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2.
Eur Heart J ; 40(48): 3924-3933, 2019 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31365073

RESUMO

AIMS: A persistent cardiac T-cell response initiated by myocardial infarction is linked to subsequent adverse ventricular remodelling and progression of heart failure. No data exist on T-cell receptor (TCR) repertoire changes in combination with phenotypic characterization of T cells in ischaemic failing human hearts. METHODS AND RESULTS: Analysis of TCR repertoire with high-throughput sequencing revealed that compared with T cells in control hearts, those in ischaemic failing hearts showed a clonally expanded TCR repertoire but similar usage patterns of TRBV-J rearrangements and V gene segments; compared with T cells in peripheral blood, those in ischaemic failing hearts exhibited a restricted and clonally expanded TCR repertoire and different usage patterns of TRBV-J rearrangements and V gene segments, suggesting the occurrence of tissue-specific T-cell expansion in ischaemic failing hearts. Consistently, TCR clonotype sharing was prominent in ischaemic failing hearts, especially in hearts of patients who shared human leucocyte antigen (HLA) alleles. Furthermore, ischaemia heart failure (IHF) heart-associated clonotypes were more frequent in peripheral blood of IHF patients than in that of controls. Heart-infiltrating T cells displayed memory- and effector-like characteristics. Th1 cells were the predominant phenotype among CD4+ T cells; CD8+ T cells were equally as abundant as CD4+ T cells and produced high levels of interferon-γ, granzyme B, and perforin. CONCLUSION: We provide novel evidence for a tissue-specific T-cell response predominated by Th1 cells and cytotoxic CD8+ T cells in ischaemic failing human hearts that may contribute to the progression of heart failure.


Assuntos
Insuficiência Cardíaca/patologia , Infarto do Miocárdio/patologia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/patologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Células Clonais/metabolismo , Progressão da Doença , Granzimas/metabolismo , Insuficiência Cardíaca/metabolismo , Humanos , Memória Imunológica/genética , Interferon gama/metabolismo , Isquemia , Infarto do Miocárdio/metabolismo , Perforina/metabolismo , Fenótipo , Remodelação Ventricular
3.
Theranostics ; 8(16): 4552-4562, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30214638

RESUMO

Interleukin (IL)-22 regulates tissue inflammation and repair. Here we report participation of the liver in IL-22-mediated cardiac repair after acute myocardial infarction (MI). Methods: We induced experimental MI in mice by ligation of the left ascending artery and evaluated the effect of IL-22 on post-MI cardiac function and ventricular remodeling. Results: Daily subcutaneous injection of 100 µg/kg mouse recombinant IL-22 for seven days attenuated adverse ventricular remodeling and improved cardiac function in mice at 28 days after left anterior descending coronary artery ligation-induced MI. Pharmacological inhibition of signal transducer and activator of transcription (STAT3) muted these IL-22 activities. While cardiomyocyte-selective depletion of STAT3 did not affect IL-22 activities in protecting post-MI cardiac injury, hepatocyte-specific depletion of STAT3 fully muted these IL-22 cardioprotective activities. Hepatocyte-derived fibroblast growth factor (FGF21) was markedly increased in a STAT3-dependent manner following IL-22 administration and accounted for the cardioprotective benefit of IL-22. Microarray analyses revealed that FGF21 controlled the expression of cardiomyocyte genes that are involved in cholesterol homeostasis, DNA repair, peroxisome, oxidative phosphorylation, glycolysis, apoptosis, and steroid responses, all of which are responsible for cardiomyocyte survival. Conclusions: Supplementation of IL-22 in the first week after acute MI effectively prevented left ventricular dysfunction and heart failure. This activity of IL-22 involved crosstalk between the liver and heart after demonstrating a role of the hepatic STAT3-FGF21 axis in IL-22-induced post-MI cardiac protection.


Assuntos
Coração/fisiologia , Interleucinas/administração & dosagem , Fígado/metabolismo , Infarto do Miocárdio/patologia , Regeneração , Animais , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/análise , Perfilação da Expressão Gênica , Testes de Função Cardíaca , Injeções Subcutâneas , Camundongos , Fator de Transcrição STAT3/análise , Remodelação Ventricular , Interleucina 22
4.
Cell Physiol Biochem ; 46(1): 23-35, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29566367

RESUMO

BACKGROUND/AIMS: Newly identified IL-10-producing regulatory B cells (Bregs) have been shown to play an important role in the suppression of immune responses. Chronic immune activation participates in the pathogenesis of dilated cardiomyopathy (DCM) but whether Bregs are involved in its development remains unclear. We aimed to investigate the circulating frequency and function of Bregs in DCM. METHODS: In total, 35 DCM patients (20 men and 15 women) and 44 healthy controls (23 men and 21 women) were included in the experiment, and the frequency of Bregs was detected using flow cytometry. RESULTS: According to our results, the frequency of circulating IL-10-producing Bregs was significantly lower in DCM patients compared with healthy controls. Furthermore, the CD24hiCD27+ B cell subset in which IL-10-producing Bregs were mainly enriched from DCM patients showed impaired IL-10 expression and a decreased ability to suppress the TNF-α production of CD4+CD25- Tconv cells and to maintain Tregs differentiation. Correlation analysis showed that the frequency of IL-10-producing Bregs and the suppressive function of CD24hiCD27+ B cells were positively correlated with left ventricular ejection fraction and negatively correlated with NT-proBNP in DCM patients. CONCLUSIONS: In conclusion, the reduced frequency and impaired functions suggest a potential role of Bregs in the development of DCM.


Assuntos
Linfócitos B Reguladores/metabolismo , Cardiomiopatia Dilatada/patologia , Adulto , Idoso , Linfócitos B Reguladores/citologia , Antígeno CD24/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Cardiomiopatia Dilatada/imunologia , Cardiomiopatia Dilatada/metabolismo , Estudos de Casos e Controles , Diferenciação Celular , Proliferação de Células , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Interleucina-10/metabolismo , Leucócitos Mononucleares/citologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/análise , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/análise , Fragmentos de Peptídeos/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
5.
Ann Med ; 47(3): 245-52, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25856542

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell accumulation in AAA lesions that produce inflammatory cytokines and advance its pathogenesis. Peripheral cytokines may predict the degree or risk of AAA. METHODS AND RESULTS: ELISA determined plasma interleukin-6 (IL6), IL10, IL17A, IFN-γ, and C-reactive protein (CRP) from 476 AAA patients and 200 controls. AAA patients had lower IL6, IFN-γ, IL10, IL17A, and higher CRP than controls. IL10 correlated positively with IFN-γ, IL17A, or IL6, but not CRP in control or AAA populations. IL10 associated negatively with systolic blood pressure, whereas CRP associated positively with diastolic blood pressure and body mass index. CRP was an independent AAA risk factor and correlated positively with aortic diameters before and after adjustments for other risk factors. IFN-γ, IL17A, and CRP correlated positively with cross-sectional AAA area after adjustment. IL10 correlated positively with AAA growth rate before and after adjustment. The risk of death doubled in AAA patients with CRP levels above the median. CONCLUSIONS: Reduced IFN-γ, IL10, and IL17A in AAA patients, positive correlations of IFN-γ and IL17A with cross-sectional AAA area, IL10 with AAA growth rate, and IL10 with IFN-γ and IL17A suggest combined Th1, Th2, and Th17 immune responses in human AAAs.


Assuntos
Aneurisma da Aorta Abdominal/sangue , Citocinas/sangue , Idoso , Aneurisma da Aorta Abdominal/epidemiologia , Aneurisma da Aorta Abdominal/patologia , Pressão Sanguínea/fisiologia , Proteína C-Reativa/metabolismo , Estudos de Coortes , Estudos Transversais , Dinamarca/epidemiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-17/sangue , Interleucina-6/sangue , Masculino , Estudos Prospectivos , Fatores de Risco
6.
Clin Sci (Lond) ; 128(10): 679-93, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25558978

RESUMO

Regulatory T-cells (Tregs) are generally regarded as key immunomodulators that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. However, its role in myocardial ischaemia/reperfusion injury (MIRI) remains unknown. The purpose of the present study was to determine whether Tregs exert a beneficial effect on mouse MIRI. We examined the role of Tregs in murine MIRI by depletion using 'depletion of regulatory T-cell' (DEREG) mice and adoptive transfer using Forkhead box P3 (Foxp3)-GFP knockin mice and the mechanisms of cardio protection were further studied in vivo and in vitro. Tregs rapidly accumulated in murine hearts following MIRI. Selective depletion of Tregs in the DEREG mouse model resulted in aggravated MIRI. In contrast, the adoptive transfer of in vitro-activated Tregs suppressed MIRI, whereas freshly isolated Tregs had no effect. Mechanistically, activated Treg-mediated protection against MIRI was not abrogated by interleukin (IL)-10 or transforming growth factor (TGF)-ß1 inhibition but was impaired by the genetic deletion of cluster of differentiation 39 (CD39). Moreover, adoptive transfer of in vitro-activated Tregs attenuated cardiomyocyte apoptosis, activated a pro-survival pathway involving Akt and extracellular-signal-regulated kinase (ERK) and inhibited neutrophil infiltration, which was compromised by CD39 deficiency. Finally, the peripheral blood mononuclear cells of acute myocardial infarction (AMI) patients after primary percutaneous coronary intervention (PCI) revealed a decrease in CD4+CD25+CD127low Tregs and a relative increase in CD39+ cells within the Treg population. In conclusion, our data validated a protective role for Tregs in MIRI. Moreover, in vitro-activated Tregs ameliorated MIRI via a CD39-dependent mechanism, representing a putative therapeutic strategy.


Assuntos
Antígenos CD/metabolismo , Apirase/metabolismo , Imunoterapia/métodos , Ativação Linfocitária/imunologia , Traumatismo por Reperfusão Miocárdica/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva/métodos , Análise de Variância , Animais , Fatores de Transcrição Forkhead/genética , Técnicas de Introdução de Genes , Proteínas de Fluorescência Verde/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/metabolismo
7.
Sci China Life Sci ; 57(8): 795-801, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25104452

RESUMO

Aortic aneurysms are common and life threatening problems with high rates of death. The initiation and progression of aneurysms are characterized by extensive extracellular matrix degradation and immune cells invasion within arterial wall. During the pathogenesis of all aneurysms, inflammation and immune cells play a significant role. Although T cells are abundant in aneurysm tissue, their functions in initiation and propagation of aneurysms remain unclear. This review summarizes the current state of knowledge of T lymphocytes on this disease and focuses on potential mechanisms of specific T cell responses.


Assuntos
Aneurisma Aórtico/imunologia , Linfócitos T/imunologia , Matriz Extracelular/imunologia , Humanos , Subpopulações de Linfócitos T
8.
J Mol Med (Berl) ; 92(10): 1105-16, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24965614

RESUMO

Inflammatory responses play an important role in the pathogenesis of adverse ventricular remodeling after myocardial infarction (MI). We previously demonstrated that interleukin (IL)-17A plays a pathogenic role in myocardial ischemia/reperfusion injury and viral myocarditis. However, the role of IL-17A in post-MI remodeling and the related mechanisms have not been fully elucidated. Acute MI was induced by permanent ligation of the left anterior descending coronary artery in C57BL/6 mice. Repletion of IL-17A significantly aggravated both early- and late-phase ventricular remodeling, as demonstrated by increased infarct size, deteriorated cardiac function, increased myocardial fibrosis, and cardiomyocyte apoptosis. By contrast, genetic IL-17A deficiency had the opposite effect. Additional studies in vitro indicated that IL-17A induces neonatal cardiomyocyte (from C57BL/6 mice) apoptosis through the activation of p38, p53 phosphorylation, and Bax redistribution. These data demonstrate that IL-17A induces cardiomyocyte apoptosis through the p38 mitogen-activated protein kinase (MAPK)-p53-Bax signaling pathway and promotes both early- and late-phase post-MI ventricular remodeling. IL-17A might be an important target in preventing heart failure after MI. Key message: We demonstrated that IL-17A plays a pathogenic role both in the early and late stages of post-MI remodeling. IL-17A induces murine cardiomyocyte apoptosis. IL-17A induces murine cardiomyocyte apoptosis through the p38 MAPK-p53-Bax signaling pathway.


Assuntos
Interleucina-17/metabolismo , Infarto do Miocárdio/metabolismo , Remodelação Ventricular/fisiologia , Animais , Apoptose/efeitos dos fármacos , Citocromos c/metabolismo , Fibrose , Interleucina-17/genética , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , RNA Mensageiro/metabolismo , Receptores de Interleucina-17/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Atherosclerosis ; 230(1): 100-105, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23958260

RESUMO

BACKGROUND: Cathepsin L (CatL), cathepsin K (CatK), and cathepsin V (CatV) are potent elastases implicated in human arterial wall remodeling. Whether plasma levels of these cathepsins are altered in patients with abdominal aortic aneurysms (AAAs) remains unknown. METHODS AND RESULTS: Plasma samples were collected from 476 male AAA patients and 200 age-matched male controls to determine CatL, CatK, and CatV levels by ELISA. Student's t-test demonstrated significantly higher plasma CatL levels in AAA patients than in controls (P < 0.0001), whereas CatK and CatV levels were lower in AAA patients than in controls (P = 0.052, P = 0.025). ROC curve analysis confirmed higher plasma CatL levels in AAA patients than in controls (P < 0.001). As potential confounders, current smoking and use of angiotensin-converting enzyme (ACE) inhibitors, aspirin, clopidogrel, and statins associated with significantly increased plasma CatL. Pearson's correlation test demonstrated that plasma CatL associated positively with CatS (r = 0.43, P < 0.0001), body-mass index (BMI) (r = 0.07, P = 0.047) and maximal aortic diameter (r = 0.29, P < 0.001), and negatively with lowest measured ankle-brachial index (ABI) (r = -0.22, P < 0.001). Plasma CatL remained associated positively with CatS (r = 0.43, P < 0.0001) and aortic diameter (r = 0.212, P < 0.001) and negatively with ABI (r = -0.10, P = 0.011) after adjusting for the aforementioned potential confounders in a partial correlation analysis. Multivariate logistic regression analysis indicated that plasma CatL was a risk factor of AAA before (odds ratio [OR] = 3.04, P < 0.001) and after (OR = 2.42, P < 0.001) the same confounder adjustment. CONCLUSIONS: Correlation of plasma CatL levels with aortic diameter and the lowest ABI suggest that this cysteinyl protease plays a detrimental role in the pathogenesis of human peripheral arterial diseases and AAAs.


Assuntos
Aneurisma da Aorta Abdominal/sangue , Catepsina K/sangue , Catepsina L/sangue , Catepsinas/sangue , Cisteína Endopeptidases/sangue , Regulação da Expressão Gênica , Idoso , Aorta/patologia , Aneurisma da Aorta Abdominal/epidemiologia , Índice de Massa Corporal , Estudos de Casos e Controles , Dinamarca/epidemiologia , Ensaio de Imunoadsorção Enzimática , Humanos , Masculino , Distribuição Aleatória , Fatores de Risco
10.
PLoS One ; 7(7): e41813, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22844527

RESUMO

BACKGROUND: Human abdominal aortic aneurysm (AAA) lesions contain high levels of cathepsin S (CatS), but are deficient in its inhibitor, cystatin C. Whether plasma CatS and cystatin C levels are also altered in AAA patients remains unknown. METHODS AND RESULTS: Plasma samples were collected from 476 male AAA patients and 200 age-matched male controls to determine CatS and cystatin C levels by ELISA. Student's t test demonstrated higher plasma levels of total, active, and pro-CatS in AAA patients than in controls (P<0.001). ROC curve analysis confirmed higher plasma total, active, and pro-CatS levels in AAA patients than in controls (P<0.001). Logistic regression suggested that plasma total (odds ratio [OR] = 1.332), active (OR = 1.21), and pro-CatS (OR = 1.25) levels were independent AAA risk factors that associated positively with AAA (P<0.001). Plasma cystatin C levels associated significantly, but negatively, with AAA (OR = 0.356, P<0.001). Univariate correlation demonstrated that plasma total and active CatS levels correlated positively with body-mass index, diastolic blood pressure, and aortic diameter, but negatively with the lowest ankle-brachial index (ABI). Plasma cystatin C levels also correlated negatively with the lowest ABI. Multivariate linear regression showed that plasma total, active, and pro-CatS levels correlated positively with aortic diameter and negatively with the lowest ABI, whereas plasma cystatin C levels correlated negatively with aortic diameter and the lowest ABI, after adjusting for common AAA risk factors. CONCLUSIONS: Correlation of plasma CatS and cystatin C with aortic diameter and the lowest ABI suggest these serological parameters as biomarkers for human peripheral arterial diseases and AAA.


Assuntos
Aneurisma da Aorta Abdominal/sangue , Catepsinas/sangue , Cistatina C/sangue , Idoso , Aneurisma da Aorta Abdominal/complicações , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/fisiopatologia , Pressão Sanguínea , Estudos de Coortes , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertensão/complicações , Masculino , Fatores de Risco , Fumar/efeitos adversos
11.
J Am Coll Cardiol ; 59(4): 420-9, 2012 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-22261166

RESUMO

OBJECTIVES: This study tested whether interleukin (IL)-17A is involved in the pathogenesis of mouse myocardial ischemia/reperfusion (I/R) injury and investigated the mechanisms. BACKGROUND: Inflammatory processes play a major role in myocardial I/R injury. We recently identified IL-17A as an important cytokine in inflammatory cardiovascular diseases such as atherosclerosis and viral myocarditis. However, its role in myocardial I/R injury remains unknown. METHODS: The involvement of IL-17A was assessed in functional assays in mouse myocardial I/R injury by neutralization/repletion or genetic deficiency of IL-17A, and its mechanism on cardiomyocyte apoptosis and neutrophil infiltration were further studied in vivo and in vitro. RESULTS: Interleukin-17A was elevated after murine left coronary artery ligation and reperfusion. Intracellular cytokine staining revealed that γδT lymphocytes but not CD4(+) helper T cells were a major source of IL-17A. Anti-IL-17A monoclonal antibody treatment or IL-17A knockout markedly ameliorated I/R injury, as demonstrated by reduced infarct size, reduced cardiac troponin T levels, and improved cardiac function. This improvement was associated with a reduction in cardiomyocyte apoptosis and neutrophil infiltration. In contrast, repletion of exogenous IL-17A induced the opposite effect. In vitro study showed that IL-17A mediated cardiomyocyte apoptosis through regulating the Bax/Bcl-2 ratio, induced CXC chemokine-mediated neutrophil migration and promoted neutrophil-endothelial cell adherence through induction of endothelial cell E-selectin and inter-cellular adhesion molecule-1 expression. CONCLUSIONS: IL-17A mainly produced by γδT cells plays a pathogenic role in myocardial I/R injury by inducing cardiomyocyte apoptosis and neutrophil infiltration.


Assuntos
Apoptose , Interleucina-17/fisiologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Infiltração de Neutrófilos , Subpopulações de Linfócitos T/metabolismo , Animais , Adesão Celular , Quimiocinas CXC/metabolismo , Selectina E/metabolismo , Células Endoteliais/fisiologia , Técnicas de Inativação de Genes , Molécula 1 de Adesão Intercelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica/imunologia , Miócitos Cardíacos/fisiologia , Estresse Oxidativo
12.
Acta Ophthalmol ; 90(2): e138-43, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22136411

RESUMO

PURPOSE: To investigate the effects of secreted protein acidic and rich in cysteine (SPARC) on the expression of components of the extracellular matrix (ECM) in cultured human trabecular meshwork (TM) cells. METHODS: Cultured human trabecular cells were transfected with small interfering RNAs (siRNAs) specific for the human SPARC gene. Protein and mRNA expressions of fibronectin (FN) and the α1chains of collagen I and collagen III were quantified. RESULTS: After silencing of the SPARC gene by transfection of cells with SPARC siRNA, the expression of COL1A1 and COL3A1 mRNAs and proteins was significantly enhanced, as compared to that in the control group (all, p < 0.001). In contrast, SPARC siRNA significantly reduced the expression of FN and SPARC mRNAs and FN protein, as compared to that in the control group (all, p < 0.001.). CONCLUSIONS: SPARC modulates the expression of several ECM genes in cultured human TM cells.


Assuntos
Colágeno Tipo III/genética , Colágeno Tipo I/genética , Fibronectinas/genética , Regulação da Expressão Gênica/fisiologia , Malha Trabecular/metabolismo , Proteínas Supressoras de Tumor/genética , Western Blotting , Células Cultivadas , Cadeia alfa 1 do Colágeno Tipo I , Inativação Gênica/fisiologia , Humanos , Osteonectina , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção
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