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1.
Int Heart J ; 60(5): 1142-1146, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31447467

RESUMO

The aim of this study was to assess whether a specific cardiovascular disease was related to an increased antibody level against a periodontal pathogen.A strong association between cardiovascular disease and periodontitis was shown, however, the causal relationship was not proven. Increased inflammatory reaction of patients with periodontitis was a possible factor, which connected periodontal infection and vascular diseases.We assessed medical history, blood data, and periodontal conditions in patients with cardiovascular diseases. Serum IgG antibody titers against major periodontal pathogens and existence of salivary periodontal bacteria were analyzed.In total, 348 subjects were enrolled in this study. The patients who exhibited 10,000 counts/mL or more of salivary Porphyromonas gingivalis were divided into two groups according to the antibody level of the pathogen. Patients with a high antibody level against Porphyromonas gingivalis exhibited a high rate of heart failure compared to the low antibody group. Mean probing pocket depth and clinical attachment level significantly increased in the high antibody group. We found that the high anti-Porphyromonas gingivalis antibody group also experienced enhanced antibody levels against other periodontal bacteria.An increased heart failure prevalence was found in patients with a high antibody level against a major periodontal pathogen, Porphyromonas gingivalis.


Assuntos
Anticorpos Antibacterianos/sangue , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/imunologia , Periodontite/epidemiologia , Periodontite/imunologia , Porphyromonas gingivalis/imunologia , Idoso , Estudos Transversais , Feminino , Insuficiência Cardíaca/diagnóstico , Hospitais Universitários , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Periodontite/microbiologia , Porphyromonas gingivalis/isolamento & purificação , Prevalência , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença
2.
Am J Surg ; 218(4): 737-743, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31353032

RESUMO

BACKGROUND: Aging and loss of estrogen suppress immune function, potentially improving survival after orthotopic heart transplant (OHT). The effect of female aging on OHT outcomes is unknown. METHODS: Between 1995 and 2015, 41,299 adult OHT recipients (24.3% women) were studied using a retrospective multi-institutional cohort. Patients were stratified by age and gender into premenopausal (18-39 years), perimenopausal (40-49 years), and postmenopausal (≥50 years) groups. Kaplan-Meier survival analyses and risk-adjusted models examined gender differences across groups at one, five, and ten years. RESULTS: Kaplan-Meier survival was equivalent for postmenopausal women and men, and lower for premenopausal women than men at all time points (p ≤ 0.05). Postmenopausal women had higher risk-adjusted five-year survival than premenopausal women (AOR 1.61, 95% CI 1.15-2.25, p = 0.006). CONCLUSIONS: Premenopausal women have lower unadjusted survival than men after OHT. Post-menopausal women have significantly better five-year survival than pre-menopausal women. Menopause may contribute to improved survival after OHT.


Assuntos
Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/cirurgia , Transplante de Coração/mortalidade , Adolescente , Adulto , Fatores Etários , Débito Cardíaco , Estrogênios , Feminino , Insuficiência Cardíaca/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores Sexuais , Taxa de Sobrevida , Adulto Jovem
3.
Int J Mol Sci ; 20(7)2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959745

RESUMO

Heart failure is a complex clinical syndrome involving a multitude of neurohormonal pathways including the renin-angiotensin-aldosterone system, sympathetic nervous system, and natriuretic peptides system. It is now emerging that neurohumoral mechanisms activated during heart failure, with both preserved and reduced ejection fraction, modulate cells of the immune system. Indeed, these cells express angiotensin I receptors, adrenoceptors, and natriuretic peptides receptors. Ang II modulates macrophage polarization, promoting M2 macrophages phenotype, and this stimulation can influence lymphocytes Th1/Th2 balance. ß-AR activation in monocytes is responsible for inhibition of free oxygen radicals production, and together with α2-AR can modulate TNF-α receptor expression and TNF-α release. In dendritic cells, activation of ß2-AR inhibits IL-12 production, resulting in the inhibition of Th1 and promotion of Th2 differentiation. ANP induces the activation of secretion of superoxide anion in polymorphonucleated cells; reduces TNF-α and nitric oxide secretion in macrophages; and attenuates the exacerbated TH1 responses. BNP in macrophages can stimulate ROS production, up-regulates IL-10, and inhibits IL-12 and TNF-α release by dendritic cells, suggesting an anti-inflammatory cytokines profile induction. Therefore, different neurohormonal-immune cross-talks can determine the phenotype of cardiac remodeling, promoting either favorable or maladaptive responses. This review aims to summarize the available knowledge on neurohormonal modulation of immune responses, providing supportive rational background for further research.


Assuntos
Insuficiência Cardíaca/imunologia , Sistema Imunitário/metabolismo , Neurotransmissores/metabolismo , Animais , Humanos , Imunomodulação , Modelos Biológicos , Pesquisa Médica Translacional
4.
Front Biosci (Landmark Ed) ; 24: 1037-1049, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844728

RESUMO

An autoimmune reaction directed against the cardiac b1-adrenergic receptor (beta1-ADR) leading to the generation of autoantibodies (AA) against this G-coupled receptor has been described in patients with heart failure (HF). Agonist-like beta1-ADR-AA are associated with morbidity in HF patients and even predict mortality. Standardised and valid diagnostic tools to detect beta 1-ADR-AA in clinical routine are lacking. We used a novel ELISA approach to investigate beta 1-ADR-AA in a cohort of 574 HF patients of the CIBIS-ELD trial with follow up. The CIBIS-ELD trial compared the titration of bisoprolol and carvedilol to recommended target doses in regard to BB tolerability in patients aged 65 years and older. Patient with left ventricular (LV) ejection fraction (EF) less than 50% or LV diameter end diastolic (DED) more than 55 cm showed significantly higher levels of beta1-ADR-AA. Although not yet fully validated, this ELISA allowed for a negative correlation of beta1-ADR-AA with the EF at baseline and at the follow up, beta1-ADR-AA further correlated positively with basal heart rate at follow up 12 weeks later. beta1-ADR-AA levels thus determined  significantly increased under titration with beta-blockers (pless  than 0.01). Changes in beta1-ADR-AA between F-Up and baseline were significantly higher in patients who used beta blockers (p=0.016) before study inclusion. The type of beta-blocker titrated in this study did not affect log beta1-ADR-AA levels at baseline (p=0.132), follow-up (p=0.058), nor the change (p=0.426). beta1-ADR-AA levels were estimated using a novel, commercially available ELISA. Although not yet fully validated, this ELISA allowed for pathophysiological insights: beta1-ADR-AA levels thus determined significantly increased under titration with beta-blockers (pless  than 0.01), irrespective of type of BB. Higher levels of beta1-ADR-AA at baseline are associated with higher heart rates, lower ejection fraction and enlarged left ventricles. The relevance of the beta1-ADR-AA biomarker should be further evaluated.


Assuntos
Autoanticorpos/sangue , Insuficiência Cardíaca/imunologia , Receptores Adrenérgicos beta 1/imunologia , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Bisoprolol/uso terapêutico , Carvedilol/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Taxa de Filtração Glomerular , Insuficiência Cardíaca/tratamento farmacológico , Frequência Cardíaca , Humanos , Masculino , Resultado do Tratamento , Função Ventricular Esquerda
5.
Herz ; 44(2): 96-106, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30715565

RESUMO

Inflammation plays a central role in the development of heart failure, especially in heart failure with preserved ejection fraction (HFpEF). Furthermore, the inflammatory response enables the induction of regenerative processes following acute myocardial injury. Recent studies in humans and animals have greatly advanced our understanding of the underlying mechanisms behind these adaptations. Importantly, inflammation can have both beneficial and detrimental effects, dependent on its extent, localization, and duration. Therefore, modulation of cardiac inflammation has been suggested as an attractive target for the treatment of heart failure, which has been investigated in numerous clinical trials. This review discusses key inflammatory mechanisms contributing to the pathogenesis of heart failure and their potential impact as therapeutic targets.


Assuntos
Insuficiência Cardíaca , Inflamação , Animais , Arritmias Cardíacas , Insuficiência Cardíaca/imunologia , Humanos , Volume Sistólico
6.
Cardiovasc Drugs Ther ; 33(2): 149-161, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30747396

RESUMO

BACKGROUND: Numerous studies have reported significantly elevated titers of serum autoantibody against the second extracellular loop of ß1-adrenoceptor (ß1-AA), a catecholamine-like substance with ß1-adrenergic activity, in patients with heart failure. Although evidence demonstrates that this autoantibody may alter T cell proliferation and secretion, the role of T lymphocytes in heart failure induced by ß1-AA remains unclear. The current study was designed to determine whether T cell disorder contributes to heart failure induced by ß1-AA. METHODS AND RESULTS: ß1-AA monoclonal antibodies (ß1-AAmAb) produced using the hybridoma technique were administered in wild-type mice or T lymphocyte deficiency nudes for 12 weeks. T lymphocytes from heart failure patients and neonatal cardiomyocytes were utilized in vitro. Mouse protein antibody array analysis was employed to detect the cytokines responsible for ß1-AAmAb-induced heart failure. Compared to wild-type mice, T lymphocyte deficiency mice prevented cardiac function from getting worse, attenuated adverse remodeling, and ameliorated cardiomyocyte apoptosis and fibrosis. As shown by protein array, the serum level of interleukin (IL)-6 was significantly lower in the nude group as compared to wild-type after ß1-AAmAb treatment. Mechanistic studies in vitro demonstrated that T lymphocyte culture supernatants stimulated by ß1-AAmAb caused direct damage in the cardiomyocytes, and ß1-AAmAb promoted proliferation of T lymphocytes isolated from patients with heart failure and increased IL-6 release. IL-6-specific siRNA virtually abolished cardiomyocyte apoptosis, suggesting that IL-6 may be a key cytokine released by T lymphocytes and responsible for ß1-AAmAb-induced cardiac remodeling. CONCLUSIONS: Collectively, we demonstrate that ß1-AAmAb-induced cardiac remodeling via mediating T lymphocyte disorder and releasing a variety of IL-6.


Assuntos
Autoanticorpos/imunologia , Insuficiência Cardíaca/imunologia , Ativação Linfocitária , Miócitos Cardíacos/imunologia , Receptores Adrenérgicos beta 1/imunologia , Linfócitos T/imunologia , Função Ventricular Esquerda , Remodelação Ventricular , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Autoanticorpos/metabolismo , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Feminino , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Interleucina-6/imunologia , Interleucina-6/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Receptores Adrenérgicos beta 1/deficiência , Receptores Adrenérgicos beta 1/genética , Transdução de Sinais , Linfócitos T/metabolismo
7.
Biochem Biophys Res Commun ; 510(1): 163-170, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30678811

RESUMO

Autoantibody against ß1-adrenoceptor (ß1-AA) has been shown to be closely linked to the aggravation of heart failure. Removal of ß1-AA remarkably attenuated patients' cardiac dysfunction. We found that ß1-AA induced rat heart failure with increased CD4+ T cells. However, whether or not ß1-AA interacts with T cells isolated from heart failure patients remains unknown. Twenty-one ß1-AA-negative heart failure patients were divided into those taking ß-adrenergic blocker and those not. The effects of ß1-AA monoclonal antibodies (ß1-AAmAb) on T cells proliferation were detected using the CCK-8 assay. IFN-γ and IL-4 production by human T cells were measured by after the administration of ß1-AAmAb. The levels of cardiomyocyte apoptosis and hypertrophy were detected after co-cultured with the supernatant of T cells pre-stimulated by ß1-AAmAb. It was found that ß1-AAmAb promoted T cell proliferation via the ß1-AR/cAMP/PKA pathway in patients who not take ß-blocker. ß1-AAmAb inhibited the characteristic cytokine secretion of Th1, IFN-γ, but had no significant effect on the Th2 cytokine IL-4. Supernatant resulted from the T cells pre-treated with ß1-AAmAb induced cardiomyocytes remodeling, as evidenced by increased levels of cardiomyocytes apoptosis and hypertrophy. We propose that heart failure is likely to be an interference factor for Th-mediated immunity, and the presence of ß1-AAmAb may aggravate this effect and deteriorate concomitant inflammatory injury in cardiomyocytes, partially via ß1-AR/cAMP/PKA pathway.


Assuntos
Autoanticorpos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Receptores Adrenérgicos beta 1/imunologia , Linfócitos T/patologia , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/patologia , Humanos , Linfócitos T Auxiliares-Indutores/imunologia
8.
Can J Cardiol ; 35(3): 299-309, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30621958

RESUMO

With the advent and widespread use of antiretroviral therapy (ART), the epidemiology of cardiomyopathy and heart failure (HF) associated with HIV infection is changing. Near-normal life expectancy in contemporary HIV-infected populations has been associated with prolonged exposure to increased cardiometabolic burden and chronic immune activation and systemic inflammation. Therefore, the pre-ART phenotype of HIV-associated cardiomyopathy with overt left ventricular systolic dysfunction and poor prognosis has been replaced over time by cardiomyopathy with a more insidious course, more frequent ischemic background, and highly prevalent left ventricular diastolic dysfunction. Patients with HIV are more prone to development of coronary artery disease and development of HF after myocardial infarction. The role of ongoing immune activation and systemic inflammation, despite highly active ART (HAART), appears to be central in this process. The role of HAART toxicity is controversial, as HAART itself appears to be protective for the development of HF, but recent data suggest that protease inhibitors might adversely affect the course of HIV-associated HF. Because of these unique features, the optimal therapeutic approach for HIV-associated cardiomyopathy remains unknown. The current therapeutic approaches are an extrapolation from noninfected populations. Importantly, the significance of the highly prevalent diastolic abnormalities among HIV-infected patients is not known. Therefore, further research is needed to identify its prognostic implications. Considering the prevalence of structural and functional cardiac abnormalities in HIV-infected persons and the lack of evidence on how to best screen and treat these patients, systematic research on this topic is a public health priority.


Assuntos
Cardiomiopatias , Infecções por HIV/complicações , Insuficiência Cardíaca , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Cardiomiopatias/etiologia , Cardiomiopatias/imunologia , Cardiomiopatias/fisiopatologia , Cardiomiopatias/prevenção & controle , Infecções por HIV/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Prognóstico , Prevenção Secundária
9.
FASEB J ; 33(1): 909-916, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30052486

RESUMO

Chronic heart failure (CHF) is characterized by an ongoing nonresolving inflammatory status, where T lymphocytes seem critical. It has been recently recognized that transition from acute to chronic inflammation could be caused by defects in resolving inflammation, the resolution of which is mediated by a novel family of ω-3-derived specialized proresolving lipid mediators such as resolvins. We analyzed 27 elderly patients with CHF and 23 healthy age-matched control subjects, and we reported significantly lower levels of D-series resolvin (RvD)1 in plasma of patients with CHF that were associated with a reduced ability of their leukocytes to produce this lipid via its biosynthetic enzyme 15-lipoxygenase and that correlated with gas exchange dysfunction. Furthermore, when pretreating ex vivo peripheral blood mononuclear cells of patients with CHF with RvD1 or RvD2, we found that neither of them was able to modulate the immune response of CD8+ and CD4+ T cells in terms of proinflammatory cytokine production, namely TNF-α, IFN-γ, IL-17, and IL-2. Such impaired T-cell responsiveness in patients with CHF was associated with a significant reduction in mRNA and protein expression of RvD1 receptor GPR32, suggesting a defective signaling in the proresolving pathway. We conclude that patients with CHF show alterations in producing proresolving mediator RvD1 and a failure of adaptive immune cells in responding to the anti-inflammatory actions of RvDs that may contribute to the progression of chronic inflammation. Thus, the proresolution pathway might be a potential candidate to design better treatments for CHF aimed at reducing T cell-mediated chronic inflammation.-Chiurchiù, V., Leuti, A., Saracini, S., Fontana, D., Finamore, P., Giua, R., Padovini, L., Incalzi, R. A., Maccarrone, M. Resolution of inflammation is altered in chronic heart failure and entails a dysfunctional responsiveness of T lymphocytes.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Insuficiência Cardíaca/imunologia , Inflamação/imunologia , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Feminino , Humanos , Masculino
10.
Cytokine ; 113: 319-325, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30360948

RESUMO

This study was aimed to elucidate the immunoregulatory properties of human cardiac fibroblasts cultured under pro-inflammatory and hypoxic conditions. Human heart tissue for isolating cardiac cells is generally hard to obtain, particularly from all four chambers of the same heart. Since different parts of the heart have different functions and therefore may have different immunoregulatory properties, ability to analyse cells from all chambers allows for a unique and comprehensive investigation. Cells were isolated from all four chambers of the heart from patients undergoing cardiac transplantation surgery due to severe chronic heart failure (CHF) (n = 6). Cells isolated from one donor heart, were used for comparison with the experimental group. Primary cultured human cardiac fibroblasts were treated with Lipopolysaccharide (LPS) to induce an inflammatory response. Cells were also subjected to hypoxia. To determine immunoregulatory properties of the cells, cytokine and chemokine profiles were determined using multiplex ELISA. RESULTS: On average, the fibroblasts population constituted approximately 90% of the expanded non-myocytes. Levels of cytokines and chemokines were markedly increased in human cardiac fibroblasts cultured under inflammatory conditions, with a similar response in fibroblasts from all compartments of the heart. Unexpectedly, hypoxia did not further augment cytokine and chemokine secretion. In conclusion, human cardiac fibroblasts are a robust source of pro-inflammatory mediators in the failing heart, independent of hypoxia, and might play a critical role in inflammation associated with the pathogenesis of CHF.


Assuntos
Quimiocinas/imunologia , Fibroblastos/imunologia , Insuficiência Cardíaca/imunologia , Miocárdio/imunologia , Adulto , Idoso , Células Cultivadas , Feminino , Fibroblastos/patologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/cirurgia , Transplante de Coração , Humanos , Inflamação/imunologia , Inflamação/patologia , Inflamação/cirurgia , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Índice de Gravidade de Doença
11.
Am J Physiol Heart Circ Physiol ; 316(3): H435-H445, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30525893

RESUMO

Among the different cardiovascular disease complications, atherosclerosis-induced myocardial infarction (MI) is the major contributor of heart failure (HF) and loss of life. This review presents short- and long-term features of post-MI in human hearts and animal models. It is known that the heart does not regenerate, and thus loss of cardiac cells after an MI event is permanent. In survivors of a heart attack, multiple neurohumoral adjustments as well as simultaneous remodeling in both infarcted and noninfarcted regions of the heart help sustain pump function post-MI. In the early phase, migration of inflammatory cells to the infarcted area helps repair and remove the cell debris, while apoptosis results in the elimination of damaged cardiomyocytes, and there is an increase in the antioxidant response to protect the survived myocardium against oxidative stress (OS) injury. However, in the late phase, it appears that there is a relative increase in OS and activation of the innate inflammatory response in cardiomyocytes without any obvious inflammatory cells. In this late stage in survivors of MI, a progressive slow activation of these processes leads to apoptosis, fibrosis, cardiac dysfunction, and HF. Thus, this second phase of an increase in OS, innate inflammatory response, and apoptosis results in wall thinning, dilatation, and consequently HF. It is important to note that this inflammatory response appears to be innate to cardiomyocytes. Blunting of this innate immune cardiomyocyte response may offer new hope for the management of HF.


Assuntos
Insuficiência Cardíaca/imunologia , Imunidade Inata , Infarto do Miocárdio/imunologia , Animais , Apoptose , Insuficiência Cardíaca/etiologia , Humanos , Infarto do Miocárdio/etiologia , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/metabolismo , Estresse Oxidativo
12.
Mol Med Rep ; 19(2): 994-1003, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30569169

RESUMO

Heart failure (HF) is a principal cause of morbidity and mortality worldwide, affecting an estimated 38 million people. Although significant progress has been made with respect to the underlying molecular mechanisms, the role of the competing endogenous RNA (ceRNA) network in the pathogenesis of HF remains largely unknown. In this study, an HF­associated ceRNA network was constructed based on the differentially expressed long noncoding RNAs (lncRNAs), microRNAs (miRNAs) and mRNAs obtained, respectively, from the GSE77399, GSE104150 and GSE84796 datasets. The ceRNA network consisted of 12 lncRNA nodes, 43 miRNA nodes, 343 mRNA nodes and 530 edges. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that the ceRNA network was primarily enriched in the immune response, inflammatory response and T cell and B cell receptor signaling pathways. In addition, three lncRNAs (growth arrest specific 5, taurine upregulated 1 and HOX transcript antisense RNA) and three miRNAs [hsa­miRNA (miR)­26b­5p, hsa­miR­8485 and hsa­miR­940] with higher node degrees compared with other genes were selected as hub nodes. The expression of hub nodes in patients with HF was verified by reverse transcription­quantitative polymerase chain reaction analysis. The present study provided further insights into the important roles of the ceRNA network in HF development, and indicated the potential use of these hub nodes as diagnostic biomarkers and therapeutic targets.


Assuntos
Redes Reguladoras de Genes , Insuficiência Cardíaca/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Idoso , Estudos de Casos e Controles , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/patologia , Humanos , Masculino , MicroRNAs/imunologia , Anotação de Sequência Molecular , RNA Longo não Codificante/imunologia , RNA Mensageiro/imunologia , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais
13.
Vascul Pharmacol ; 112: 79-90, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30213580

RESUMO

Upon myocardial infarction (MI) immune system becomes activated by extensive necrosis of cardiomyocytes releasing intracellular molecules called damage-associated molecular patterns. Overactive and prolonged immune responses are likely to be responsible for heart failure development and progression in patients surviving the ischemic episode. Heme oxygenase-1 (HO-1) plays a crucial role in heme degradation and in this way releases carbon monoxide, free iron, and biliverdin. This stress-inducible enzyme is induced by various oxidative and inflammatory signals. Consequently, biological actions of HO-1 are not limited to degradation of a toxic heme released from hemoproteins, but also provide an adaptive cellular response against chronic inflammation and oxidative injury. Indeed, the immunomodulatory and anti-inflammatory properties of HO-1 were demonstrated in several experimental studies, as well as in human cases of genetic HO-1 deficiency. HO-1 was shown to suppress the production, myocardial infiltration and inflammatory properties of monocytes and macrophages what resulted in limitation of post-MI cardiac damage. This review specifically addresses the role of HO-1, heme and its degradation products in macrophage biology and post-ischemic cardiac repair. A more complete understanding of these mechanisms is essential to develop new therapeutic approaches.


Assuntos
Fármacos Cardiovasculares/farmacologia , Terapia Genética/métodos , Heme Oxigenase-1/metabolismo , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Miocárdio/enzimologia , Animais , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/patologia , Heme Oxigenase-1/genética , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/enzimologia , Macrófagos/imunologia , Terapia de Alvo Molecular , Monócitos/enzimologia , Monócitos/imunologia , Miocárdio/imunologia , Miocárdio/patologia , Necrose , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
14.
Artigo em Inglês | MEDLINE | ID: mdl-29773070

RESUMO

Cardiovascular Disease (CVD) is a class of diseases that involve disorders of heart and blood vessels, including hypertension, coronary heart disease, cerebrovascular disease, peripheral vascular disease, which finally lead to Heart Failure (HF). There are several treatments available all over the world, but still, CVD and heart failure became the number one problem causing death every year worldwide. Both experimental and clinical studies have shown a role for inflammation in the pathogenesis of heart failure. This seems related to an imbalance between pro-inflammatory and anti-inflammatory cytokines. Cardiac inflammation is a major pathophysiological mechanism operating in the failing heart, regardless of HF aetiology. Disturbances of the cellular and humoral immune system are frequently observed in heart failure. This review describes how B-cells play a specific role in the heart failure states. There is an urgent need to identify novel therapeutic targets and develop advanced therapeutic strategies to combat the syndrome of HF. Understanding and describing the elements of the humoral immunity function are essential and may suggest potential new treatment strategies.


Assuntos
Insuficiência Cardíaca/imunologia , Imunidade Humoral/imunologia , Humanos
15.
PLoS One ; 14(12): e0227283, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31891633

RESUMO

Upon myocardial damage, the release of cardiac proteins induces a strong antibody-mediated immune response, which can lead to adverse cardiac remodeling and eventually heart failure (HF). Stem cell therapy using mesenchymal stromal cells (MSCs) or cardiomyocyte progenitor cells (CPCs) previously showed beneficial effects on cardiac function despite low engraftment in the heart. Paracrine mediators are likely of great importance, where, for example, MSC-derived extracellular vesicles (EVs) also show immunosuppressive properties in vitro. However, the limited capacity of MSCs to differentiate into cardiac cells and the sufficient scaling of MSC-derived EVs remain a challenge to clinical translation. Therefore, we investigated the immunosuppressive actions of endogenous CPCs and CPC-derived EVs on antibody production in vitro, using both healthy controls and end-stage HF patients. Both MSCs and CPCs strongly inhibit lymphocyte proliferation and antibody production in vitro. Furthermore, CPC-derived EVs significantly lowered the levels of IgG1, IgG4, and IgM, especially when administered for longer duration. In line with previous findings, plasma cells of end-stage HF patients showed high production of IgG3, which can be inhibited by MSCs in vitro. MSCs and CPCs inhibit in vitro antibody production of both healthy and end-stage HF-derived immune cells. CPC-derived paracrine factors, such as EVs, show similar effects, but do not provide the complete immunosuppressive capacity of CPCs. The strongest immunosuppressive effects were observed using MSCs, suggesting that MSCs might be the best candidates for therapeutic targeting of B-cell responses in HF.


Assuntos
Linfócitos B/imunologia , Insuficiência Cardíaca/terapia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Transplante de Células-Tronco Mesenquimais , Mioblastos Cardíacos/transplante , Linfócitos B/citologia , Proliferação de Células , Células Cultivadas , Vesículas Extracelulares/imunologia , Insuficiência Cardíaca/imunologia , Humanos
16.
Front Immunol ; 9: 2665, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30498501

RESUMO

Heart failure due to pressure overload is frequently associated with inflammation. In addition to inflammatory responses of the innate immune system, autoimmune reactions of the adaptive immune system appear to be triggered in subgroups of patients with heart failure as demonstrated by the presence of autoantibodies against myocardial antigens. Moreover, T cell-deficient and T cell-depleted mice have been reported to be protected from heart failure induced by transverse aortic constriction (TAC) and we have shown recently that CD4+-helper T cells with specificity for an antigen in cardiomyocytes accelerate TAC-induced heart failure. In this study, we set out to investigate the potential contribution of CD8+-cytotoxic T cells with specificity to a model antigen (ovalbumin, OVA) in cardiomyocytes to pressure overload-induced heart failure. In 78% of cMy-mOVA mice with cardiomyocyte-specific OVA expression, a low-grade OVA-specific cellular cytotoxicity was detected after TAC. Adoptive transfer of OVA-specific CD8+-T cells from T cell receptor transgenic OT-I mice before TAC did not increase the risk of OVA-specific autoimmunity in cMy-mOVA mice. After TAC, again 78% of the mice displayed an OVA-specific cytotoxicity with on average only a three-fold higher killing of OVA-expressing target cells. More CD8+ cells were present after TAC in the myocardium of cMy-mOVA mice with OT-I T cells (on average 17.5/mm2) than in mice that did not receive OVA-specific CD8+-T cells (3.6/mm2). However, the extent of fibrosis was similar in both groups. Functionally, as determined by echocardiography, the adoptive transfer of OVA-specific CD8+-T cells did not significantly accelerate the progression from hypertrophy to heart failure in cMy-mOVA mice. These findings argue therefore against a major impact of cytotoxic T cells with specificity for autoantigens of cardiomyocytes in pressure overload-induced heart failure.


Assuntos
Autoantígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Insuficiência Cardíaca/imunologia , Miócitos Cardíacos/imunologia , Transferência Adotiva/métodos , Animais , Autoimunidade/imunologia , Constrição , Citotoxicidade Imunológica/imunologia , Progressão da Doença , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ovalbumina/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-30519544

RESUMO

Background: Archaeal genes present in Trypanosoma cruzi may represent symbionts that would explain development of heart failure in 30% of Chagas disease patients. Extracellular vesicles in peripheral blood, called exosomes (< 0.1 µm) or microvesicles (>0.1 µm), present in larger numbers in heart failure, were analyzed to determine whether they are derived from archaea in heart failure Chagas disease. Methods: Exosomes and microvesicles in serum supernatant from 3 groups were analyzed: heart failure Chagas disease (N = 26), asymptomatic indeterminate form (N = 21) and healthy non-chagasic control (N = 16). Samples were quantified with transmission electron microscopy, flow cytometer immunolabeled with anti-archaemetzincin-1 antibody (AMZ 1, archaea collagenase) and probe anti-archaeal DNA and zymography to determine AMZ1 (Archaeal metalloproteinase) activity. Results: Indeterminate form patients had higher median numbers of exosomes/case vs. heart failure patients (58.5 vs. 25.5, P < 0.001), higher exosome content of AMZ1 antigens (2.0 vs. 0.0; P < 0.001), and lower archaeal DNA content (0.2 vs. 1.5, P = 0.02). A positive correlation between exosomes and AMZ1 content was seen in indeterminate form (r = 0.5, P < 0.001), but not in heart failure patients (r = 0.002, P = 0.98). Higher free archaeal DNA (63.0 vs. 11.1, P < 0.001) in correlation with exosome numbers (r = 0.66, P = 0.01) was seen in heart failure but not in indeterminate form (r = 0.29, P = 0.10). Flow cytometer showed higher numbers of AMZ1 microvesicles in indeterminate form (64 vs. 36, P = 0.02) and higher archaeal DNA microvesicles in heart failure (8.1 vs. 0.9, P < 0.001). Zymography showed strong% collagenase activity in HF group, mild activity in IF compared to non-chagasic healthy group (121 ± 14, 106 ± 13 and 100; P < 0.001). Conclusions: Numerous exosomes, possibly removing and degrading abnormal AMZ1 collagenase, are associated with indeterminate form. Archaeal microvesicles and their exosomes, possibly associated with release of archaeal AMZ1 in heart failure, are future candidates of heart failure biomarkers if confirmed in larger series, and the therapeutic focus in the treatment of Chagas disease.


Assuntos
Archaea/fisiologia , Doença de Chagas/imunologia , Insuficiência Cardíaca/imunologia , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Bactérias/sangue , Biomarcadores , Doença de Chagas/sangue , Colagenases , Exossomos , Feminino , Citometria de Fluxo , Insuficiência Cardíaca/sangue , Humanos , Masculino , Metaloproteases , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade
18.
Int J Mol Sci ; 19(12)2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30467294

RESUMO

Heart failure (HF) is a cardiovascular syndrome characterized by maladaptive changes with an underlying inflammatory mediated pathogenesis. Nevertheless, current therapy is aimed at the heart workload and neurohormonal axis; thus, prognosis remains poor. To continue improving treatment, we rely on murine models for a better understanding of HF pathophysiology. Among them, pressure overload HF (PO-HF) animal models are a common strategy. Development of PO-HF is characterized by monocyte infiltration, which orchestrates a cascade of events leading to sustained inflammation and maladaptive changes. Here, we divide the PO-HF model progression into four phases and describe the inflammatory, structural, and gene expression profiles. This division is relevant due to its similarities with clinical hypertensive heart disease progression to HF. Evidence shows improvement in hemodynamic and other local parameters by altering the inflammatory response in a specific immune response at a specific point of time. Thus, it is relevant to focus on the time-dependent immune response interaction in order to provide more effective therapy. This review summarizes the pathogenesis of PO-HF murine models, highlighting the inflammatory events in a time frame view. By this approach, we expect to provide researchers with a better understanding of the intertwining time-dependent events that occur in PO-HF.


Assuntos
Linfócitos B/imunologia , Insuficiência Cardíaca/imunologia , Hipertensão/imunologia , Monócitos/imunologia , Linfócitos T/imunologia , Angiotensina II/administração & dosagem , Angiotensina II/efeitos adversos , Animais , Aorta/imunologia , Aorta/patologia , Linfócitos B/patologia , Cardiomegalia/imunologia , Cardiomegalia/patologia , Movimento Celular , Constrição Patológica/imunologia , Constrição Patológica/patologia , Citocinas/biossíntese , Citocinas/imunologia , Modelos Animais de Doenças , Fibrose Endomiocárdica/imunologia , Fibrose Endomiocárdica/patologia , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Humanos , Hipertensão/complicações , Hipertensão/patologia , Camundongos , Monócitos/patologia , Linfócitos T/patologia , Fatores de Tempo , Disfunção Ventricular Esquerda/imunologia , Disfunção Ventricular Esquerda/patologia
19.
Circ Heart Fail ; 11(8): e005036, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30354558

RESUMO

Background Enhanced inflammation may lead to exercise intolerance in heart failure with preserved ejection fraction. The aim of the current study was to determine whether IL (interleukin)-1 blockade with anakinra improved cardiorespiratory fitness in heart failure with preserved ejection fraction. Methods and Results Thirty-one patients with heart failure with preserved ejection fraction and CRP (C-reactive protein) >2 mg/L were randomized to anakinra (100 mg subcutaneously daily, N=21) or placebo (N=10) for 12 weeks. We measured peak oxygen consumption (Vo2), ventilatory efficiency (VE/Vco2 slope), and high-sensitivity CRP and NT-proBNP (N-terminal pro-B-type natriuretic peptide) at 4, 12, and 24 weeks. Twenty-eight patients completed ≥2 visits, 18 women (64%), 27 (96%) obese. There were no differences in peak Vo2 or VE/Vco2 slope between groups at baseline. Peak Vo2 was not changed after 12 weeks of anakinra (from 13.6 [11.8-18.0] to 14.2 [11.2-18.5] mL·kg-1·min-1, P=0.89), or placebo (14.9 [11.7-17.2] to 15.0 [13.8-16.9] mL·kg-1·min-1, P=0.40), without significant between-group differences in changes at 12 weeks (-0.4 [95% CI, -2.2 to +1.4], P=0.64). VE/Vco2 slope was also unchanged with anakinra (from 28.3 [27.2-33.0] to 30.5 [26.3-32.8], P=0.97) or placebo (from 31.6 [27.3-36.9] to 31.2 [27.8-33.4], P=0.78), without significant between-group differences in changes at 12 weeks (+1.2 [95% CI, -1.8 to +4.3], P=0.97). Within the anakinra-treated patients, high-sensitivity CRP and NT-proBNP levels were lower at 4 weeks compared with baseline ( P=0.026 and P=0.022 versus placebo [between-group analysis], respectively). Conclusions Treatment with anakinra for 12 weeks failed to improve peak Vo2 and VE/Vco2 slope in a group of obese heart failure with preserved ejection fraction patients. The favorable trends in high-sensitivity CRP and NT-proBNP with anakinra deserve exploration in future studies. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02173548.


Assuntos
Anti-Inflamatórios/uso terapêutico , Aptidão Cardiorrespiratória , Tolerância ao Exercício/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1/antagonistas & inibidores , Volume Sistólico , Função Ventricular Esquerda , Anti-Inflamatórios/efeitos adversos , Proteína C-Reativa/metabolismo , Método Duplo-Cego , Ecocardiografia Doppler , Teste de Esforço , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Interleucina-1/imunologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Consumo de Oxigênio/efeitos dos fármacos , Fragmentos de Peptídeos/sangue , Qualidade de Vida , Recuperação de Função Fisiológica , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento
20.
Front Immunol ; 9: 2015, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30233596

RESUMO

Aims: Cardiac dysfunction can be a fatal complication during severe sepsis. The migration of neutrophils is significantly impaired during severe sepsis. We sought to determine the role of trimetazidine (TMZ) in regulation of neutrophil migration to the heart in a mouse model of sepsis and endotoxemia, and to identify the mechanism whereby TMZ confers a survival advantage. Methods and Results: C57/BL6 mice were (1) injected with LPS followed by 24-h TMZ administration, or (2) treated with TMZ (20 mg/kg/day) for 1 week post cecal ligation and puncture (CLP) operation. Echocardiography and Millar system detection showed that TMZ alleviated cardiac dysfunction and histological staining showed the failure of neutrophils migration to heart in both LPS- and CLP-induced mice. Bone marrow transplantation revealed that TMZ-pretreated bone marrow cells improved LPS- and CLP-induced myocardial dysfunction and enhanced neutrophil recruitment in heart. In CXCL2-mediated chemotaxis assays, TMZ increased neutrophils migration via AMPK/Nrf2-dependent up-regulation of CXCR2 and inhibition of GRK2. Furthermore, using luciferase reporter gene and chromatin immunoprecipitation assays, we found that TMZ promoted the binding of the Nrf2 and CXCR2 promoter regions directly. Application of CXCR2 inhibitor completely reversed the protective effects of TMZ in vivo. Co-culture of neutrophils and cardiomyocytes further validated that TMZ decreased LPS-induced cardiomyocyte pyroptosis by targeting neutrophils. Conclusion: Our findings suggested TMZ as a potential therapeutic agent for septic or endotoxemia associated cardiac dysfunction in mice. STUDY HIGHLIGHTS  What is the current knowledge on the topic? Migration of neutrophils is significantly impaired during severe sepsis, but the underlying mechanisms remain unknown. What question did this study address? The effects of TMZ on cardiac dysfunction via neutrophils migration. What this study adds to our knowledge TMZ attenuated LPS-induced cardiomyocyte pyroptosis and cardiac dysfunction by promoting neutrophils recruitment to the heart tissues via CXCR2. How this might change clinical pharmacology or translational science Our findings suggested TMZ as a potential therapeutic agent for septic cardiac dysfunction.


Assuntos
Endotoxemia/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Neutrófilos/imunologia , Sepse/tratamento farmacológico , Trimetazidina/uso terapêutico , Vasodilatadores/uso terapêutico , Adenilato Quinase/metabolismo , Animais , Ceco/cirurgia , Células Cultivadas , Quimiocina CXCL2/metabolismo , Quimiotaxia , Modelos Animais de Doenças , Endotoxemia/imunologia , Insuficiência Cardíaca/imunologia , Humanos , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Neutrófilos/efeitos dos fármacos , Sepse/imunologia , Transdução de Sinais
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