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1.
Eur Heart J ; 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31004144

RESUMO

AIMS: Heart failure with preserved ejection fraction (HFpEF) and pathological cardiac aging share a complex pathophysiology, including extracellular matrix remodelling (EMR). Protease-activated receptor 2 (PAR2) deficiency is associated with EMR. The roles of PAR1 and PAR2 have not been studied in HFpEF, age-dependent cardiac fibrosis, or diastolic dysfunction (DD). METHODS AND RESULTS: Evaluation of endomyocardial biopsies from patients with HFpEF (n = 14) revealed that a reduced cardiac PAR2 expression was associated with aggravated DD and increased myocardial fibrosis (r = -0.7336, P = 0.0028). In line, 1-year-old PAR2-knockout (PAR2ko) mice suffered from DD with preserved systolic function, associated with an increased age-dependent α-smooth muscle actin expression, collagen deposition (1.7-fold increase, P = 0.0003), lysyl oxidase activity, collagen cross-linking (2.2-fold increase, P = 0.0008), endothelial activation, and inflammation. In the absence of PAR2, the receptor-regulating protein caveolin-1 was down-regulated, contributing to an augmented profibrotic PAR1 and transforming growth factor beta (TGF-ß)-dependent signalling. This enhanced TGF-ß/PAR1 signalling caused N-proteinase (ADAMTS3) and C-proteinase (BMP1)-related increased collagen I production from cardiac fibroblasts (CFs). PAR2 overexpression in PAR2ko CFs reversed these effects. The treatment with the PAR1 antagonist, vorapaxar, reduced cardiac fibrosis by 44% (P = 0.03) and reduced inflammation in a metabolic disease model (apolipoprotein E-ko mice). Patients with HFpEF with upstream PAR inhibition via FXa inhibitors (n = 40) also exhibited reduced circulating markers of fibrosis and DD compared with patients treated with vitamin K antagonists (n = 20). CONCLUSIONS: Protease-activated receptor 2 is an important regulator of profibrotic PAR1 and TGF-ß signalling in the heart. Modulation of the FXa/FIIa-PAR1/PAR2/TGF-ß-axis might be a promising therapeutic approach to reduce HFpEF.

2.
Arterioscler Thromb Vasc Biol ; 36(6): 1263-71, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27127202

RESUMO

OBJECTIVE: Diabetes mellitus involves vascular inflammatory processes and is a main contributor to cardiovascular mortality. Notably, heightened levels of circulating tissue factor (TF) account for the increased thrombogenicity and put those patients at risk for thromboembolic events. Here, we sought to investigate the role of micro-RNA (miR)-driven TF expression and thrombogenicity in diabetes mellitus. APPROACH AND RESULTS: Plasma samples of patients with diabetes mellitus were analyzed for TF protein and activity as well as miR-126 expression before and after optimization of the antidiabetic treatment. We found low miR-126 levels to be associated with markedly increased TF protein and TF-mediated thrombogenicity. Reduced miR-126 expression was accompanied by increased vascular inflammation as evident from the levels of vascular adhesion molecule-1 and fibrinogen, as well as leukocyte counts. With optimization of the antidiabetic treatment miR-126 levels increased and thrombogenicity was reduced. Using a luciferase reporter system, we demonstrated miR-126 to directly bind to the F3-3'-untranslated region, thereby reducing TF expression both on mRNA and on protein levels in human microvascular endothelial cells as well as TF mRNA and activity in monocytes. CONCLUSIONS: Circulating miR-126 exhibits antithrombotic properties via regulating post-transcriptional TF expression, thereby impacting the hemostatic balance of the vasculature in diabetes mellitus.


Assuntos
Diabetes Mellitus/sangue , Hemostasia , MicroRNAs/sangue , Tromboplastina/metabolismo , Trombose/sangue , Regiões 3' não Traduzidas , Idoso , Sítios de Ligação , Linhagem Celular , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética , Células Endoteliais/metabolismo , Feminino , Fibrinogênio/metabolismo , Regulação da Expressão Gênica , Genes Reporter , Hemostasia/efeitos dos fármacos , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Monócitos/metabolismo , Interferência de RNA , Tromboplastina/genética , Trombose/genética , Trombose/prevenção & controle , Fatores de Tempo , Transfecção , Molécula 1 de Adesão de Célula Vascular/sangue
3.
Curr Pharm Des ; 22(4): 472-84, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26696253

RESUMO

Protease-activated receptors (PARs) are a unique group of four G-protein coupled receptors. They are widely expressed within the cardiovascular system and the heart. PARs are activated via cleavage by serine proteases. In vitro and in vivo studies showed that the activation of PAR1 and PAR2 plays a crucial role in virus induced inflammatory diseases. The receptors enable cells to recognize pathogen-derived changes in the extracellular environment. An infection with Coxsackie-virus B3 (CVB3) can cause myocarditis. Recent studies have been shown that PAR1 signaling enhanced the antiviral innate immune response via interferon ß (IFNß) and thus limited the virus replication and cardiac damage. In contrast, PAR2 signaling decreased the antiviral innate immune response via IFNß und thus increased the virus replication, which caused severe myocarditis. Along with CVB3 other viruses such as influenza A virus (IAV) and herpes simplex virus (HSV) can induce myocarditis. The role of PAR signaling in IAV infections is contrarily discussed. During HSV infections PARs facilitate the virus infection of the host cell. These studies show that PARs might be interesting drug targets for the treatment of virus infections and inflammatory heart diseases. First studies with PAR agonists, antagonists, and serine protease inhibitors have been conducted in mice. The inhibition of thrombin the main PAR1 activating protease decreased the IFNß response and increased the virus replication in CVB3-induced myocarditis. This indicates that further studies with direct PAR agonists and antagonists are needed to determine whether PARs are useful drug targets for the therapy of virus-induced heart diseases.


Assuntos
Miocardite/tratamento farmacológico , Miocardite/metabolismo , Receptores Ativados por Proteinase/antagonistas & inibidores , Receptores Ativados por Proteinase/metabolismo , Animais , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/fisiologia , Miocardite/imunologia , Receptores Ativados por Proteinase/imunologia , Receptores Toll-Like/antagonistas & inibidores , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo
4.
Trends Cardiovasc Med ; 24(6): 249-55, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25066486

RESUMO

Protease-activated receptors (PARs) are a family of G-protein-coupled receptors with a unique activation mechanism via cleavage by the serine proteases of the coagulation cascade, immune cell-released proteases, and proteases from pathogens. Pathogens, such as viruses and bacteria, cause myocarditis and heart failure and PAR1 was shown to positively regulate the anti-viral innate immune response via interferon ß during virus-induced myocarditis. In contrast, PAR2 negatively regulated the innate immune response and inhibited the interferon ß expression. Thus, PARs play a central role for the innate immune response in the heart.


Assuntos
Miocardite , Miocárdio/imunologia , Receptores Ativados por Proteinase/metabolismo , Viroses , Humanos , Imunidade Inata , Interferon beta/metabolismo , Miocardite/imunologia , Miocardite/virologia , Viroses/complicações , Viroses/imunologia
5.
Cardiovasc Ther ; 32(3): 113-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24533719

RESUMO

INTRODUCTION: Myocarditis is induced by coxsackievirus B3 (CVB3). Myocardial inflammation is tied to the activation of coagulation. Coagulation factor (F) Xa, a central player in coagulation, activates matrix metalloproteinases (MMP), which modulate the remodeling. AIMS: In this study, we investigated the effects of pharmacological FXa inhibition on myocardial function, inflammation, and remodeling during a CVB3-induced myocarditis. METHODS AND RESULTS: Immune cells and matrix proteins were detected by immunohistochemistry. The expression of cytokines was measured by real-time PCR and the activity of MMP-2 by zymography. Left ventricular function was analyzed using microconductance pressure catheter. Treatment with the FXa inhibitor fondaparinux led to an improved left ventricular function in CVB3-induced mice compared to saline-treated controls (dPdtmax: fondaparinux 4632 ± 499.6 vs. saline 3131 ± 374.0 [mmHg/s], P = 0.0503; SV: fondaparinux 33.19 ± 4.893 vs. saline 19.32 ± 2.236 [µL], P < 0.118; CO: fondaparinux 15124 ± 2183 vs. saline 8088 ± 1035 [µL/min], P < 0.05). Therapy with fondaparinux reduced the activity of MMP-2 (fondaparinux 1.208 ± 0.1247 vs. saline 1.565 ± 0.05476, P < 0.05). The collagen type I/III ratio as well as the expression of TIMP-1 was comparable in both infection groups postinfectionem (p.i.), despite an increased infiltration of macrophages into the hearts of mice treated with fondaparinux 8 days p.i. (CD68+: fondaparinux 494.2 ± 64.73 vs. saline 306.9 ± 43.73 [cells/mm(2) ], P < 0.05). Anti-inflammatory CD206-positive M2-type macrophages were increased in the infected hearts after fondaparinux treatment (CD206+: fondaparinux 182.1 ± 18.18 vs. saline 111.6 ± 21.07 [cells/mm(2) ], P < 0.05), whereas CD80-positive M1-type macrophages were comparable in both groups. CONCLUSION: In conclusion, selective inhibition of FXa improves the left ventricular function during CVB3-induced myocarditis and seems to be associated with an improved myocardial remodeling.


Assuntos
Infecções por Coxsackievirus/tratamento farmacológico , Enterovirus Humano B/patogenicidade , Inibidores do Fator Xa/farmacologia , Fator Xa/metabolismo , Miocardite/tratamento farmacológico , Polissacarídeos/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Infecções por Coxsackievirus/sangue , Infecções por Coxsackievirus/fisiopatologia , Infecções por Coxsackievirus/virologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Fondaparinux , Mediadores da Inflamação/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Miocardite/sangue , Miocardite/fisiopatologia , Miocardite/virologia , RNA Mensageiro/metabolismo , Carga Viral
6.
J Am Coll Cardiol ; 62(19): 1737-45, 2013 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-23871888

RESUMO

OBJECTIVES: This study sought to evaluate the role of protease-activated receptor-2 (PAR2) in coxsackievirus B3 (CVB3)-induced myocarditis. BACKGROUND: An infection with CVB3 leads to myocarditis. PAR2 modulates the innate immune response. Toll-like receptor-3 (TLR3) is crucial for the innate immune response by inducing the expression of the antiviral cytokine interferon-beta (IFNß). METHODS: To induce myocarditis, wild-type (wt) and PAR2 knockout (ko) mice were infected with 10(5) plaque-forming units CVB3. Mice underwent hemodynamic measurements with a 1.2-F microconductance catheter. Wt and PAR2ko hearts and cardiac cells were analyzed for viral replication and immune response with plaque assay, quantitative polymerase chain reaction, Western blot, and immunohistochemistry. RESULTS: Compared with wt mice, PAR2ko mice and cardiomyocytes exhibited a reduced viral load and developed no myocarditis after infection with CVB3. Hearts and cardiac fibroblasts from PAR2ko mice expressed higher basal levels of IFNß than wt mice did. Treatment with CVB3 and polyinosinic:polycytidylic acid led to higher IFNß expression in PAR2ko than in wt fibroblasts and reduced virus replication in PAR2ko fibroblasts was abrogated by neutralizing IFNß antibody. Overexpression of PAR2 reduced the basal IFNß expression. Moreover, a direct interaction between PAR2 and Toll-like receptor 3 was observed. PAR2 expression in endomyocardial biopsies of patients with nonischemic cardiomyopathy was positively correlated with myocardial inflammation and negatively with IFNß expression and left ventricular ejection fraction. CONCLUSIONS: PAR2 negatively regulates the innate immune response to CVB3 infection and contributes to myocardial dysfunction. The antagonism of PAR2 is of therapeutic interest to strengthen the antiviral response after an infection with a cardiotropic virus.


Assuntos
Enterovirus Humano B/imunologia , Infecções por Enterovirus/imunologia , Imunidade Inata , Miocardite/imunologia , Miocárdio/enzimologia , Receptor PAR-2/biossíntese , Animais , Anticorpos Antivirais/análise , Biópsia , Western Blotting , Modelos Animais de Doenças , Infecções por Enterovirus/virologia , Regulação da Expressão Gênica , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocardite/metabolismo , Miocardite/virologia , Miocárdio/patologia , RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor PAR-2/genética , Receptor 3 Toll-Like/biossíntese , Receptor 3 Toll-Like/genética
7.
J Clin Invest ; 123(3): 1310-22, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23391721

RESUMO

Coagulation is a host defense system that limits the spread of pathogens. Coagulation proteases, such as thrombin, also activate cells by cleaving PARs. In this study, we analyzed the role of PAR-1 in coxsackievirus B3-induced (CVB3-induced) myocarditis and influenza A infection. CVB3-infected Par1(-/-) mice expressed reduced levels of IFN-ß and CXCL10 during the early phase of infection compared with Par1(+/+) mice that resulted in higher viral loads and cardiac injury at day 8 after infection. Inhibition of either tissue factor or thrombin in WT mice also significantly increased CVB3 levels in the heart and cardiac injury compared with controls. BM transplantation experiments demonstrated that PAR-1 in nonhematopoietic cells protected mice from CVB3 infection. Transgenic mice overexpressing PAR-1 in cardiomyocytes had reduced CVB3-induced myocarditis. We found that cooperative signaling between PAR-1 and TLR3 in mouse cardiac fibroblasts enhanced activation of p38 and induction of IFN-ß and CXCL10 expression. Par1(-/-) mice also had decreased CXCL10 expression and increased viral levels in the lung after influenza A infection compared with Par1(+/+) mice. Our results indicate that the tissue factor/thrombin/PAR-1 pathway enhances IFN-ß expression and contributes to the innate immune response during single-stranded RNA viral infection.


Assuntos
Infecções por Coxsackievirus/imunologia , Imunidade Inata , Infecções por Orthomyxoviridae/imunologia , Receptor PAR-1/fisiologia , Animais , Quimiocina CXCL10/metabolismo , Infecções por Coxsackievirus/metabolismo , Enterovirus/imunologia , Enterovirus/fisiologia , Fibrina/metabolismo , Células HEK293 , Células HeLa , Humanos , Vírus da Influenza A/imunologia , Vírus da Influenza A/fisiologia , Interferon beta/genética , Interferon beta/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/sangue , Miocardite/imunologia , Miocardite/virologia , Miocárdio/metabolismo , Infecções por Orthomyxoviridae/metabolismo , Receptor PAR-1/genética , Receptor PAR-1/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Trombina/metabolismo , Tromboplastina/genética , Tromboplastina/metabolismo , Receptor 3 Toll-Like/metabolismo , Troponina I/sangue
8.
PLoS One ; 7(7): e41047, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22815907

RESUMO

Systemic application of mesenchymal stromal cells (MSCs) in inflammatory cardiomyopathy exerts cardiobeneficial effects. The mode of action is unclear since a sufficient and long-acting cardiac homing of MSCs is unlikely. We therefore investigated the regulation of the immune response in coxsackievirus B3 (CVB3)-induced acute myocarditis after intravenous application of MSCs. Wildtype mice were infected with CVB3 and treated with either PBS, human MSCs or human cardiac fibroblasts intravenously 1 day after infection. Seven days after infection, MSCs could be detected in the spleen, heart, pancreas, liver, lung and kidney, whereby the highest presence was observed in the lung. MSCs increased significantly the myocardial expression of HGF and decreased the expression of the proinflammatory cytokines TNFα, IL1ß and IL6 as well as the severity of myocarditis and ameliorated the left ventricular dysfunction measured by conductance catheter. MSCs upregulated the production of IFNγ in CD4+ and CD8+ cells, the number of IL10-producing regulatory T cells and the apoptosis rate of T cells in the spleen. An increased number of CD4+CD25+FoxP3 could be found in the spleen as well as in the circulation. In contrast, application of human cardiac fibroblasts had no effect on the severity of myocarditis and the systemic immune response observed after MSCs-administration. In conclusion, modulation of the immune response in extracardiac organs is associated with cardiobeneficial effects in experimental inflammatory cardiomyopathy after systemic application of MSCs.


Assuntos
Fibroblastos/citologia , Fatores de Transcrição Forkhead/metabolismo , Células-Tronco Mesenquimais/citologia , Miocardite/metabolismo , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Cardiomiopatias/metabolismo , Células Cultivadas , Fibroblastos/metabolismo , Citometria de Fluxo/métodos , Hemodinâmica , Humanos , Sistema Imunitário , Hibridização In Situ , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miocardite/imunologia , Fator de Necrose Tumoral alfa/metabolismo
9.
Cytokine ; 56(2): 332-7, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21733717

RESUMO

BACKGROUND: Patients with diabetes mellitus (DM) suffer from an increased risk of cardiovascular events caused by thrombotic conditions. Adipose tissue might play a crucial role in this pathogenesis by synthesis of procoagulant mediators. This study was performed to elucidate the role of the adipocytokines leptin and resistin in the development of hypercoagulability and hypofibrinolysis under diabetic conditions. METHODS: Sixty two patients with or without DM were included in our study to measure leptin, resistin and tissue factor (TF) plasma concentrations. Moreover, flow chamber experiments were performed to assess factor Xa and plasmin activity on the surface of HUVECs. Western blot and real-time PCR were performed to determine mRNA and protein expression of main factors of the coagulation and fibrinolytic system. RESULTS: Patients with diabetes showed increased levels of leptin and resistin (leptin: 25.69±13.9 vs. 15.98±17.5 ng/mL, p<0.05; resistin: 2.61±0.6 vs. 1.19±0.7 ng/mL, p<0.05), which were positively correlated with TF. In vitro, leptin and resistin induced increased factor Xa activity (leptin: 4.29±0.57-fold, p<0.05; resistin 4.19±0.7-fold, p<0.05 vs. control) on HUVECs as also reflected by elevated TF mRNA and protein expression. Moreover, stimulatory (plasminogen activator inhibitor 1) and inhibitory (tissue plasminogen activator) mediators of the fibrinolytic cascade were induced by leptin and resistin, leading to a balanced plasmin activity regulation. CONCLUSIONS: Leptin and resistin lead to a procoagulant state in HUVECs by inducing TF expression. This mechanism might be one explanation for the prothrombotic state observed under diabetic conditions.


Assuntos
Coagulação Sanguínea , Diabetes Mellitus/fisiopatologia , Leptina/fisiologia , Resistina/fisiologia , Western Blotting , Células Cultivadas , Humanos , Reação em Cadeia da Polimerase em Tempo Real
10.
Eur J Heart Fail ; 11(12): 1163-8, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19926600

RESUMO

AIMS: Chronic heart failure (CHF) is associated with a higher risk for diabetes mellitus. Retinol binding protein 4 (RBP 4) is an adipose tissue-derived protein with pro-diabetogenic effects. A complete understanding of the association of CHF and insulin resistance remains elusive. The purpose of this study was to examine the relationship between CHF and diabetes mellitus. METHODS AND RESULTS: Plasma levels of RBP 4, insulin, and interleukins (IL) 2, 8, and 10, were assessed in patients with dilated cardiomyopathy (DCM, n = 53), dilated inflammatory cardiomyopathy (DCMi, n = 54), and controls (n = 20). In addition, a possible mechanism of RBP 4 regulation was examined in adipocytes in vitro. Plasma levels of RBP 4 and insulin were measured by a specific ELISA. Interleukin concentrations were obtained by multiplex ELISA. Cell culture with 3T3-L1 adipocytes was performed to measure RBP 4 mRNA expression after stimulation with IL-8. RBP 4 levels were significantly increased in patients with DCMi (52.95 +/- 20.42 microg/mL) compared with DCM (35.54 +/- 23.08 microg/mL) and the control group (27.3 +/- 18.51 microg/mL). RBP 4 was positively correlated with IL-8 (r=0.416, P < 0.05) in human plasma in patients with DCMi. Moreover, increased insulin resistance was observed in patients with DCMi compared with the control and DCM groups. In vitro, IL-8 induced a significant upregulation of RBP 4 mRNA expression in adipocytes. CONCLUSION: Elevated RBP 4 plasma concentrations, induced by IL-8, might be one mechanism leading to a higher incidence of diabetes in patients with DCMi.


Assuntos
Cardiomiopatias/sangue , Proteínas Plasmáticas de Ligação ao Retinol/análise , Células 3T3 , Adipócitos/metabolismo , Adulto , Animais , Cardiomiopatias/patologia , Cardiomiopatia Dilatada/sangue , Células Cultivadas , Complicações do Diabetes/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/complicações , Humanos , Inflamação , Insulina/sangue , Interleucina-10/sangue , Interleucina-2/sangue , Interleucina-8/sangue , Interleucina-8/farmacologia , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo
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