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2.
BMJ Open ; 9(7): e029509, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31272982

RESUMO

BACKGROUND: A number of devices have been developed to minimise operator radiation exposure in the setting of cardiac catheterisation. The effectiveness of these devices has traditionally been explored in transfemoral coronary procedures; however, less is known for the transradial approach. We set out to examine the impact of three different radiation protection devices in a real-world setting. METHODS AND DESIGN: Consecutive coronary diagnostic and intervention procedures are randomised in a 1:1:1 ratio to a shield-only protection (shield group), shield and overlapping 0.5 mm Pb panel curtain (curtain group) or shield, curtain and additional 75×40 cm, 0.5 mm Pb drape placed across the waist of the patient (drape group).The primary outcome is the difference in relative exposure of the primary operator among groups. Relative exposure is defined as the ratio between operator's exposure (E in µSv) and patient exposure (dose area product in cGy·cm2). ETHICS AND DISSEMINATION: The protocol complies with good clinical practice and the ethical principles described in the Declaration of Helsinki and is approved by the local ethics committee. The results of the trial will be published as original article(s) in medical journals and/or as presentation at congresses. TRIAL REGISTRATION NUMBER: NCT03634657.

3.
J Am Heart Assoc ; 8(15): e010881, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31311438

RESUMO

Background Clinical characteristics and outcomes of takotsubo syndrome (TTS) patients with malignancy have not been fully elucidated. This study sought to explore differences in clinical characteristics and to investigate short- and long-term outcomes in TTS patients with or without malignancy. Methods and Results TTS patients were enrolled from the International Takotsubo Registry. The TTS cohort was divided into patients with and without malignancy to investigate differences in clinical characteristics and to assess short- and long-term mortality. A subanalysis was performed comparing long-term mortality between a subset of TTS patients with or without malignancy and acute coronary syndrome (ACS) patients with or without malignancy. Malignancy was observed in 16.6% of 1604 TTS patients. Patients with malignancy were older and more likely to have physical triggers, but less likely to have emotional triggers compared with those without malignancy. Long-term mortality was higher in patients with malignancy (P<0.001), while short-term outcome was comparable (P=0.17). In a subanalysis, long-term mortality was comparable between TTS patients with malignancies and ACS patients with malignancies (P=0.13). Malignancy emerged as an independent predictor of long-term mortality. Conclusions A substantial number of TTS patients show an association with malignancy. History of malignancy might increase the risk for TTS, and therefore, appropriate screening for malignancy should be considered in these patients. Clinical Trial Registration URL: http://www.clinicaltrial.gov. Unique identifier: NCT01947621.

4.
Eur Heart J ; 40(26): 2142-2151, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31098611

RESUMO

AIMS: We aimed to evaluate the frequency, clinical features, and prognostic implications of cardiac arrest (CA) in takotsubo syndrome (TTS). METHODS AND RESULTS: We reviewed the records of patients with CA and known heart rhythm from the International Takotsubo Registry. The main outcomes were 60-day and 5-year mortality. In addition, predictors of mortality and predictors of CA during the acute TTS phase were assessed. Of 2098 patients, 103 patients with CA and known heart rhythm during CA were included. Compared with patients without CA, CA patients were more likely to be younger, male, and have apical TTS, atrial fibrillation (AF), neurologic comorbidities, physical triggers, and longer corrected QT-interval and lower left ventricular ejection fraction on admission. In all, 57.1% of patients with CA at admission had ventricular fibrillation/tachycardia, while 73.7% of patients with CA in the acute phase had asystole/pulseless electrical activity. Patients with CA showed higher 60-day (40.3% vs. 4.0%, P < 0.001) and 5-year mortality (68.9% vs. 16.7%, P < 0.001) than patients without CA. T-wave inversion and intracranial haemorrhage were independently associated with higher 60-day mortality after CA, whereas female gender was associated with lower 60-day mortality. In the acute phase, CA occurred less frequently in females and more frequently in patients with AF, ST-segment elevation, and higher C-reactive protein on admission. CONCLUSIONS: Cardiac arrest is relatively frequent in TTS and is associated with higher short- and long-term mortality. Clinical and electrocardiographic parameters independently predicted mortality after CA.

5.
Cardiovasc Res ; 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30949687

RESUMO

AIMS: Myelomonocytic cells are critical in injury and healing post myocardial infarction (MI). Mechanisms of regulation, however, are incompletely understood. The aim of the study was to elucidate the role of interferon gamma (IFN-γ) in the orchestrated inflammatory response in a murine model of MI. METHODS AND RESULTS: MI was induced in 8 to 12 week-old male mice (C57BL/6 background) by permanent ligation of the left anterior descending coronary artery (LAD). Lysozyme M (LysM)+ cell depleted LysMiDTR transgenic mice displayed a reduced influx of CD45.2+/CD3-/CD11b+/Gr-1high neutrophils into infarcted myocardium 1d post MI compared to infarcted controls, paralleled by decreased cardiac mRNA levels of IFN-γ and tumor necrosis factor alpha (TNF-α). Mortality after MI was significantly increased in LysM+ cell-depleted mice within 28d post MI. To more specifically address the role of neutrophils, we depleted C57BL/6 mice with a monoclonal anti-Gr-1 antibody and found increased mortality, deteriorated cardiac function as well as decreased cardiac IFN-γ mRNA expression early after MI. Ccl2, Cxcl1, Cx3cl1 and Il12b mRNA were reduced 3d after MI, as was the amount of CD11b+/Ly6G-/Ly6Chigh inflammatory monocytes. LAD-ligated Cramp-/- mice lacking cathelicidin important in neutrophil-dependent monocyte chemotaxis as well as IFNγ-/- and TNFα-/- mice phenocopied Gr-1+ cell-depleted mice, supporting a regulatory role of IFN-γ impacting on both the sequence of inflammatory cell invasion and cardiac outcome early after MI. The use of conditional IFN-γ receptor deficient mice indicated a direct effect of IFN-γ on LysM+ cells in cardiac injury post MI. Using IFN-γ reporter mice and flow cytometry, we identified cardiac lymphoid cells (CD4+ and CD8+ T cells and natural killer cells) as primary source of this cytokine in the cardiac inflammatory response post MI. CONCLUSIONS: IFN-γ directs a sequential chemotactic cellular immune response and determines survival and cardiac function post MI.

7.
Biol Open ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30498015

RESUMO

The prototypic protein disulphide isomerase (PDI), encoded by the P4HB gene, has been described as a survival factor in ischemic cardiomyopathy. However, the role of protein disulfide isomerase associated 6 (PDIA6) under hypoxic conditions in the myocardium remains enigmatic and it is unknown whether the gut microbiota influences the expression of PDI and PDIA6 under conditions of acute myocardial infarction. Here, we revealed that in addition to the prototypic PDI, the PDI family member (PDIA6), a regulator of the unfolded protein response, is upregulated in the mouse cardiomyocyte cell line HL-1 when cultured under hypoxia. In vivo, in the left anterior artery descending (LAD) ligation mouse model of acute myocardial infarction, similar to PDI, PDIA6 protein expression was enhanced in the infarcted area (LAD+) relative to uninfarcted sham-tissue or the neighbouring area at risk (LAD-) of C57BL/6J mice. Interestingly, we found that ex-germ-free (ex-GF) mice subjected to the LAD ligation model for 24 hours had a reduced ejection fraction compared with their conventionally-raised (CONV-R) SPF controls. Furthermore, the LAD+ area in the infarcted heart of ex-GF mice showed reduced PDIA6 expression relative to CONV-R controls, suggesting that the presence of a gut microbiota enhanced LAD ligation-triggered PDIA6 expression. Collectively, our results demonstrate that PDIA6 is upregulated in cardiomyocytes as a consequence of hypoxia. In the LAD mouse model, PDIA6 was also increased in the infarcted area underin vivo conditions, but this increase was suppressed in ex-GF mice relative to CONV-R controls.

8.
J Am Coll Cardiol ; 72(8): 874-882, 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30115226

RESUMO

BACKGROUND: Prognosis of Takotsubo syndrome (TTS) remains controversial due to scarcity of available data. Additionally, the effect of the triggering factors remains elusive. OBJECTIVES: This study compared prognosis between TTS and acute coronary syndrome (ACS) patients and investigated short- and long-term outcomes in TTS based on different triggers. METHODS: Patients with TTS were enrolled from the International Takotsubo Registry. Long-term mortality of patients with TTS was compared to an age- and sex-matched cohort of patients with ACS. In addition, short- and long-term outcomes were compared between different groups according to triggering conditions. RESULTS: Overall, TTS patients had a comparable long-term mortality risk with ACS patients. Of 1,613 TTS patients, an emotional trigger was detected in 485 patients (30%). Of 630 patients (39%) related to physical triggers, 98 patients (6%) had acute neurologic disorders, while in the other 532 patients (33%), physical activities, medical conditions, or procedures were the triggering conditions. The remaining 498 patients (31%) had no identifiable trigger. TTS patients related to physical stress showed higher mortality rates than ACS patients during long-term follow-up, whereas patients related to emotional stress had better outcomes compared with ACS patients. CONCLUSIONS: Overall, TTS patients had long-term outcomes comparable to age- and sex-matched ACS patients. Also, we demonstrated that TTS can either be benign or a life-threating condition depending on the inciting stress factor. We propose a new classification based on triggers, which can serve as a clinical tool to predict short- and long-term outcomes of TTS. (International Takotsubo Registry [InterTAK Registry]; NCT01947621).

9.
Pharmacology ; 101(1-2): 54-63, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28988245

RESUMO

BACKGROUND/AIMS: 2-aminoethyl nitrate (CLC-1011) is a member of the class of organic nitrates that cause vasodilation by the generation of nitric oxide (•NO). These drugs are mainly used for the treatment of angina pectoris and ischemic heart disease. The aim of this study was to characterize the vasodilatory potency of this organic nitrate alone and in combination with clinically established cardiovascular drugs. METHODS: Vasodilation by CLC-1011 was tested by isometric tension studies, either alone or combined with cilostazol, valsartan, and metoprolol. Induction of oxidative stress in isolated heart mitochondria was measured by enhanced chemiluminescence. Bioactivation of CLC-1011 in aortic tissue was measured by electron paramagnetic resonance spectroscopy using an iron-based spin trap for •NO. RESULTS: We observed potent vasodilation by CLC-1011 and additive effects for all three drug combinations. In contrast to nitroglycerin (GTN), CLC-1011 did not stimulate mitochondrial oxidative stress. CLC-1011 was bioactivated to •NO in aortic tissue. CONCLUSION: In summary, the experiments described in this report demonstrate that CLC-1011 does not induce oxidative stress, is a more potent vasodilator than isosorbide-5-mononitrate and dinitrate ISDN, and displays synergistic vasodilation with other cardiovascular drugs. CLC-1011 fixed dose combinations could be used in the management of cardiovascular diseases.


Assuntos
Aorta/efeitos dos fármacos , Metoprolol/farmacologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Nitratos/farmacologia , Tetrazóis/farmacologia , Valsartana/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta/fisiologia , Cilostazol , Combinação de Medicamentos , Sinergismo Farmacológico , Masculino , Mitocôndrias Cardíacas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar
10.
Sci Transl Med ; 9(375)2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28148841

RESUMO

Multicellular interactions of platelets, leukocytes, and the blood vessel wall support coagulation and precipitate arterial and venous thrombosis. High levels of angiotensin II cause arterial hypertension by a complex vascular inflammatory pathway that requires leukocyte recruitment and reactive oxygen species production and is followed by vascular dysfunction. We delineate a previously undescribed, proinflammatory coagulation-vascular circuit that is a major regulator of vascular tone, blood pressure, and endothelial function. In mice with angiotensin II-induced hypertension, tissue factor was up-regulated, as was thrombin-dependent endothelial cell vascular cellular adhesion molecule 1 expression and integrin αMß2- and platelet-dependent leukocyte adhesion to arterial vessels. The resulting vascular inflammation and dysfunction was mediated by activation of thrombin-driven factor XI (FXI) feedback, independent of factor XII. The FXI receptor glycoprotein Ibα on platelets was required for this thrombin feedback activation in angiotensin II-infused mice. Inhibition of FXI synthesis with an antisense oligonucleotide was sufficient to prevent thrombin propagation on platelets, vascular leukocyte infiltration, angiotensin II-induced endothelial dysfunction, and arterial hypertension in mice and rats. Antisense oligonucleotide against FXI also reduced the increased blood pressure and attenuated vascular and kidney dysfunction in rats with established arterial hypertension. Further, platelet-localized thrombin generation was amplified in an FXI-dependent manner in patients with uncontrolled arterial hypertension, suggesting that platelet-localized thrombin generation may serve as an inflammatory marker of high blood pressure. Our results outline a coagulation-inflammation circuit that promotes vascular dysfunction, and highlight the possible utility of FXI-targeted anticoagulants in treating hypertension, beyond their application as antithrombotic agents in cardiovascular disease.


Assuntos
Coagulação Sanguínea , Plaquetas/citologia , Fator XI/fisiologia , Hipertensão/fisiopatologia , Trombina/fisiologia , Idoso , Angiotensina II , Animais , Pressão Sanguínea , Fator XI/antagonistas & inibidores , Feminino , Humanos , Hipertensão/induzido quimicamente , Antígeno de Macrófago 1/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Oligonucleotídeos Antissenso/farmacologia , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Ratos Wistar , Tromboplastina/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
11.
J Am Heart Assoc ; 5(9)2016 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-27577581

RESUMO

BACKGROUND: The gut microbiome is essential for physiological host responses and development of immune functions. The impact of gut microbiota on blood pressure and systemic vascular function, processes that are determined by immune cell function, is unknown. METHODS AND RESULTS: Unchallenged germ-free mice (GF) had a dampened systemic T helper cell type 1 skewing compared to conventionally raised (CONV-R) mice. Colonization of GF mice with regular gut microbiota induced lymphoid mRNA transcription of T-box expression in T cells and resulted in mild endothelial dysfunction. Compared to CONV-R mice, angiotensin II (AngII; 1 mg/kg per day for 7 days) infused GF mice showed reduced reactive oxygen species formation in the vasculature, attenuated vascular mRNA expression of monocyte chemoattractant protein 1 (MCP-1), inducible nitric oxide synthase (iNOS) and NADPH oxidase subunit Nox2, as well as a reduced upregulation of retinoic-acid receptor-related orphan receptor gamma t (Rorγt), the signature transcription factor for interleukin (IL)-17 synthesis. This resulted in an attenuated vascular leukocyte adhesion, less infiltration of Ly6G(+) neutrophils and Ly6C(+) monocytes into the aortic vessel wall, protection from kidney inflammation, as well as endothelial dysfunction and attenuation of blood pressure increase in response to AngII. Importantly, cardiac inflammation, fibrosis and systolic dysfunction were attenuated in GF mice, indicating systemic protection from cardiovascular inflammatory stress induced by AngII. CONCLUSION: Gut microbiota facilitate AngII-induced vascular dysfunction and hypertension, at least in part, by supporting an MCP-1/IL-17 driven vascular immune cell infiltration and inflammation.


Assuntos
Angiotensina II/farmacologia , Pressão Arterial/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Vida Livre de Germes , Leucócitos/efeitos dos fármacos , RNA Mensageiro/efeitos dos fármacos , Animais , Aorta/citologia , Aorta/efeitos dos fármacos , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Quimiocina CCL2/efeitos dos fármacos , Quimiocina CCL2/genética , Endotélio Vascular/efeitos dos fármacos , Hipertensão/microbiologia , Camundongos , Monócitos , NADPH Oxidase 2/efeitos dos fármacos , NADPH Oxidase 2/genética , Infiltração de Neutrófilos/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/efeitos dos fármacos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo
12.
Sci Rep ; 6: 32554, 2016 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-27624556

RESUMO

Alcoholic cardiomyopathy (ACM) resulting from excess alcohol consumption is an important cause of heart failure (HF). Although it is assumed that the cardiotoxicity of the ethanol (EtOH)-metabolite acetaldehyde (ACA) is central for its development and progression, the exact mechanisms remain obscure. Murine cardiomyocytes (CMs) exposed to ACA or EtOH showed increased superoxide (O2(•-)) levels and decreased mitochondrial polarization, both being normalized by NADPH oxidase (NOX) inhibition. C57BL/6 mice and mice deficient for the ACA-degrading enzyme mitochondrial aldehyde dehydrogenase (ALDH-2(-/-)) were fed a 2% EtOH diet for 5 weeks creating an ACA-overload. 2% EtOH-fed ALDH-2(-/-) mice exhibited a decreased cardiac function, increased heart-to-body and lung-to-body weight ratios, increased cardiac levels of the lipid peroxidation product malondialdehyde (MDA) as well as increased NOX activity and NOX2/glycoprotein 91(phox) (NOX2/gp91(phox)) subunit expression compared to 2% EtOH-fed C57BL/6 mice. Echocardiography revealed that ALDH-2(-/-)/gp91(phox-/-) mice were protected from ACA-overload-induced HF after 5 weeks of 2% EtOH-diet, demonstrating that NOX2-derived O2(•-) contributes to the development of ACM. Translated to human pathophysiology, we found increased gp91(phox) expression in endomyocardial biopsies of ACM patients. In conclusion, ACM is promoted by ACA-driven mitochondrial dysfunction and can be improved by ablation of NOX2/gp91(phox). NOX2/gp91(phox) therefore might be a potential pharmacological target to treat ACM.


Assuntos
Cardiomiopatia Alcoólica/genética , Insuficiência Cardíaca/genética , NADPH Oxidase 2/genética , Acetaldeído/toxicidade , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Cardiomiopatia Alcoólica/patologia , Modelos Animais de Doenças , Etanol/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/patologia , Humanos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismo
14.
Eur Heart J ; 36(48): 3437-46, 2015 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-26516175

RESUMO

AIMS: Heme oxygenase-1 (HO-1) confers protection to the vasculature and suppresses inflammatory properties of monocytes and macrophages. It is unclear how HO-1 determines the extent of vascular dysfunction in mice and humans. METHODS AND RESULTS: Decreased HO-1 activity and expression was paralleled by increased aortic expression and activity of the nicotinamide dinucleotide phosphate oxidase Nox2 in HO-1 deficient Hmox1⁻/⁻ and Hmox1(⁺/⁻) compared with Hmox1⁺/⁺ mice. When subjected to angiotensin II-infusion, streptozotocin-induced diabetes mellitus and aging, HO-1 deficient mice showed increased vascular dysfunction inversely correlated with HO activity. In a primary prevention population-based cohort, we assessed length polymorphisms of the HMOX1 promoter region and established a bipolar frequency pattern of allele length (long vs. short repeats) in 4937 individuals. Monocytic HMOX1 mRNA expression was positively correlated with flow-mediated dilation and inversely with CD14 mRNA expression indicating pro-inflammatory monocytes in 733 hypertensive individuals of this cohort. Hmox1⁻/⁻ mice showed drastically increased expression of the chemokine receptor CCR2 in monocytes and the aorta. Angiotensin II-infused Hmox1⁻/⁻ mice had amplified endothelial inflammation in vivo, significantly increased aortic infiltration of pro-inflammatory CD11b⁺ Ly6C(hi) monocytes and Ly6G⁺ neutrophils and were marked by Ly6C(hi) monocytosis in the circulation and an increased blood pressure response. Finally, individuals with unfavourable HMOX1 gene promoter length had increased prevalence of arterial hypertension and reduced cumulative survival after a median follow-up of 7.23 years. CONCLUSIONS: Heme oxygenase-1 is a regulator of vascular function in hypertension via determining the phenotype of inflammatory circulating and infiltrating monocytes with possible implications for all-cause mortality.


Assuntos
Endotélio Vascular/fisiopatologia , Heme Oxigenase-1/fisiologia , Hipertensão/fisiopatologia , Animais , Estudos Transversais , Feminino , Heme Oxigenase-1/deficiência , Heme Oxigenase-1/genética , Humanos , Hipertensão/mortalidade , Masculino , Camundongos , Monócitos/fisiologia , Neutrófilos/fisiologia , Estresse Oxidativo/fisiologia , Fenótipo , Polimorfismo Genético , RNA Mensageiro/metabolismo
15.
J Am Coll Cardiol ; 66(2): 154-65, 2015 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-26160631

RESUMO

BACKGROUND: Heme oxygenase-1 (HO-1) is an inducible stress-responsive enzyme converting heme to bilirubin, carbon monoxide, and free iron, which exerts anti-inflammatory and antiapoptotic effects. Although efficient cardioprotection after HO-1 overexpression has been reported in rodents, its role in attenuating post-ischemic inflammation is unclear. OBJECTIVES: This study assessed the efficacy of recombinant adenoassociated virus (rAAV)-encoding human heme oxygenase-1 (hHO-1) in attenuating post-ischemic inflammation in a murine and a porcine ischemia/reperfusion model. METHODS: Murine ischemia was induced by 45 min of left anterior descending occlusion, followed by 24 h of reperfusion and functional as well as fluorescent-activated cell sorting analysis. Porcine hearts were subjected to 60 min of ischemia and 24h of reperfusion before hemodynamic and histologic analyses were performed. RESULTS: Human microvascular endothelial cells transfected with hHO-1 displayed an attenuated interleukin-6 and intercellular adhesion molecule 1 expression, resulting in reduced monocytic THP-1 cell recruitment in vitro. In murine left anterior descending occlusion and reperfusion, the post-ischemic influx of CD45(+) leukocytes, Ly-6G(+) neutrophils, and Ly-6C(high) monocytes was further exacerbated in HO-1-deficient hearts and reversed by rAAV.hHO-1 treatment. Conversely, in our porcine model of ischemia, the post-ischemic influx of myeloperoxidase-positive neutrophils and CD14(+) monocytes was reduced by 49% and 87% after rAAV.hHO-1 transduction, similar to hHO-1 transgenic pigs. Functionally, rAAV.hHO-1 and hHO-1 transgenic left ventricles displayed a smaller loss of ejection fraction than control animals. CONCLUSIONS: Whereas HO-1 deficiency exacerbates post-ischemic cardiac inflammation in mice, hHO-1 gene therapy attenuates inflammation after ischemia and reperfusion in murine and porcine hearts. Regional hHO-1 gene therapy provides cardioprotection in a pre-clinical porcine ischemia/reperfusion model.


Assuntos
Terapia Genética/métodos , Heme Oxigenase-1/genética , Inflamação/prevenção & controle , Isquemia Miocárdica/complicações , Animais , Dependovirus , Modelos Animais de Doenças , Vetores Genéticos , Camundongos , Traumatismo por Reperfusão , Suínos
16.
Arterioscler Thromb Vasc Biol ; 34(12): 2658-68, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25341795

RESUMO

OBJECTIVE: Interleukin (IL)-17A is regarded as an important cytokine to drive psoriasis, an inflammatory skin disease marked by increased cardiovascular mortality. We aimed to test the hypothesis that overproduction of IL-17A in the skin leading to dermal inflammation may systemically cause vascular dysfunction in psoriasis-like skin disease. APPROACH AND RESULTS: Conditional overexpression of IL-17A in keratinocytes caused severe psoriasis-like skin inflammation in mice (K14-IL-17A(ind/+) mice), associated with increased reactive oxygen species formation and circulating CD11b(+) inflammatory leukocytes in blood, with endothelial dysfunction, increased systolic blood pressure, left ventricular hypertrophy, and reduced survival compared with controls. In K14-IL-17A(ind/+) mice, immunohistochemistry and flow cytometry revealed increased vascular production of the nitric oxide/superoxide reaction product peroxynitrite and infiltration of the vasculature with myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) cells accompanied by increased expression of the inducible nitric oxide synthase and the nicotinamide dinucleotide phosphate (NADPH) oxidase, nox2. Neutrophil depletion by anti-GR-1 antibody injections reduced oxidative stress in blood and vessels. Neutralization of tumor necrosis factor-α and IL-6 (both downstream of IL-17A) reduced skin lesions, attenuated oxidative stress in heart and blood, and partially improved endothelial dysfunction in K14-IL-17A(ind/+) mice. CONCLUSIONS: Dermal overexpression of IL-17A induces systemic endothelial dysfunction, vascular oxidative stress, arterial hypertension, and increases mortality mainly driven by myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) inflammatory cells. Depletion of the GR-1(+) immune cells or neutralization of IL-17A downstream cytokines by biologicals attenuates the vascular phenotype in K14-IL-17A(ind/+) mice.


Assuntos
Interleucina-17/fisiologia , Psoríase/etiologia , Psoríase/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Aorta/patologia , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Endotélio Vascular/imunologia , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Hipertensão/etiologia , Hipertensão/imunologia , Hipertensão/fisiopatologia , Interleucina-17/genética , Interleucina-6/antagonistas & inibidores , Interleucina-6/fisiologia , Queratinócitos/imunologia , Queratinócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Miócitos Cardíacos/patologia , Neutrófilos/patologia , Neutrófilos/fisiologia , Óxido Nítrico/metabolismo , Psoríase/complicações , Espécies Reativas de Oxigênio/metabolismo , Fatores de Risco , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/fisiologia , Regulação para Cima , Vasculite/etiologia , Vasculite/imunologia , Vasculite/fisiopatologia
17.
Front Physiol ; 5: 295, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25177297

RESUMO

Inflammatory monocytes and macrophages have been identified as key players in the pathogenesis of atherosclerosis, arterial hypertension, and myocardial infarction (MI). They become powerful mediators of vascular inflammation through their capacity to secrete and induce the production of proinflammatory cytokines, chemokines and adhesion molecules and through the production of reactive oxygen species mainly via their NADPH oxidase. Importantly, a crosstalk exists between NK cells and monocytes that works via a feedforwad amplification loop of T-bet/Interferon-gamma/interleukin-12 signaling, that causes mutual activation of both NK cells and monocytes and that fosters recruitment of inflammatory cells to sites of inflammation. Recently, we have discovered that this crosstalk is crucial for the unrestricted development of angiotensin II (ATII) induced vascular injury in arterial hypertension, the most important risk factor for atherosclerosis and cardiovascular disease worldwide. In this review, we will also discuss possible implications of this interplay between NK cells and monocytes for the pathogenesis of coronary atherosclerosis and myocardial infarction and potential therapeutic options.

18.
J Biol Chem ; 289(40): 27540-50, 2014 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-25143378

RESUMO

Endothelial nitric-oxide synthase (eNOS) uncoupling and increased inducible NOS (iNOS) activity amplify vascular oxidative stress. The role of inflammatory myelomonocytic cells as mediators of these processes and their impact on tetrahydrobiopterin availability and function have not yet been defined. Angiotensin II (ATII, 1 mg/kg/day for 7 days) increased Ly6C(high) and CD11b(+)/iNOS(high) leukocytes and up-regulated levels of eNOS glutathionylation in aortas of C57BL/6 mice. Vascular iNOS-dependent NO formation was increased, whereas eNOS-dependent NO formation was decreased in aortas of ATII-infused mice as assessed by electron paramagnetic resonance (EPR) spectroscopy. Diphtheria toxin-mediated ablation of lysozyme M-positive (LysM(+)) monocytes in ATII-infused LysM(iDTR) transgenic mice prevented eNOS glutathionylation and eNOS-derived N(ω)-nitro-L-arginine methyl ester-sensitive superoxide formation in the endothelial layer. ATII increased vascular guanosine triphosphate cyclohydrolase I expression and biopterin synthesis in parallel, which was reduced in monocyte-depleted LysM(iDTR) mice. Vascular tetrahydrobiopterin was increased by ATII infusion but was even higher in monocyte-depleted ATII-infused mice, which was paralleled by a strong up-regulation of dihydrofolate reductase expression. EPR spectroscopy revealed that both vascular iNOS- and eNOS-dependent NO formation were normalized in ATII-infused mice following monocyte depletion. Additionally, deletion as well as pharmacologic inhibition of iNOS prevented ATII-induced endothelial dysfunction. In summary, ATII induces an inflammatory cell-dependent increase of iNOS, guanosine triphosphate cyclohydrolase I, tetrahydrobiopterin, NO formation, and nitro-oxidative stress as well as eNOS uncoupling in the vessel wall, which can be prevented by ablation of LysM(+) monocytes.


Assuntos
Angiotensina II/imunologia , Monócitos/enzimologia , Óxido Nítrico Sintase Tipo III/imunologia , Estresse Oxidativo , Angiotensina II/genética , Animais , Biopterina/análogos & derivados , Biopterina/imunologia , Endotélio Vascular/enzimologia , Endotélio Vascular/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Óxido Nítrico/imunologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Óxido Nítrico Sintase Tipo III/genética
19.
Pharmacology ; 93(5-6): 203-15, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24923291

RESUMO

BACKGROUND/AIMS: Organic nitrates represent a group of nitrovasodilators that are clinically used for the treatment of ischemic heart disease. The new compound CLC-3000 is an aminoethyl nitrate (AEN) derivative of pioglitazone, a thiazolidinedione antidiabetic agent combining the peroxisome proliferator-activated receptor γ agonist activity of pioglitazone with the NO-donating activity of the nitrate moiety. METHODS: In vitro and in vivo characterization was performed by isometric tension recording, platelet function, bleeding time and detection of oxidative stress. RESULTS: In vitro, CLC-3000 displayed more potent vasodilation than pioglitazone alone or classical nitrates. In vitro, some effects on oxidative stress parameters were observed. Authentic AEN or the AEN-containing linker CLC-1275 displayed antiaggregatory effects. In vivo treatment with CLC-3000 for 7 days did neither induce endothelial dysfunction nor nitrate tolerance nor oxidative stress. Acute or chronic administration of AEN increased the tail vein bleeding time in mice. CONCLUSION: In summary, the results of these studies demonstrate that CLC-3000 contains a vasodilative and antithrombotic activity that is not evident with pioglitazone alone, and that 7 days of exposure in vivo showed no typical signs of nitrate tolerance, endothelial dysfunction or other safety concerns in Wistar rats.


Assuntos
Fibrinolíticos/farmacologia , Nitratos/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Tempo de Sangramento , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Humanos , Hipoglicemiantes/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Pioglitazona , Agregação Plaquetária/efeitos dos fármacos , Ratos Wistar , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tiazolidinedionas/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
20.
Arterioscler Thromb Vasc Biol ; 33(6): 1313-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23520167

RESUMO

OBJECTIVE: Immune cells contribute to angiotensin II (ATII)-induced vascular dysfunction and inflammation. Interferon-γ (IFN-γ), an inflammatory cytokine exclusively produced by immune cells, seems to be involved in ATII-driven cardiovascular injury, but the actions and cellular source of IFN-γ remain incompletely understood. APPROACH AND RESULTS: IFN-γ(-/-) and Tbx21(-/-) mice were partially protected from ATII-induced (1 mg/kg per day of ATII, infused subcutaneously by miniosmotic pumps) vascular endothelial and smooth muscle dysfunction, whereas mice overexpressing IFN-γ showed constitutive vascular dysfunction. Absence of T-box expressed in T cells (T-bet), the IFN-γ transcription factor encoded by Tbx21, reduced vascular superoxide and peroxynitrite formation and attenuated expression of nicotinamide adenosine dinucleotide phosphate oxidase subunits as well as inducible NO synthase, monocyte chemoattractant protein 1, and interleukin-12 in aortas of ATII-infused mice. Compared with controls, IFN-γ(-/-) and Tbx21(-/-) mice were characterized by reduced ATII-mediated vascular recruitment of both natural killer (NK)1.1(+) NK-cells as the major producers of IFN-γ and CD11b(+)Gr-1(low) interleukin-12 secreting monocytes. Selective depletion and adoptive transfer experiments identified NK-cells as essential contributors to vascular dysfunction and showed that T-bet(+)lysozyme M(+) myelomonocytic cells were required for NK-cell recruitment into vascular tissue and local IFN-γ production. CONCLUSIONS: We provide first evidence that NK-cells play an essential role in ATII-induced vascular dysfunction. In addition, we disclose the T-bet-IFN-γ pathway and mutual monocyte-NK-cell activation as potential therapeutic targets in cardiovascular disease.


Assuntos
Angiotensina II/farmacologia , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Monócitos/metabolismo , Doenças Vasculares/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Interferon gama/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Estresse Oxidativo/imunologia , Estresse Oxidativo/fisiologia , Distribuição Aleatória , Valores de Referência , Doenças Vasculares/imunologia
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