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1.
Oxid Med Cell Longev ; 2018: 1860513, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29983855

RESUMO

Pulmonary embolism (PE) results from deep vein thrombosis (DVT) and can lead to chronic thromboembolic pulmonary hypertension (CTEPH) involving vascular dysfunction. Mechanisms are incompletely understood, in part due to lack of mouse models. We induced PE in C57BL/6 mice by intravenous injection of thrombin (166 U/kg BW), confirmed by a sudden bradycardia, bradypnea, and an increase in pulmonary artery (PA) pressure observed by high-frequency ultrasound. While symptoms resolved rapidly after single thrombin application, repeated PEs resulted in sustained PA-pressure increase, increased PA superoxide formation assessed by oxidative fluorescent microtopography, increased PA gp91phox expression, and endothelial dysfunction assessed by isometric tension studies of isolated PA segments after 24 hours. DVT was modeled in C57BL/6 mice by ligation of the inferior vena cava (IVC). Importantly, small pulmonary emboli could be detected along with a mild phenotype of PA endothelial dysfunction and oxidative stress in the absence of PA-pressure elevation. mRNA expression of plasminogen activator inhibitor-1 was increased in PAs of mice with recurrent PE after repetitive thrombin injections and to a lesser extent in DVT mice. In summary, our data suggest that PA endothelial dysfunction, induced by gp91phox-derived ROS, is an early event upon repetitive PE. This phenomenon might help to elucidate the mechanisms of PA dysfunction in the pathogenesis of CTEPH.


Assuntos
Hipertensão Pulmonar/metabolismo , NADPH Oxidases/metabolismo , Embolia Pulmonar/metabolismo , Superóxidos/metabolismo , Trombose Venosa/metabolismo , Animais , Linhagem Celular , Ecocardiografia , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Veia Cava Inferior/metabolismo
2.
Cardiovasc Res ; 114(14): 1883-1893, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29982418

RESUMO

Aims: Immune cell function involves energy-dependent processes including growth, proliferation, and cytokine production. Since the AMP-activated protein kinase (AMPK) is a crucial regulator of intracellular energy homeostasis, its expression and activity may also affect innate and adaptive immune cell responses. Therefore, we aimed to investigate the consequences of α1AMPK deletion in myelomonocytic cells on vascular function, inflammation, and hypertension during chronic angiotensin II (ATII) treatment. Methods and results: We generated a mouse strain with α1AMPK deletion in lysozyme M+ myelomonocytic cells. Compared to controls, chronic ATII infusion (1 mg/kg/day for 7 days) lead to increased vascular oxidative stress and aggravated endothelial dysfunction in LysM-Cre+ x α1AMPKfl/fl mice. This was accompanied by an increased aortic infiltration of CD11b+F4/80+ macrophages and enhanced pro-inflammatory cytokine release (tumour necrosis factor-alpha, interferon-gamma, and interleukin-6). Mechanistically, we found that increased expression of C-C chemokine receptor 2 (CCR2) in α1AMPK deficient myelomonocytic cells facilitated their recruitment to the vascular wall. In addition, expression of the ATII receptor type 1a and the oxidative burst was increased in these cells, indicating an increased susceptibility towards pro-oxidant stimuli. Conclusions: In summary, α1AMPK deletion in myelomonocytic cells aggravates vascular oxidative stress and dysfunction by enhancing their recruitment to the vascular wall and increasing their susceptibility towards pro-oxidant stimuli. Our observations suggest that metabolic control in myelomonocytic cells has profound implications for their inflammatory phenotype and may trigger the development of vascular disease.


Assuntos
Proteínas Quinases Ativadas por AMP/deficiência , Aorta/enzimologia , Doenças da Aorta/enzimologia , Citocinas/metabolismo , Deleção de Genes , Mediadores da Inflamação/metabolismo , Macrófagos/enzimologia , Estresse Oxidativo , Vasodilatação , Proteínas Quinases Ativadas por AMP/genética , Angiotensina II , Animais , Aorta/fisiopatologia , Doenças da Aorta/induzido quimicamente , Doenças da Aorta/genética , Doenças da Aorta/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Predisposição Genética para Doença , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Transdução de Sinais
3.
Blood Adv ; 2(11): 1300-1314, 2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29891592

RESUMO

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in elderly people. Increased expression of tumor suppressor protein 53 (p53) has been implicated in vascular senescence. Here, we examined the importance of endothelial p53 for venous thrombosis and whether endothelial senescence and p53 overexpression are involved in the exponential increase of VTE with age. Mice with conditional, endothelial-specific deletion of p53 (End.p53-KO) and their wild-type littermates (End.p53-WT) underwent subtotal inferior vena cava (IVC) ligation to induce venous thrombosis. IVC ligation in aged (12-month-old) End.p53-WT mice resulted in higher rates of thrombus formation and greater mean thrombus size vs adult (12-week-old) End.p53-WT mice, whereas aged End.p53-KO mice were protected from vein thrombosis. Analysis of primary endothelial cells from aged mice or human vein endothelial cells after induction of replicative senescence revealed significantly increased early growth response gene-1 (Egr1) and heparanase expression, and plasma factor Xa levels were elevated in aged End.p53-WT, but not in End.p53-KO mice. Increased endothelial Egr1 and heparanase expression also was observed after doxorubicin-induced p53 overexpression, whereas p53 inhibition using pifithrin-α reduced tissue factor (TF) expression. Importantly, inhibition of heparanase activity using TF pathway inhibitor-2 (TFPI2) peptides prevented the enhanced venous thrombus formation in aged mice and restored it to the thrombotic phenotype of adult mice. Our findings suggest that p53 accumulation and heparanase overexpression in senescent endothelial cells are critically involved in mediating the increased risk of venous thrombosis with age and that heparanase antagonization may be explored as strategy to ameliorate the prothrombotic endothelial phenotype with age.


Assuntos
Envelhecimento/metabolismo , Células Endoteliais/metabolismo , Proteína Supressora de Tumor p53/biossíntese , Trombose Venosa/metabolismo , Envelhecimento/genética , Envelhecimento/patologia , Animais , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Proteína 1 de Resposta de Crescimento Precoce/genética , Células Endoteliais/patologia , Fator Xa/biossíntese , Fator Xa/genética , Glicoproteínas/genética , Glicoproteínas/metabolismo , Heparina Liase/genética , Camundongos , Camundongos Knockout , Proteína Supressora de Tumor p53/genética , Trombose Venosa/genética
4.
Sci Rep ; 8(1): 3013, 2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29445199

RESUMO

The role of leukocytes in deep vein thrombosis (DVT) resolution is incompletely understood. We determined how depletion of lysozyme positive (LysM+) cells and a switched-off type 1 immune response influences thrombus resolution. DVT was induced in 12-week-old male mice by inferior vena cava (IVC) stenosis. Toxin mediated depletion of myeloid cells improved thrombus resolution in mice with Cre-inducible expression of the diphtheria toxin receptor in LysM+ cells. This correlated with decreased CD45+ cells, a population shift of Gr-1+ to Gr-1- CD11b+ myelomonocytic cells (flow cytometry) and an increase in CC-chemokine ligand 2, interleukin-4 and interleukin-10 mRNA expressions. Tbx21-/- mice (lacking transcription factor T-bet and marked by an attenuated type 1 immune response) with DVT had faster thrombus resolution, a reduction of pro-inflammatory Ly6Chi monocytes in thrombi and decreased interleukin-12p40 mRNA expression than control mice resulting in increased vascular endothelial growth factor mRNA expression and improved neovascularization of thrombotic veins. Transfer of Tbx21-/- bone marrow into irradiated Tbx21+/+ recipients lead to accelerated thrombus resolution with lower T-bet-dependent interleukin-12p40 mRNA levels following IVC-stenosis. We conclude that inhibition of Tbet+ interleukin-12 forming myelomonocytic cells accelerated thrombus resolution. Modulating the inflammatory immune response might be an approach to improve therapy of DVT.


Assuntos
Subunidade p40 da Interleucina-12/metabolismo , Monócitos/fisiologia , Proteínas com Domínio T/metabolismo , Trombose Venosa/imunologia , Animais , Antígenos Ly/metabolismo , Toxina Diftérica/genética , Modelos Animais de Doenças , Humanos , Subunidade p40 da Interleucina-12/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neovascularização Fisiológica , Proteínas com Domínio T/genética , Quimeras de Transplante , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Veia Cava Inferior/cirurgia
5.
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
6.
Circ Res ; 119(12): 1286-1295, 2016 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-27707800

RESUMO

RATIONALE: Immune cells play an important role during the generation and resolution of thrombosis. T cells are powerful regulators of immune and nonimmune cell function, however, their role in sterile inflammation in venous thrombosis has not been systematically examined. OBJECTIVE: This study investigated the recruitment, activation, and inflammatory activity of T cells in deep vein thrombosis and its consequences for venous thrombus resolution. METHODS AND RESULTS: CD4+ and CD8+ T cells infiltrate the thrombus and vein wall rapidly on deep vein thrombosis induction and remain in the tissue throughout the thrombus resolution. In the vein wall, recruited T cells largely consist of effector-memory T (TEM) cells. Using T-cell receptor transgenic reporter mice, we demonstrate that deep vein thrombosis-recruited TEM receive an immediate antigen-independent activation and produce IFN-γ (interferon) in situ. Mapping inflammatory conditions in the thrombotic vein, we identify a set of deep vein thrombosis upregulated cytokines and chemokines that synergize to induce antigen-independent IFN-γ production in CD4+ and CD8+ TEM cells. Reducing the number of TEM cells through a depletion recovery procedure, we show that intravenous TEM activation determines neutrophil and monocyte recruitment and delays thrombus neovascularization and resolution. Examining T-cell recruitment in human venous stasis, we show that superficial varicose veins preferentially contain activated memory T cells. CONCLUSIONS: TEM orchestrate the inflammatory response in venous thrombosis affecting thrombus resolution.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Imunidade Inata/fisiologia , Varizes/metabolismo , Trombose Venosa/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Trombose/imunologia , Trombose/metabolismo , Varizes/imunologia , Trombose Venosa/imunologia
7.
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
8.
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
9.
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
10.
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 , Biopterinas/análogos & derivados , Biopterinas/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
11.
Clin Hemorheol Microcirc ; 56(2): 145-52, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23403491

RESUMO

BACKGROUND: Interaction between vascular wall abnormalities, inflammatory leukocytes, platelets, coagulation factors and hemorheology in the pathogenesis of deep vein thrombosis (DVT) is incompletely understood, requiring well defined animal models of human disease. METHODS AND RESULTS: We subjected male C57BL/6 mice to ligation of the inferior vena cava (IVC) as a flow reduction model to induce DVT. Thrombus size and weight were analyzed macroscopically and sonographically by B-mode, pulse wave (pw) Doppler and power Doppler imaging (PDI) using high frequency ultrasound. Thrombus size varied substantially between individual procedures and mice, irrespective of the flow reduction achieved by the ligature. Interestingly, PDI accurately predicted thrombus size in a very robust fashion (r2 = 0.9734, p < 0.0001). Distance of the insertion of side branches from the ligature significantly determines thrombus weight (r2 = 0.5597, p < 0.0001) and length (r2 = 0.5441, p < 0.0001) in the IVC, regardless of the flow measured by pw-Doppler with distances <1.5 mm drastically impairing thrombus formation. Occlusion of side branches prior to ligation of IVC did not increase thrombus size, probably due to patent side branches inaccessible to surgery. CONCLUSION: Venous side branches influence thrombus size in experimental DVT and might therefore prevent thrombus formation. This renders vessel anatomy and hemorheology important determinants in mouse models of DVT, which should be controlled for.


Assuntos
Veia Cava Inferior/fisiopatologia , Trombose Venosa/fisiopatologia , Animais , Velocidade do Fluxo Sanguíneo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Veia Cava Inferior/patologia , Trombose Venosa/patologia
12.
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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