the notion that increased occurrence of myocarditis after SARS-CoV-2-spike vaccination is mediated by a cross-reactive adaptive immune response.


Assuntos
Antígenos/genética , COVID-19/genética , Epitopos/genética , Miocardite/genética , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Imunidade Adaptativa , Antígenos/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/genética , Vacinas contra COVID-19/imunologia , Reações Cruzadas , Epitopos/imunologia , Humanos , Miocardite/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia
8.
Cardiovasc Res ; 118(2): 573-584, 2022 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33576779

RESUMO

AIMS: Angiotensin (Ang) II signalling has been suggested to promote cardiac fibrosis in inflammatory heart diseases; however, the underlying mechanisms remain obscure. Using Agtr1a-/- mice with genetic deletion of angiotensin receptor type 1 (ATR1) and the experimental autoimmune myocarditis (EAM) model, we aimed to elucidate the role of Ang II-ATR1 pathway in development of heart-specific autoimmunity and post-inflammatory fibrosis. METHODS AND RESULTS: EAM was induced in wild-type (WT) and Agtr1a-/- mice by subcutaneous injections with alpha myosin heavy chain peptide emulsified in complete Freund's adjuvant. Agtr1a-/- mice developed myocarditis to a similar extent as WT controls at day 21 but showed reduced fibrosis and better systolic function at day 40. Crisscross bone marrow chimaera experiments proved that ATR1 signalling in the bone marrow compartment was critical for cardiac fibrosis. Heart infiltrating, bone-marrow-derived cells produced Ang II, but lack of ATR1 in these cells reduced transforming growth factor beta (TGF-ß)-mediated fibrotic responses. At the molecular level, Agtr1a-/- heart-inflammatory cells showed impaired TGF-ß-mediated phosphorylation of Smad2 and TAK1. In WT cells, TGF-ß induced formation of RhoA-GTP and RhoA-A-kinase anchoring protein-Lbc (AKAP-Lbc) complex. In Agtr1a-/- cells, stabilization of RhoA-GTP and interaction of RhoA with AKAP-Lbc were largely impaired. Furthermore, in contrast to WT cells, Agtr1a-/- cells stimulated with TGF-ß failed to activate canonical Wnt pathway indicated by suppressed activity of glycogen synthase kinase-3 (GSK-3)ß and nuclear ß-catenin translocation and showed reduced expression of Wnts. In line with these in vitro findings, ß-catenin was detected in inflammatory regions of hearts of WT, but not Agtr1a-/- mice and expression of canonical Wnt1 and Wnt10b were lower in Agtr1a-/- hearts. CONCLUSION: Ang II-ATR1 signalling is critical for development of post-inflammatory fibrotic remodelling and dilated cardiomyopathy. Our data underpin the importance of Ang II-ATR1 in effective TGF-ß downstream signalling response including activation of profibrotic Wnt/ß-catenin pathway.


Assuntos
Angiotensina II/metabolismo , Doenças Autoimunes/metabolismo , Autoimunidade , Linfócitos T CD4-Positivos/metabolismo , Miocardite/metabolismo , Miócitos Cardíacos/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Via de Sinalização Wnt , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Mediadores da Inflamação/metabolismo , Ativação Linfocitária , Camundongos Endogâmicos BALB C , Camundongos Knockout , Miocardite/genética , Miocardite/imunologia , Miocardite/patologia , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/patologia , Receptor Tipo 1 de Angiotensina/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Proteína Wnt1/genética , Proteína Wnt1/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
9.
Biomolecules ; 11(12)2021 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-34944410

RESUMO

Ethyl pyruvate (EP) has profound anti-inflammatory and immunomodulatory properties. Here, its effects were determined on experimental autoimmune myocarditis (EAM) induced in mice by heart-specific myosin-alpha heavy chain peptide immunization. EP was applied intraperitoneally, daily, starting with the immunization. Severity of EAM was determined by histological assessment of immune cell infiltrates into the heart. Cells were phenotypically characterized by flow cytometry. Concentration of cytokines in cell culture supernatants and sera was determined by ELISA. EP reduced the infiltration of immune cells into the heart and lessened heart inflammation. Smaller number of total immune cells, as well as of CD11b+ and CD11c+ cells were isolated from the hearts of EP-treated mice. A reduced number of antigen-presenting cells, detected by anti-CD11c, MHC class II and CD86 antibodies, as well as of T helper (Th)1 and Th17 cells, detected by anti-CD4, IFN-γ and IL-17 antibodies, was determined in mediastinal lymph nodes draining the heart, in parallel. In the spleen, only the number of CD11c+ cells were reduced, but not of the other examined populations, thus implying limited systemic effect of EP. Reduced production of IFN-γ and IL-17 by myosin-alpha heavy chain peptide-restimulated cells of the lymph nodes draining the site of immunization was observed in EP-treated mice. Our results clearly imply that EP restrains autoimmunity in EAM. Therapeutic application of EP in the treatment of myocarditis in humans should be addressed in the forthcoming studies.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Citocinas/metabolismo , Miocardite/imunologia , Piruvatos/administração & dosagem , Animais , Apresentação de Antígeno , Células Cultivadas , Meios de Cultura/química , Modelos Animais de Doenças , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Masculino , Camundongos , Miocardite/tratamento farmacológico , Fenótipo , Piruvatos/farmacologia , Células Th1/imunologia , Células Th17/imunologia
10.
Front Immunol ; 12: 779026, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956207

RESUMO

A 26-year-old otherwise healthy man died of fulminant myocarditis. Nasopharyngeal specimens collected premortem tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Histopathological evaluation of the heart showed myocardial necrosis surrounded by cytotoxic T-cells and tissue-repair macrophages. Myocardial T-cell receptor (TCR) sequencing revealed hyper-dominant clones with highly similar sequences to TCRs that are specific for SARS-CoV-2 epitopes. SARS-CoV-2 RNA was detected in the gut, supporting a diagnosis of multisystem inflammatory syndrome in adults (MIS-A). Molecular targets of MIS-associated inflammation are not known. Our data indicate that SARS-CoV-2 antigens selected high-frequency T-cell clones that mediated fatal myocarditis.


Assuntos
COVID-19/complicações , Miocardite/patologia , Miocardite/virologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Linfócitos T/imunologia , Adulto , COVID-19/imunologia , COVID-19/patologia , Humanos , Masculino , Miocardite/imunologia , RNA Viral/análise , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica/imunologia
11.
Cell Physiol Biochem ; 55(6): 679-703, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34791861

RESUMO

Viral diseases are a major threat to modern society and the global health system. It is therefore of utter relevance to understand the way viruses affect the host as a basis to find new treatment solutions. The understanding of viral myocarditis (VMC) is incomplete and effective treatment options are lacking. This review will discuss the mechanism, effects, and treatment options of the most frequent myocarditis-causing viruses namely enteroviruses such as Coxsackievirus B3 (CVB3) and Parvovirus B19 (PVB19) on the human heart. Thereby, we focus on: 1. Viral entry: CVB3 use Coxsackievirus-Adenovirus-Receptor (CAR) and Decay Accelerating Factor (DAF) to enter cardiac myocytes while PVB19 use the receptor globoside (Gb4) to enter cardiac endothelial cells. 2. Immune system responses: The innate immune system mediated by activated cardiac toll-like receptors (TLRs) worsen inflammation in CVB3-infected mouse hearts. Different types of cells of the adaptive immune system are recruited to the site of inflammation that have either protective or adverse effects during VMC. 3. Autophagy: CVB3 evades autophagosomal degradation and misuses the autophasomal pathway for viral replication and release. 4. Viral replication sites: CVB3 promotes the formation of double membrane vesicles (DMVs), which it uses as replication sites. PVB19 uses the host cell nucleus as the replication site and uses the host cell DNA replication system. 5. Cell cycle manipulation: CVB3 attenuates the cell cycle at the G1/S phase, which promotes viral transcription and replication. PVB19 exerts cell cycle arrest in the S phase using its viral endonuclease activity. 6. Regulation of apoptosis: Enteroviruses prevent apoptosis during early stages of infection and promote cell death during later stages by using the viral proteases 2A and 3C, and viroporin 2B. PVB19 promotes apoptosis using the non-structural proteins NS1 and the 11 kDa protein. 7. Energy metabolism: Dysregulation of respiratory chain complex expression, activity and ROS production may be altered in CVB3- and PVB19-mediated myocarditis. 8. Ion channel modulation: CVB3-expression was indicated to alter calcium and potassium currents in Xenopus laevis oocytes and rodent cardiomyocytes. The phospholipase 2-like activity of PVB19 may alter several calcium, potassium and sodium channels. By understanding the general pathophysiological mechanisms of well-studied myocarditis-linked viruses, we might be provided with a guideline to handle other less-studied human viruses.


Assuntos
Infecções por Coxsackievirus/imunologia , Interações Hospedeiro-Patógeno/imunologia , Miocardite , Infecções por Parvoviridae/imunologia , Parvovirus B19 Humano/fisiologia , Replicação Viral , Infecções por Coxsackievirus/patologia , Humanos , Miocardite/imunologia , Miocardite/patologia , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/virologia , Infecções por Parvoviridae/patologia , Receptores Virais/imunologia
12.
Viruses ; 13(10)2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34696354

RESUMO

Viruses are an underappreciated cause of heart failure. Indeed, several types of viral infections carry cardiovascular risks. Understanding shared and unique mechanisms by which each virus compromises heart function is critical to inform on therapeutic interventions. This review describes how the key viruses known to lead to cardiac dysfunction operate. Both direct host-damaging mechanisms and indirect actions on the immune systems are discussed. As viral myocarditis is a key pathologic driver of heart failure in infected individuals, this review also highlights the role of cytokine storms and inflammation in virus-induced cardiomyopathy.


Assuntos
Insuficiência Cardíaca/virologia , Coração/virologia , Miocardite/virologia , Animais , Cardiomiopatias/virologia , Cardiomiopatia Dilatada/virologia , Síndrome da Liberação de Citocina , Cardiopatias/imunologia , Cardiopatias/terapia , Cardiopatias/virologia , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/terapia , Humanos , Inflamação , Miocardite/imunologia , Miocardite/terapia , Viroses/imunologia , Viroses/terapia , Viroses/virologia
14.
Cardiovasc Res ; 117(13): 2610-2623, 2021 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-34609508

RESUMO

Infection of the heart muscle with cardiotropic viruses is one of the major aetiologies of myocarditis and acute and chronic inflammatory cardiomyopathy (DCMi). However, viral myocarditis and subsequent dilated cardiomyopathy is still a challenging disease to diagnose and to treat and is therefore a significant public health issue globally. Advances in clinical examination and thorough molecular genetic analysis of intramyocardial viruses and their activation status have incrementally improved our understanding of molecular pathogenesis and pathophysiology of viral infections of the heart muscle. To date, several cardiotropic viruses have been implicated as causes of myocarditis and DCMi. These include, among others, classical cardiotropic enteroviruses (Coxsackieviruses B), the most commonly detected parvovirus B19, and human herpes virus 6. A newcomer is the respiratory virus that has triggered the worst pandemic in a century, SARS-CoV-2, whose involvement and impact in viral cardiovascular disease is under scrutiny. Despite extensive research into the pathomechanisms of viral infections of the cardiovascular system, our knowledge regarding their treatment and management is still incomplete. Accordingly, in this review, we aim to explore and summarize the current knowledge and available evidence on viral infections of the heart. We focus on diagnostics, clinical relevance and cardiovascular consequences, pathophysiology, and current and novel treatment strategies.


Assuntos
COVID-19/virologia , Cardiomiopatia Dilatada/virologia , Miocardite/virologia , Infecções por Parvoviridae/virologia , Parvovirus B19 Humano/patogenicidade , SARS-CoV-2/patogenicidade , Animais , Antivirais/uso terapêutico , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/terapia , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/imunologia , Cardiomiopatia Dilatada/terapia , Terapia Genética , Interações Hospedeiro-Patógeno , Humanos , Miocardite/diagnóstico , Miocardite/imunologia , Miocardite/terapia , Infecções por Parvoviridae/diagnóstico , Infecções por Parvoviridae/imunologia , Infecções por Parvoviridae/terapia , Parvovirus B19 Humano/imunologia , SARS-CoV-2/imunologia
15.
Sci Rep ; 11(1): 20961, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34702968

RESUMO

Cardioprotective effect of prostaglandin-E2 receptor-4 (EP4) stimulation on the ischemic heart has been demonstrated. Its effect on the heart affected by myocarditis, however, remains uncertain. In this study, we investigated therapeutic effect of EP4 stimulant using a mouse model of autoimmune myocarditis (EAM) that progresses to dilated cardiomyopathy (DCM). EP4 was present in the hearts of EAM mice. Treatment with EP4 agonist (ONO-0260164: 20 mg/kg/day) improved an impaired left ventricular (LV) contractility and reduction of blood pressure on day 21, a peak myocardial inflammation. Alternatively, DCM phenotype, characterized by LV dilation, LV systolic dysfunction, and collagen deposition, was observed on day 56, along with activation of matrix metalloproteinase (MMP)-2 critical for myocardial extracellular matrix disruption, indicating an important molecular mechanism underlying adverse ventricular remodeling after myocarditis. Continued treatment with ONO-0260164 alleviated the DCM phenotype, but this effect was counteracted by its combination with a EP4 antagonist. Moreover, ONO-0260164 inhibited in vivo proteolytic activity of MMP-2 in association with up-regulation of tissue inhibitor of metalloproteinase (TIMP)-3. EP4 stimulant may be a promising and novel therapeutic agent that rescues cardiac malfunction during myocarditis and prevents adverse ventricular remodeling after myocarditis by promoting the TIMP-3/MMP-2 axis.


Assuntos
Miocardite/tratamento farmacológico , Receptores de Prostaglandina E Subtipo EP4/agonistas , Remodelação Ventricular/efeitos dos fármacos , Animais , Cardiomiopatia Dilatada/tratamento farmacológico , Modelos Animais de Doenças , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos Endogâmicos BALB C , Miocardite/imunologia , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Inibidor Tecidual de Metaloproteinase-3/metabolismo
16.
Biomolecules ; 11(10)2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34680049

RESUMO

BACKGROUND: Acute myocarditis often progresses to heart failure because there is no effective, etiology-targeted therapy of this disease. Simvastatin has been shown to be cardioprotective by decreasing matrix metalloproteinases' (MMPs) activity. The study was designed to determine whether simvastatin inhibits MMPs activity, decreases the severity of inflammation and contractile dysfunction of the heart in experimental autoimmune myocarditis (EAM). METHODS: Simvastatin (3 or 30 mg/kg/day) was given to experimental rats with EAM by gastric gavage for 21 days. Then transthoracic echocardiography was performed, MMPs activity and troponin I level were determined and tissue samples were assessed under a light and transmission electron microscope. RESULTS: Hearts treated with simvastatin did not show left ventricular enlargement. As a result of EAM, there was an enhanced activation of MMP-9, which was significantly reduced in the high-dose simvastatin group compared to the low-dose group. It was accompanied by prevention of myofilaments degradation and reduction of severity of inflammation. CONCLUSIONS: The cardioprotective effects of simvastatin in the acute phase of EAM are, at least in part, due to its ability to decrease MMP-9 activity and subsequent decline in myofilaments degradation and suppression of inflammation. These effects were achieved in doses equivalent to therapeutic doses in humans.


Assuntos
Inflamação/tratamento farmacológico , Metaloproteases/genética , Miocardite/tratamento farmacológico , Sinvastatina/farmacologia , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Cardiotônicos/farmacologia , Ecocardiografia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Metaloproteases/antagonistas & inibidores , Modelos Animais , Miocardite/genética , Miocardite/imunologia , Miocardite/patologia , Ratos , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/prevenção & controle
17.
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
18.
FASEB J ; 35(11): e21975, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34618980

RESUMO

Autoimmunity contributes to the pathogenesis of viral myocarditis (VMC), which is characterized by the production of anti-heart autoantibodies (AHA) from lymphoid follicles. Recently, the formation of ectopic lymphoid follicles (ELFs) was reported in heart grafts. However, the existence and role of ELFs in myocardial tissues of VMC remain unclear. This study aimed to explore whether and how cardiac ELFs with germinal centers (GCs) could be generated during the development of VMC. We identified the existence of ELFs and explored the underlying mechanism. In a BALB/c mouse model of VMC, the dynamic myocardial infiltrations of lymphocytic aggregates and expressions of associated lymphorganogenic factors were investigated, accompanied by the detection of the production and location of myocardial AHA. The data indicated ELFs formation in myocardial tissues of VMC, and the number of ELFs was in accordance with the severity of VMC. Moreover, the functional ELFs with GCs were capable of facilitating the production of local AHA. Blocking IL-17 or podoplanin (PDPN) could inhibit cardiac ELFs generation, perhaps due to the negative regulation of PDPN neutralization in Th17 cell proliferation and differentiation. The presence of cardiac ELFs and AHA might offer new opportunities for stratification and early identification of VMC patients.


Assuntos
Infecções por Coxsackievirus/imunologia , Interleucina-17/imunologia , Glicoproteínas de Membrana/imunologia , Miocardite/imunologia , Estruturas Linfoides Terciárias/imunologia , Células Th17/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células Th17/citologia
19.
Zhongguo Fei Ai Za Zhi ; 24(9): 668-672, 2021 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-34521189

RESUMO

Immune checkpoint inhibitors (ICIs) is a negative regulatory factor antibody, which activates T cells to play an anti-tumor effect in immunotherapy, and can also cause immune-related adverse responses, thereby inducing a series of immune related adverse events (irAEs). Among these irAEs, although the incidence of ICIs-related myocarditis is very low, the fatality rate is significantly higher than other adverse reactions, close to 50%. Clinicians should be vigilant when applying ICIs, but the pathogenesis of ICIs-related myocarditis is still unclear. This article combines the recent research results of ICIs to summarize the mechanism and clinical manifestations of ICIs-related myocarditis, so as to improve clinicians' understanding of the adverse reactions.
.


Assuntos
Inibidores de Checkpoint Imunológico , Miocardite , Neoplasias , Pesquisa Biomédica/tendências , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Cardiotoxicidade/imunologia , Cardiotoxicidade/fisiopatologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/efeitos adversos , Miocardite/induzido quimicamente , Miocardite/diagnóstico , Miocardite/imunologia , Miocardite/fisiopatologia , Neoplasias/tratamento farmacológico
20.
Cell Immunol ; 369: 104427, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34482259

RESUMO

Chagas disease is an important disease of the heart. Lipoxins have important regulatory functions in host immune response (IR). Herein, we examined whether the receptor for lipoxin A4, the formyl peptide receptor (FPR) 2, had an effect on Trypanosoma cruzi infection. In vitro, FPR2 deficiency or inhibition improved the activity of macrophages against T. cruzi. In vivo, during the acute phase, the absence of FPR2 reduced parasitemia and increased type 2 macrophages, type 2 neutrophils, and IL-10-producing dendritic cells. Moreover, the acquired IR was characterized by greater proportions of Th1/Th2/Treg, and IFNγ-producing CD8+T cells, and reductions in Th17 and IL-17-producing CD8+T cells. However, during the chronic phase, FPR2 deficient mice presented and increased inflammatory profile regarding innate and acquired IR cells (Th1/IFN-γ-producing CD8+T cells). Notably, FPR2 deficiency resulted in increased myocarditis and impaired heart function. Collectively, our data suggested that FPR2 is important for the orchestration of IR and prevention of severe T. cruzi-induced disease.


Assuntos
Cardiomiopatia Chagásica/imunologia , Miocardite/imunologia , Receptores de Formil Peptídeo/imunologia , Animais , Cardiomiopatia Chagásica/complicações , Modelos Animais de Doenças , Feminino , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/imunologia
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