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1.
J Am Heart Assoc ; 8(2): e008968, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30638108

RESUMO

Background Myocarditis is an important cause of acute and chronic heart failure. Men with myocarditis have worse recovery and an increased need for transplantation compared with women, but the reason for the sex difference remains unclear. Elevated sera soluble (s) ST2 predicts mortality from acute and chronic heart failure, but has not been studied in myocarditis patients. Methods and Results Adults with a diagnosis of clinically suspected myocarditis (n=303, 78% male) were identified according to the 2013 European Society of Cardiology position statement. Sera sST2 levels were examined by ELISA in humans and mice and correlated with heart function according to sex and age. Sera sST2 levels were higher in healthy men ( P=8×10-6) and men with myocarditis ( P=0.004) compared with women. sST2 levels were elevated in patients with myocarditis and New York Heart Association class III - IV heart failure ( P=0.002), predominantly in men ( P=0.0003). Sera sST2 levels were associated with New York Heart Association class in men with myocarditis who were ≤50 years old ( r=0.231, P=0.0006), but not in women ( r=0.172, P=0.57). Sera sST2 levels were also significantly higher in male mice with myocarditis ( P=0.005) where levels were associated with cardiac inflammation. Gonadectomy with hormone replacement showed that testosterone ( P<0.001), but not estradiol ( P=0.32), increased sera sST2 levels in male mice with myocarditis. Conclusions We show in a well-characterized subset of heart failure patients with clinically suspected and biopsy-confirmed myocarditis that elevated sera sST2 is associated with an increased risk of heart failure based on New York Heart Association class in men ≤50 years old.

3.
Nat Med ; 22(5): 547-56, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27089514

RESUMO

Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but it causes a dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate the predilection to DIC of individual patients at the cellular level. hiPSC-CMs derived from individuals with breast cancer who experienced DIC were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not experience DIC, with decreased cell viability, impaired mitochondrial and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased reactive oxygen species production. Taken together, our data indicate that hiPSC-CMs are a suitable platform to identify and characterize the genetic basis and molecular mechanisms of DIC.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Insuficiência Cardíaca/induzido quimicamente , Mitocôndrias Cardíacas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Adulto , Idoso , Antibióticos Antineoplásicos/efeitos adversos , Cálcio/metabolismo , Cardiotoxicidade/genética , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Suscetibilidade a Doenças , Doxorrubicina/efeitos adversos , Feminino , Citometria de Fluxo , Imunofluorescência , Insuficiência Cardíaca/genética , Humanos , Células-Tronco Pluripotentes Induzidas , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pessoa de Meia-Idade , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Polimorfismo de Nucleotídeo Único , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma
4.
J Cardiovasc Transl Res ; 7(2): 192-202, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24402571

RESUMO

Myocarditis is more severe in men than in women and difficult to diagnose due to a lack of imaging modalities that directly detect myocardial inflammation. Translocator protein 18 kDa (TSPO) is used extensively to image brain inflammation due to its presence in CD11b(+) brain microglia. In this study, we examined expression of TSPO and CD11b in mice with coxsackievirus B3 (CVB3) myocarditis and biopsy sections from myocarditis patients in order to determine if it could be used to image myocarditis. We found that male mice with CVB3 myocarditis upregulated more genes associated with TSPO activation than female mice. TSPO expression was increased in the heart of male mice and men with myocarditis compared with female subjects due to testosterone, where it was expressed predominantly in CD11b(+) immune cells. We show that TSPO ligands detect myocardial inflammation using microSPECT, with increased uptake of [(125)I]-IodoDPA-713 in male mice with CVB3 myocarditis compared with undiseased controls.


Assuntos
Enterovirus Humano B/patogenicidade , Infecções por Enterovirus/diagnóstico por imagem , Imagem Molecular/métodos , Miocardite/diagnóstico por imagem , Miocárdio/metabolismo , Receptores de GABA/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Acetamidas , Animais , Biomarcadores/metabolismo , Biópsia , Antígeno CD11b/metabolismo , Modelos Animais de Doenças , Infecções por Enterovirus/genética , Infecções por Enterovirus/metabolismo , Infecções por Enterovirus/patologia , Feminino , Regulação da Expressão Gênica , Terapia de Reposição Hormonal , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Imagem Multimodal , Miocardite/genética , Miocardite/metabolismo , Miocardite/patologia , Miocárdio/patologia , Orquiectomia , Valor Preditivo dos Testes , Pirimidinas , Receptores de GABA/genética , Índice de Gravidade de Doença , Fatores Sexuais , Testosterona/administração & dosagem , Testosterona/metabolismo , Tomografia Computadorizada por Raios X
5.
Am J Physiol Regul Integr Comp Physiol ; 304(4): R267-77, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23255589

RESUMO

Recent findings indicate that TLR3 polymorphisms increase susceptibility to enteroviral myocarditis and inflammatory dilated cardiomyopathy (iDCM) in patients. TLR3 signaling has been found to inhibit coxsackievirus B3 (CVB3) replication and acute myocarditis in mouse models, but its role in the progression from myocarditis to iDCM has not been previously investigated. In this study we found that TLR3 deficiency increased acute (P = 5.9 × 10(-9)) and chronic (P = 6.0 × 10(-7)) myocarditis compared with WT B6.129, a mouse strain that is resistant to chronic myocarditis and iDCM. Using left ventricular in vivo hemodynamic assessment, we found that TLR3-deficient mice developed progressively worse chronic cardiomyopathy. TLR3 deficiency significantly increased viral replication in the heart during acute myocarditis from day 3 through day 12 after infection, but infectious virus was not detected in the heart during chronic disease. TLR3 deficiency increased cytokines associated with a T helper (Th)2 response, including IL-4 (P = 0.03), IL-10 (P = 0.008), IL-13 (P = 0.002), and TGF-ß(1) (P = 0.005), and induced a shift to an immunoregulatory phenotype in the heart. However, IL-4-deficient mice had improved heart function during acute CVB3 myocarditis by echocardiography and in vivo hemodynamic assessment compared with wild-type mice, indicating that IL-4 impairs cardiac function during myocarditis. IL-4 deficiency increased regulatory T-cell and macrophage populations, including FoxP3(+) T cells (P = 0.005) and Tim-3(+) macrophages (P = 0.004). Thus, TLR3 prevents the progression from myocarditis to iDCM following CVB3 infection by reducing acute viral replication and IL-4 levels in the heart.


Assuntos
Cardiomiopatia Dilatada/virologia , Infecções por Coxsackievirus/imunologia , Enterovirus Humano B/fisiologia , Interleucina-4/imunologia , Miocardite/virologia , Receptor 3 Toll-Like/imunologia , Doença Aguda , Animais , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/imunologia , Doença Crônica , Infecções por Coxsackievirus/genética , Citocinas/biossíntese , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Interleucina-4/análise , Macrófagos/imunologia , Macrófagos/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/genética , Miocardite/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/virologia , Receptor 3 Toll-Like/genética , Replicação Viral/imunologia
6.
Circ Heart Fail ; 5(3): 366-75, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22454393

RESUMO

BACKGROUND: IL-33 through its receptor ST2 protects the heart from myocardial infarct and hypertrophy in animal models but, paradoxically, increases autoimmune disease. In this study, we examined the effect of IL-33 or ST2 administration on autoimmune heart disease. METHODS AND RESULTS: We used pressure-volume relationships and isoproterenol challenge to assess the effect of recombinant (r) IL-33 or rST2 (eg, soluble ST2) administration on the development of autoimmune coxsackievirus B3 myocarditis and dilated cardiomyopathy in male BALB/c mice. The rIL-33 treatment significantly increased acute perimyocarditis (P=0.006) and eosinophilia (P=1.3×10(-5)), impaired cardiac function (maximum ventricular power, P=0.0002), and increased ventricular dilation (end-diastolic volume, P=0.01). The rST2 treatment prevented eosinophilia and improved heart function compared with rIL-33 treatment (ejection fraction, P=0.009). Neither treatment altered viral replication. The rIL-33 treatment increased IL-4, IL-33, IL-1ß, and IL-6 levels in the heart during acute myocarditis. To determine whether IL-33 altered cardiac function on its own, we administered rIL-33 to undiseased mice and found that rIL-33 induced eosinophilic pericarditis and adversely affected heart function. We used cytokine knockout mice to determine that this effect was due to IL-33-mediated signaling but not to IL-1ß or IL-6. CONCLUSIONS: We show for the first time to our knowledge that IL-33 induces eosinophilic pericarditis, whereas soluble ST2 prevents eosinophilia and improves systolic function, and that IL-33 independently adversely affects heart function through the IL-33 receptor.


Assuntos
Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/prevenção & controle , Eosinofilia/etiologia , Coração/fisiopatologia , Interleucinas/efeitos adversos , Pericardite/etiologia , Receptores de Interleucina/uso terapêutico , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/prevenção & controle , Doenças Autoimunes/virologia , Cardiomiopatia Dilatada/metabolismo , Infecções por Coxsackievirus/complicações , Modelos Animais de Doenças , Eosinofilia/prevenção & controle , Eosinofilia/virologia , Coração/efeitos dos fármacos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-1beta/deficiência , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-33 , Interleucina-6/deficiência , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucinas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Pericardite/prevenção & controle , Pericardite/virologia , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
7.
Expert Rev Clin Immunol ; 8(3): 269-84, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22390491

RESUMO

Cardiovascular disease (CVD) and autoimmune diseases (ADs) are the first and third highest causes of death in the USA, respectively. Men have an increased incidence of the majority of CVDs, including atherosclerosis, myocarditis, dilated cardiomyopathy and heart failure. By contrast, nearly 80% of all ADs occur in women. However, in one category of ADs, rheumatic diseases, CVD is the main cause of death. Factors that link rheumatic ADs to CVD are inflammation and the presence of autoantibodies. In this review we will examine recent findings regarding sex differences in the immunopathogenesis of CVD and ADs, explore possible reasons for the increased occurrence of CVD within rheumatic ADs and discuss whether autoantibodies, including rheumatoid factor, could be involved in disease pathogenesis.


Assuntos
Doenças Autoimunes/imunologia , Doenças Cardiovasculares/imunologia , Hormônios Esteroides Gonadais/imunologia , Coração/fisiopatologia , Fatores Sexuais , Autoanticorpos/imunologia , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/fisiopatologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Feminino , Coração/fisiologia , Humanos , Mediadores da Inflamação/imunologia , Masculino , Células Th1/imunologia , Equilíbrio Th1-Th2 , Células Th2/imunologia
8.
Am J Physiol Heart Circ Physiol ; 302(8): H1726-36, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22328081

RESUMO

Myocarditis and dilated cardiomyopathy (DCM) are often caused by viral infections and occur more frequently in men than in women, but the reasons for the sex difference remain unclear. The aim of this study was to assess whether gene changes in the heart during coxsackievirus B3 (CVB3) myocarditis in male and female BALB/c mice predicted worse DCM in males. Although myocarditis (P = 4.2 × 10(-5)) and cardiac dilation (P = 0.008) were worse in males, there was no difference in viral replication in the heart. Fibrotic remodeling genes, such as tissue inhibitor of metalloproteinase (TIMP)-1 and serpin A 3n, were upregulated in males during myocarditis rather than during DCM. Using gonadectomy and testosterone replacement, we showed that testosterone increased cardiac TIMP-1 (P = 0.04), serpin A 3n (P = 0.007), and matrix metalloproteinase (MMP)-8 (P = 0.04) during myocarditis. Testosterone increased IL-1ß levels in the heart (P = 0.02), a cytokine known to regulate cardiovascular remodeling, and IL-1ß in turn increased cardiac serpin A 3n mRNA (P = 0.005). We found that 39 of 118 (33%) genes identified in acute DCM patients were significantly altered in the heart during CVB3 myocarditis in mice, including serpin A 3n (3.3-fold change, P = 0.0001). Recombinant serpin A 3n treatment induced cardiac fibrosis during CVB3 myocarditis (P = 0.0008) while decreasing MMP-3 (P = 0.04) and MMP-9 (P = 0.03) levels in the heart. Thus, serpin A 3n was identified as a gene associated with fibrotic cardiac remodeling and progression to DCM in male myocarditis patients and mice.


Assuntos
Proteínas da Fase Aguda/farmacologia , Infecções por Coxsackievirus/fisiopatologia , Interleucina-1beta/farmacologia , Miocardite/fisiopatologia , Serpinas/farmacologia , Testosterona/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Proteínas da Fase Aguda/metabolismo , Animais , Doenças Autoimunes/fisiopatologia , Citocinas/metabolismo , Progressão da Doença , Feminino , Fibrose , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Análise em Microsséries , Dados de Sequência Molecular , Miocardite/genética , Miocardite/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Orquiectomia , Ovariectomia , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Recombinantes/farmacologia , Serpinas/metabolismo , Caracteres Sexuais , Remodelação Ventricular/fisiologia , Ensaio de Placa Viral
9.
Clin Dev Immunol ; 2012: 129486, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22013485

RESUMO

Viral infections are able to induce autoimmune inflammation in the heart. Here, we investigated the role of virus-activated Toll-like receptor (TLR)3 and its adaptor TRIF on the development of autoimmune coxsackievirus B3 (CVB3) myocarditis in mice. Although TLR3- or TRIF-deficient mice developed similarly worse acute CVB3 myocarditis and viral replication compared to control mice, disease was significantly worse in TRIF compared to TLR3-deficient mice. Interestingly, TLR3-deficient mice developed an interleukin (IL)-4-dominant T helper (Th)2 response during acute CVB3 myocarditis with elevated markers of alternative activation, while TRIF-deficient mice elevated the Th2-associated cytokine IL-33. Treatment of TLR3-deficient mice with recombinant IL-33 improved heart function indicating that elevated IL-33 in the context of a classic Th2-driven response protects against autoimmune heart disease. We show for the first time that TLR3 versus TRIF deficiency results in different Th2 responses that uniquely influence the progression to chronic myocarditis.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Infecções por Coxsackievirus/imunologia , Enterovirus/fisiologia , Miocardite/imunologia , Receptor 3 Toll-Like/metabolismo , Doença Aguda , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/imunologia , Animais , Autoimunidade/genética , Doença Crônica , Infecções por Coxsackievirus/complicações , Infecções por Coxsackievirus/genética , Infecções por Coxsackievirus/fisiopatologia , Progressão da Doença , Enterovirus/patogenicidade , Regulação da Expressão Gênica/imunologia , Interleucina-33 , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-4/metabolismo , Interleucinas/genética , Interleucinas/imunologia , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/etiologia , Miocardite/genética , Miocardite/fisiopatologia , Células Th2/imunologia , Células Th2/virologia , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Replicação Viral
10.
Biol Sex Differ ; 2: 2, 2011 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-21338512

RESUMO

BACKGROUND: Men are at an increased risk of dying from heart failure caused by inflammatory heart diseases such as atherosclerosis, myocarditis and dilated cardiomyopathy (DCM). We previously showed that macrophages in the spleen are phenotypically distinct in male compared to female mice at 12 h after infection. This innate immune profile mirrors and predicts the cardiac immune response during acute myocarditis. METHODS: In order to study sex differences in the innate immune response, five male and female BALB/c mice were infected intraperitoneally with coxsackievirus B3 (CVB3) or phosphate buffered saline and their spleens were harvested 12 h later for microarray analysis. Gene expression was determined using an Affymetrix Mouse Gene 1.0 ST Array. Significant gene changes were verified by quantitative real-time polymerase chain reaction or ELISA. RESULTS: During the innate immune response to CVB3 infection, infected males had higher splenic expression of genes which are important in regulating the influx of cholesterol into macrophages, such as phospholipase A2 (PLA2) and the macrophage scavenger receptor compared to the infected females. We also observed a higher expression in infected males compared to infected females of squalene synthase, an enzyme used to generate cholesterol within cells, and Cyp2e1, an enzyme important in metabolizing cholesterol and steroids. Infected males also had decreased levels of the translocator protein 18 kDa (TSPO), which binds PLA2 and is the rate-limiting step for steroidogenesis, as well as decreased expression of the androgen receptor (AR), which indicates receptor activation. Gene differences were not due to increased viral replication, which was unaltered between sexes. CONCLUSIONS: We found that, compared to females, male mice had a greater splenic expression of genes which are important for cholesterol metabolism and activation of the AR at 12 h after infection. Activation of the AR has been linked to increased cardiac hypertrophy, atherosclerosis, myocarditis/DCM and heart failure in male mice and humans.

11.
Brain Behav Immun ; 23(5): 649-57, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19126426

RESUMO

The incidence of cardiovascular disease, including inflammatory heart diseases like myocarditis, is increased in men. Similarly, male BALB/c mice infected with coxsackievirus B3 (CVB3) develop more severe acute inflammation in the heart compared to females. To better understand the effect of male sex hormones on cardiac inflammation, we gonadectomized (Gdx) male BALB/c mice and examined acute CVB3-induced myocarditis compared to sham controls. Viral replication in the heart was not significantly altered between Gdx and sham mice. However, gonadectomy significantly reduced testosterone levels and inflammation in the heart. FACS analysis of cell populations isolated from the heart revealed that CD11b(+) cells were significantly reduced in Gdx males. However, a GR1(+)F4/80(+) subset of CD11b(+) cells was significantly increased. Because this subset also expressed the interleukin (IL)-4R and IL-10, we refer to these cells as "alternatively activated" or M2 macrophages. A greater percentage of M2 macrophages in Gdx males expressed the inhibitory receptor Tim-3, while fewer expressed IL-1beta and IL-10. Only M2 macrophages upregulated TLR4 and Tim-3, whereas GR1(-)IL-4R(lo) macrophages did not. Additionally, IL-4(+)CD4(+) Th2 cells, Foxp3(+) regulatory T (Treg) cells and Tim-3(+)CD4(+) T cells were significantly increased in the heart following Gdx. Thus, we report for the first time that the inhibitory receptor Tim-3 is expressed on M2 macrophages. Our findings show that sex hormones and/or other mediators released from the testes inhibit anti-inflammatory populations in the heart including Tim-3(+) M2, Tim-3(+)CD4(+) T cells, Th2 and Treg resulting in more severe acute cardiac inflammation in males following CVB3 infection.


Assuntos
Infecções por Coxsackievirus/imunologia , Ativação de Macrófagos , Miocardite/imunologia , Orquiectomia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Doença Aguda , Animais , Antígeno CD11b/análise , Infecções por Coxsackievirus/sangue , Infecções por Coxsackievirus/fisiopatologia , Citocinas/sangue , Enterovirus Humano B/fisiologia , Receptor Celular 2 do Vírus da Hepatite A , Antígenos Comuns de Leucócito/análise , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/sangue , Miocardite/fisiopatologia , Miocárdio/imunologia , Receptores Virais/análise , Testosterona/sangue , Replicação Viral
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