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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.
Cardiovasc Diabetol ; 17(1): 34, 2018 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-29477147

RESUMO

BACKGROUND: Diabetes mellitus is characterized by chronic vascular disorder and presents a main risk factor for cardiovascular mortality. In particular, hyperglycaemia and inflammatory cytokines induce vascular circulating tissue factor (TF) that promotes pro-thrombotic conditions in diabetes. It has recently become evident that alterations of the post-transcriptional regulation of TF via specific microRNA(miR)s, such as miR-126, contribute to the pathogenesis of diabetes and its complications. The endothelial miR-19a is involved in vascular homeostasis and atheroprotection. However, its role in diabetes-related thrombogenicity is unknown. Understanding miR-networks regulating procoagulability in diabetes may help to develop new treatment options preventing vascular complications. METHODS AND RESULTS: Plasma of 44 patients with known diabetes was assessed for the expression of miR-19a, TF protein, TF activity, and markers for vascular inflammation. High miR-19a expression was associated with reduced TF protein, TF-mediated procoagulability, and vascular inflammation based on expression of vascular adhesion molecule-1 and leukocyte count. We found plasma expression of miR-19a to strongly correlate with miR-126. miR-19a reduced the TF expression on mRNA and protein level in human microvascular endothelial cells (HMEC) as well as TF activity in human monocytes (THP-1), while anti-miR-19a increased the TF expression. Interestingly, miR-19a induced VCAM expression in HMEC. However, miR-19a and miR-126 co-transfection reduced total endothelial VCAM expression and exhibited additive inhibition of a luciferase reporter construct containing the F3 3'UTR. CONCLUSIONS: While both miRs have differential functions on endothelial VCAM expression, miR-19a and miR-126 cooperate to exhibit anti-thrombotic properties via regulating vascular TF expression. Modulating the post-transcriptional control of TF in diabetes may provide a future anti-thrombotic and anti-inflammatory therapy.

3.
Semin Immunopathol ; 40(2): 145-156, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29124320

RESUMO

The mucosal immune system and the microbiota in the intestinal tract have recently been shown to play a key role in the pathogenesis of inflammatory bowel disease (IBD). Both of these can be influenced by food. Thus, we propose dietary intervention as a therapeutic option for IBD. In this review, we discuss the interaction of the intestinal mucosal immune system and the intestinal microbiota in the context of IBD. In addition, we discuss the impact of food components on immune responses in IBD. Finally, we address the current evidence of how this interaction (i.e., immune system-microbiota) can be modulated by food components, pre/probiotics, and fecal microbiota transplantation (FMT) and how these approaches can support intestinal homeostasis. By gathering the vast amount of literature available on the impact of food on IBD, we aim to distinguish between scientifically sound data and theories, which have not been included in this review.

6.
Science ; 354(6310): 358-362, 2016 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-27846573

RESUMO

Intestinal inflammation can impair mucosal healing, thereby establishing a vicious cycle leading to chronic inflammatory bowel disease (IBD). However, the signaling networks driving chronic inflammation remain unclear. Here we report that CD4+ T cells isolated from patients with IBD produce high levels of interleukin-22 binding protein (IL-22BP), the endogenous inhibitor of the tissue-protective cytokine IL-22. Using mouse models, we demonstrate that IBD development requires T cell-derived IL-22BP. Lastly, intestinal CD4+ T cells isolated from IBD patients responsive to treatment with antibodies against tumor necrosis factor-α (anti-TNF-α), the most effective known IBD therapy, exhibited reduced amounts of IL-22BP expression but still expressed IL-22. Our findings suggest that anti-TNF-α therapy may act at least in part by suppressing IL-22BP and point toward a more specific potential therapy for IBD.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Receptores de Interleucina/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anticorpos/uso terapêutico , Modelos Animais de Doenças , Humanos , Imunidade nas Mucosas , Imunoterapia , Doenças Inflamatórias Intestinais/terapia , Camundongos , Receptores de Interleucina/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
7.
Crit Care Med ; 44(10): e1014-5, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27635513
8.
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
9.
Trends Cardiovasc Med ; 26(4): 297-303, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26877187

RESUMO

Due to its receptor activity for factor VII, tissue factor (TF) is primary initiator of the blood coagulation cascade and ensures rapid hemostasis in case of organ damage. Inflammatory cytokines, such as tumor necrosis factor-α or interleukins, strongly induce expression of both full-length TF as well as the alternatively spliced TF in endothelial and blood cells. Beyond its role in hemostasis, TF also has signaling activity and promotes pleiotropic inflammatory responses via protease-activated receptors in concert with other coagulation factors. Alteration of TF expression and TF alternative splicing provides an effective means to change the endothelial phenotype and modulate inflammatory responses of the vessel.


Assuntos
Coagulação Sanguínea , Mediadores da Inflamação/sangue , Inflamação/sangue , Tromboplastina/metabolismo , Processamento Alternativo , Animais , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Conformação Proteica , Transdução de Sinais , Tromboplastina/química , Tromboplastina/genética
10.
Thromb Res ; 139: 90-7, 2016 03.
Artigo em Inglês | MEDLINE | ID: mdl-26916302

RESUMO

Thrombosis is a leading cause of morbidity and mortality. Detection of a prothrombotic state using biomarkers would be of great benefit to identify patients at risk of thrombosis that would benefit from thromboprophylaxis. Tissue factor (TF) is a highly procoagulant protein that under normal conditions is not present in the blood. However, increased levels of TF in the blood in the form of microparticles (MPs) (also called extracellular vesicles) are observed under various pathological conditions. In this review, we will discuss studies that have measured MP-TF activity in a variety of diseases using two similar FXa generation assay. One of the most robust signals for MP-TF activity (16-26 fold higher than healthy controls) is observed in pancreatic cancer patients with venous thromboembolism. In this case, the TF+ MPs appear to be derived from the cancer cells. Surprisingly, cirrhosis and acute liver injury are associated with 17-fold and 38-fold increases in MP-TF activity, respectively. Based on mouse models, we speculate that the TF+ MPs are derived from hepatocytes. More modest increases are observed in patients with urinary tract infections (6-fold) and in a human endotoxemia model (9-fold) where monocytes are the likely source of the TF+ MPs. Finally, there is no increase in MP-TF activity in the majority of cardiovascular disease patients. These studies indicate that MP-TF activity may be a useful biomarker to identify patients with particular diseases that have an increased risk of thrombosis.


Assuntos
Micropartículas Derivadas de Células/patologia , Tromboplastina/metabolismo , Trombose/diagnóstico , Animais , Biomarcadores/análise , Biomarcadores/sangue , Biomarcadores/metabolismo , Testes de Coagulação Sanguínea/métodos , Micropartículas Derivadas de Células/metabolismo , Fator Xa/metabolismo , Humanos , Neoplasias/sangue , Neoplasias/complicações , Neoplasias/metabolismo , Neoplasias/patologia , Tromboplastina/análise , Trombose/sangue , Trombose/complicações , Trombose/metabolismo
11.
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
12.
Crit Care Med ; 44(4): e227-30, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26571183

RESUMO

OBJECTIVE: To report a case of intra-arterial amiodarone injection in a hemodynamically unstable patient leading to acute vessel occlusion and a subsequent compartment syndrome. DESIGN: Case report. SETTING: Prehospital setting, emergency department and ICU of a university hospital. PATIENT: A 58-year-old woman presenting with a ventricular tachycardia of 190 beats/min was administered amiodarone through an accidently placed arterial access in the left cubital fossa. Quickly, the woman developed clinical signs of an acute arterial occlusion. INTERVENTIONS: Immediate left brachial artery angiography with subsequent thrombectomy was performed. MEASUREMENTS AND MAIN RESULTS: A thrombotic occlusion at the injection side was found, which was immediately recanalized by thrombus aspiration. In addition to anticoagulation and an adenosine diphosphate-antagonist an adjunct therapy with vasodilators and gpIIb/IIIa inhibitors was given and repetitive duplex sonography confirmed arterial flow. However, despite restoration of blood flow the patient developed a severe compartment syndrome of the arm and had to receive multistep surgical interventions. CONCLUSIONS: This is the first report of an acute thrombotic vessel occlusion leading to a compartment syndrome upon accidental intra-arterial injection of amiodarone in an emergency setting. In the hemodynamically unstable patient healthcare providers should be aware of arterial miscanulation and its consequences. Upon intra-arterial injection, a direct antithrombotic and vasodilative therapy should be administered via the initially misplaced arterial access, which may include a gpIIb/IIIa inhibitor.


Assuntos
Amiodarona/administração & dosagem , Antiarrítmicos/administração & dosagem , Síndromes Compartimentais/etiologia , Infusões Intra-Arteriais/efeitos adversos , Trombose/etiologia , Artéria Braquial/diagnóstico por imagem , Feminino , Humanos , Pessoa de Meia-Idade , Taquicardia Ventricular/complicações , Taquicardia Ventricular/tratamento farmacológico , Tomografia Computadorizada por Raios X
14.
Cardiovasc Diabetol ; 14: 15, 2015 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-25645908

RESUMO

BACKGROUND: Although antiplatelet therapy involving clopidogrel is a standard treatment for preventing cardiovascular events after coronary stent implantation, patients can display differential responses. Here, we assessed the effectiveness of clopidogrel on platelet function inhibition in subjects with and without type-2 diabetes and stable coronary artery disease. In addition, we investigated the correlation between platelet function and routine clinical parameters. METHODS: A total of 64 patients with stable coronary heart disease were enrolled in the study. Among these, 32 had known type-2 diabetes, whereas the remaining 32 subjects were non-diabetics (control group). A loading dose of 300 mg clopidogrel was given to clopidogrel-naïve patients (13 patients in the diabetes group and 14 control patients). All patients were given a daily maintenance dose of 75 mg clopidogrel. In addition, all patients received 100 mg ASA per day. Agonist-induced platelet aggregation measurements were performed on hirudin-anticoagulated blood using an impedance aggregometer (Multiple Platelet Function Analyzer, Dynabyte, Munich, Germany). Blood samples were drawn from the antecubital vein 24 h after coronary angiography with percutaneous coronary intervention. The platelets were then stimulated with ADP alone or ADP and prostaglandin-E (ADP and ADP-PGE tests, respectively) in order to evaluate clopidogrel-mediated inhibition of platelet function. The effectiveness of ASA was measured by stimulation with arachidonic acid (ASPI test). In addition, maximal platelet aggregation was assessed via stimulation with thrombin receptor-activating peptide (TRAP test). RESULTS: Patients with diabetes exhibited significantly less inhibition of platelet function than patients without diabetes (ADP-PGE test p = 0.003; ASPI test p = 0.022). Administering a clopidogrel loading dose of 300 mg did not result in a lower level of ADP-PGE-induced platelet reactivity in comparison to the use of a 75 mg maintenance dose. Moreover, we observed that ADP-PGE-induced platelet inhibition was positively correlated with fasting blood glucose and HbA1c (p < 0.01). CONCLUSIONS: Patients with type-2 diabetes exhibited increased platelet reactivity compared to patients without diabetes despite combined treatment with clopidogrel and ASA. Using a loading dose of clopidogrel rather than small daily doses was not sufficient for adequately overcoming increased platelet reactivity in patients with type-2 diabetes, highlighting the need for more effective anti-platelet drugs for such patients.


Assuntos
Plaquetas/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/uso terapêutico , Ticlopidina/análogos & derivados , Idoso , Plaquetas/metabolismo , Clopidogrel , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ativação Plaquetária/fisiologia , Inibidores da Agregação de Plaquetas/farmacologia , Ticlopidina/farmacologia , Ticlopidina/uso terapêutico , Resultado do Tratamento
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