RESUMO
OBJECTIVE: In atherosclerosis, Toll-like receptors (TLRs) are traditionally linked to effects on tissue macrophages or foam cells. RP105, a structural TLR4 homolog, is an important regulator of TLR signaling. The effects of RP105 on TLR signaling vary for different leukocyte subsets known to be involved in atherosclerosis, making it unique in its role of either suppressing (in myeloid cells) or enhancing (in B cells) TLR-regulated inflammation in different cell types. We aimed to identify a role of TLR accessory molecule RP105 on circulating cells in atherosclerotic plaque formation. APPROACH AND RESULTS: Irradiated low density lipoprotein receptor deficient mice received RP105(-/-) or wild-type bone marrow. RP105(-/-) chimeras displayed a 57% reduced plaque burden. Interestingly, total and activated B-cell numbers were significantly reduced in RP105(-/-) chimeras. Activation of B1 B cells was unaltered, suggesting that RP105 deficiency only affected inflammatory B2 B cells. IgM levels were unaltered, but anti-oxidized low-density lipoprotein and anti-malondialdehyde-modified low-density lipoprotein IgG2c antibody levels were significantly lower in RP105(-/-) chimeras, confirming effects on B2 B cells rather than B1 B cells. Moreover, B-cell activating factor expression was reduced in spleens of RP105(-/-) chimeras. CONCLUSIONS: RP105 deficiency on circulating cells results in an intriguing unexpected TLR-associated mechanisms that decrease atherosclerotic lesion formation with alterations on proinflammatory B2 B cells.
Assuntos
Antígenos CD/metabolismo , Aorta/imunologia , Doenças da Aorta/imunologia , Aterosclerose/imunologia , Subpopulações de Linfócitos B/imunologia , Inflamação/imunologia , Ativação Linfocitária , Baço/imunologia , Animais , Antígenos CD/genética , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Fator Ativador de Células B/metabolismo , Subpopulações de Linfócitos B/metabolismo , Transplante de Medula Óssea , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Inflamação/sangue , Inflamação/genética , Inflamação/patologia , Lipoproteínas LDL/imunologia , Masculino , Malondialdeído/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica , Quimera por Radiação , Receptores de LDL/genética , Receptores de LDL/metabolismo , Baço/metabolismoRESUMO
OBJECTIVES: To quantify the association between systemic levels of the chemokine regulated on activation normal T-cell expressed and secreted (RANTES/CCL5), interferon-γ-inducible protein-10 (IP-10/CXCL10), monocyte chemoattractant protein-1 (MCP-1/CCL2), and eotaxin-1 (CCL11) with future coronary heart disease (CHD) and ischemic stroke events and to assess their usefulness for CHD and ischemic stroke risk prediction in the PRIME Study. METHODS: After 10 years of follow-up of 9,771 men, 2 nested case-control studies were built including 621 first CHD events and 1,242 matched controls and 95 first ischemic stroke events and 190 matched controls. Standardized hazard ratios (HRs) for each log-transformed chemokine were estimated by conditional logistic regression. RESULTS: None of the 4 chemokines were independent predictors of CHD, either with respect to stable angina or to acute coronary syndrome. Conversely, RANTES (HR = 1.70; 95% confidence interval [CI] 1.05-2.74), IP-10 (HR = 1.53; 95% CI 1.06-2.20), and eotaxin-1 (HR = 1.59; 95% CI 1.02-2.46), but not MCP-1 (HR = 0.99; 95% CI 0.68-1.46), were associated with ischemic stroke independently of traditional cardiovascular risk factors, hs-CRP, and fibrinogen. When the first 3 chemokines were included in the same multivariate model, RANTES and IP-10 remained predictive of ischemic stroke. Their addition to a traditional risk factor model predicting ischemic stroke substantially improved the C-statistic from 0.6756 to 0.7425 (p = 0.004). CONCLUSIONS: In asymptomatic men, higher systemic levels of RANTES and IP-10 are independent predictors of ischemic stroke but not of CHD events. RANTES and IP-10 may improve the accuracy of ischemic stroke risk prediction over traditional risk factors.
Assuntos
Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico , Quimiocinas/sangue , Doença das Coronárias/sangue , Doença das Coronárias/diagnóstico , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Estudos de Casos e Controles , Estudos de Coortes , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
Oxidized LDLs (oxLDLs) induce apoptosis, which contributes to the pathogenesis of atherosclerosis. The 150 kDa oxygen-regulated protein (ORP150), an endoplasmic reticulum (ER)-resident chaperone, is upregulated by hypoxia and prevents ischemia-induced cell death. The aim of this work was to investigate whether and how ORP150 can prevent apoptosis induced by oxLDLs in vascular cells. OxLDLs induced ORP150 expression in the ER of human microvascular endothelial cell line (HMEC-1). ORP150 expression was blocked by antioxidants, by the permeant calcium chelator BAPTA-AM, and by inhibitors of the inositol-1,4,5 trisphosphate (IP3) receptors, 2-aminoethyl diphenylborinate (2-APB) and xestospongin C. ORP150 silencing by siRNA-enhanced oxLDL-induced apoptosis, while forced ORP150 expression increased the resistance of cells via an inhibition of the oxLDL-induced calcium rise, and of subsequent calpain activation, cytochrome c release, caspase 3 activation and apoptosis. A similar protective effect was achieved by BAPTA-AM, 2-APB and xestospongin C. Altogether, these data indicate that (i)ORP150 inhibits oxLDL-induced apoptosis by blocking calcium signaling and subsequent apoptosis, (ii)calcium released from ER stores through IP3 channels is involved in the oxLDL-induced calcium rise and apoptosis, and is inhibited by ORP150. Finally, ORP150 is expressed in advanced atherosclerotic lesions, where it may locally participate to reduce the apoptotic effect of oxLDLs and the subsequent risk of plaque rupture.
Assuntos
Apoptose , Aterosclerose/metabolismo , Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , Células Endoteliais/metabolismo , Lipoproteínas LDL/metabolismo , Proteínas/metabolismo , Antioxidantes/farmacologia , Compostos de Boro/farmacologia , Sinalização do Cálcio , Doenças das Artérias Carótidas/metabolismo , Linhagem Celular , Quelantes/farmacologia , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Proteínas de Choque Térmico HSP70 , Homeostase , Humanos , Compostos Macrocíclicos/farmacologia , Oxazóis/farmacologia , Interferência de RNARESUMO
Atherosclerosis is a chronic inflammatory disease of the arterial wall where both innate and adaptive immune responses contribute to disease initiation and progression. Recent studies from several groups suggest that subtypes of T cells, called regulatory T cells, previously shown to maintain immunological tolerance, inhibit the development and progression of atherosclerosis. Here, we review the current knowledge on the regulatory T-cell response and the major cytokines involved in its modulation in the context of atherosclerosis.
Assuntos
Aterosclerose/imunologia , Citocinas/imunologia , Imunidade Inata , Linfócitos T Reguladores/imunologia , Animais , Antígenos CD/imunologia , Aterosclerose/fisiopatologia , Fatores de Transcrição Forkhead/imunologia , Interleucina-10/imunologia , Camundongos , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Fator de Crescimento Transformador beta/imunologiaRESUMO
Circulating procoagulant microparticles (MP) were measured as markers of vascular damage and prothrombotic risk in patients undergoing ST-segment myocardial infarction (STEMI) treated by primary percutaneous transluminal coronary angioplasty (PTCA) and additional GPIIb-IIIa antagonists. Cells possibly more responsive to GPIIb-IIIa (alpha(IIb)beta(3)) antagonists were evidenced through MP phenotypes by comparison with healthy volunteers (HV) and STEMI patients treated by PTCA without GPIIb-IIIa antagonist (CP). In 50 STEMI patients, blood samples were collected at day 1 and day 6. Circulating procoagulant MP were captured on annexin V and quantified by prothrombinase assay as nanomolar phosphatidylserine equivalents (nm PhtdSer). Platelet activation by thrombin was confirmed through independent measurement of soluble GPV (sGPV). With respect to HV, procoagulant MP levels were high in patients with STEMI or unstable angina, platelet-derived MP and elevated sGPV testifying to significant platelet activation. A substantial release of endothelial-derived MP was evidenced simultaneously. In abciximab-treated patients, procoagulant MP, mainly of platelet origin, decreased precociously at day 1 (4.2 +/- 0.6 vs. CP 15.5 +/- 2.1 nm PhtdSer; P = 0.001) together with sGPV (36 +/- 3 vs. CP 58 +/- 8 ng mL(-1); P = 0.02). Leukocyte-derived MP decreased at day 6 (0.12 +/- 0.04 vs. CP 0.56 +/- 0.12 nm PhtdSer; P = 0.01) suggesting a possible effect on underlying inflammatory status. In patients presenting cardiovascular events at 6-month follow-up, procoagulant MP levels at day 1 could be indicative of a worsened outcome. MP could constitute a relevant parameter for the follow-up of STEMI patients treated by GPIIb-IIIa antagonists.
Assuntos
Angioplastia Coronária com Balão/efeitos adversos , Infarto do Miocárdio/sangue , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Complexo Glicoproteico GPIb-IX de Plaquetas/análise , Trombofilia/tratamento farmacológico , Abciximab , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Aspirina/uso terapêutico , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Fragmentos Fab das Imunoglobulinas/farmacologia , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/terapia , Tamanho da Partícula , Inibidores da Agregação Plaquetária/uso terapêutico , Complexo Glicoproteico GPIb-IX de Plaquetas/efeitos dos fármacos , Valor Preditivo dos Testes , Prognóstico , Solubilidade , Trombofilia/diagnóstico , Trombofilia/etiologiaRESUMO
BACKGROUND: The mechanisms of thrombosis on plaque erosion are poorly understood. We examined the potential role of endothelial apoptosis in endothelial erosion and vessel thrombosis. METHODS AND RESULTS: Segments of New Zealand White rabbit femoral arteries were temporarily isolated in vivo. One artery was incubated with staurosporin for 30 minutes, whereas the contralateral artery was incubated with saline and served as control. Three days later, thrombosis was evaluated angiographically and histologically. TUNEL score in the endothelial layer was significantly increased in staurosporin-treated arteries compared with controls (2.43+/-0.30 versus 0.93+/-0.44, respectively; P=0.001). Large areas of endothelial denudation were detectable in staurosporin-treated vessels, whereas endothelium integrity was almost preserved in the saline group. Vessel thrombosis occurred in 58% of staurosporin-treated arteries (7 of 12) but in only 8% of saline-treated segments (P<0.01). Immunoreactivities for tissue factor, platelets, and fibrin were detectable within the thrombus. Addition of ZVAD-fmk (0.1 mmol/L) significantly reduced the occurrence of thrombosis (1 of 7 arteries or 14%, P=0.04). These results were confirmed in balloon-injured atheromatous arteries. CONCLUSIONS: In vivo induction of endothelial apoptosis leads to both vessel thrombosis and endothelial denudation. Endothelial apoptosis may be a critical step in the transition from a stable endothelialized plaque to plaque erosion and thrombosis.
Assuntos
Apoptose , Cateterismo/efeitos adversos , Endotélio Vascular/patologia , Trombose/patologia , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Arteriosclerose/complicações , Arteriosclerose/patologia , Arteriosclerose/terapia , Inibidores de Cisteína Proteinase/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/lesões , Artéria Femoral , Fibrina/administração & dosagem , Marcação In Situ das Extremidades Cortadas , Contagem de Plaquetas , Coelhos , Estaurosporina/toxicidade , Tromboplastina/administração & dosagem , Trombose/induzido quimicamente , Trombose/etiologia , Trombose/prevenção & controle , Túnica Íntima/patologiaAssuntos
Valva Aórtica/metabolismo , Valva Aórtica/patologia , Proteínas de Transporte/metabolismo , Glicoproteínas/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Esclerose/metabolismo , Transdução de Sinais , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Humanos , Osteogênese , Osteoprotegerina , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Receptores do Fator de Necrose TumoralRESUMO
Atherosclerosis is a vascular pathology in which inflammation plays a major role at every stage of the disease. The inflammatory process develops in response to abnormal cholesterol deposits in the intima of large arteries. The inflammatory reaction is initiated by a phase of endothelial activation induced by cytokines, oxidized low density lipoprotein (LDL) and/or changes in endothelial shear stress. This leads to the primary expression of endothelial adhesion molecules and chemokines followed by the recruitment and activation of circulating monocytes and lymphocytes. The clinical manifestations of atherosclerosis, including acute coronary syndromes, are the consequences of atherosclerotic plaque rupture/erosion that triggers thrombus formation leading to the occlusion of the vessel lumen. The local inflammatory process at the level of the atherosclerotic plaque might influence the stability of the plaque through its potential effects on the extracellular matrix, and on the plaque thrombogenicity. In humans, systemic inflammation has been recognized as a major risk factor of occurrence of acute coronary syndromes.
Assuntos
Arteriosclerose/metabolismo , Inflamação/metabolismo , Glicoproteínas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Interleucina-10/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Clinical manifestations of atherosclerosis are the consequences of atherosclerotic plaque rupture which triggers thrombus formation. Tissue factor (TF) is a key element in the initiation of the coagulation cascade and is crucial in thrombus formation following plaque disruption. TF activity is highly dependent on the presence of phosphatidylserine (PS), an anionic phospholipid that is redistributed on the cell surface during apoptotic death conferring a potent procoagulant activity to the apoptotic cell. Apoptosis occurs in the human atherosclerotic plaque, and shed membrane apoptotic microparticles rich in PS are produced in considerable amounts within the lipid core. These microparticles carry almost all TF activity and are responsible for the procoagulant activity of the plaque. Moreover, luminal endothelial cell apoptosis might be responsible for thrombus formation on eroded plaques without rupture. Apoptosis might also play a major role in blood thrombogenicity via circulating procoagulant microparticles that are found at high levels in patients with acute coronary syndromes.
Assuntos
Apoptose , Arteriosclerose/patologia , Arteriosclerose/fisiopatologia , Trombose/patologia , Trombose/fisiopatologia , Arteriosclerose/complicações , Cardiopatias/fisiopatologia , Humanos , Modelos Cardiovasculares , Ruptura Espontânea , Trombose/etiologiaRESUMO
BACKGROUND: Uncoupling protein 2 (UCP2) regulates the production of reactive oxygen species in macrophages. However, its role in atherosclerosis is unknown. METHODS AND RESULTS: Irradiated low-density lipoprotein receptor deficient mice (LDLR-/-) were transplanted with bone marrow from either UCP2 deficient mice (Ucp2-/-) or wild type mice (Ucp2+/+). Mice were fed an atherogenic diet for 7 weeks. Engraftment of bone marrow cells was confirmed by the presence of UCP2 protein expression in spleen cell mitochondria of Ucp2+/+ transplanted mice and its absence in Ucp2-/- transplanted mice. Leukocyte counts and plasma cholesterol levels were comparable in both groups. We found a marked increase in atherosclerotic lesion size in the thoracic aorta of Ucp2-/- transplanted mice compared with control Ucp2+/+ transplanted mice (8.3+/-0.9% versus 4.3+/-0.4%, respectively; P<0.005), as well as in the aortic sinus (150 066+/-12 388 microm2 versus 105 689+/-9 727 microm2, respectively; P<0.05). This was associated with increased nitrotyrosine staining, which suggests enhanced oxidative stress. Analysis of plaque composition revealed a significant increase in macrophage accumulation (P<0.05) and apoptosis (P<0.05), along with a decrease in collagen content (P<0.05), suggesting a potentially more vulnerable phenotype. CONCLUSION: These results suggest a protective role for UCP2 against atherosclerosis.
Assuntos
Arteriosclerose/etiologia , Proteínas de Membrana Transportadoras , Proteínas Mitocondriais , Proteínas/fisiologia , Animais , Arteriosclerose/sangue , Arteriosclerose/patologia , Transplante de Medula Óssea , Cardiotônicos , Colesterol/sangue , Feminino , Canais Iônicos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo , Proteínas/genética , Receptores de LDL/genética , Proteína Desacopladora 2RESUMO
The mechanisms that mediate the atheroprotective properties of estrogens remain obscure. In the present study, we evaluated the involvement of the adhesion molecule P-selectin, intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) in the atheroprotective effect of estrogens in murine models evaluating early steps of atherosclerosis. First, we studied the effect of 17 beta-estradiol (E2) administration for 12 weeks on fatty streak constitution at the root aorta of ovariectomized female mice deficient in apolipoprotein E (apoE) alone or deficient in both apoE and either P-selectin or ICAM-1. Compared with respective placebo groups, E2 significantly prevented the development of fatty streak, to a similar extent in all three genotypes (-70.0% in apoE(-/-), -77.4% in apoE(-/-) P-selectin(-/-), and -77.1% in apoE(-/-) ICAM-1(-/-)). Second, the endothelial expression of VCAM-1 at the root aorta was assessed by immunohistochemistry in either placebo or E2-treated ovariectomized C57BL/6 female mice fed an atherogenic diet. Compared with placebo, E2 treatment resulted in a 31.8% decrease of VCAM-1 endothelial expression at this lesion-prone site (P=0.03). These results demonstrate that P-selectin and ICAM-1 are not involved in the atheroprotective effect of estrogens, and suggest that VCAM-1 could play a role in this process.
Assuntos
Apolipoproteínas E/deficiência , Arteriosclerose/metabolismo , Estradiol/farmacologia , Molécula 1 de Adesão Intercelular/metabolismo , Selectina-P/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Apolipoproteínas E/genética , Arteriosclerose/patologia , Modelos Animais de Doenças , Feminino , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Molécula 1 de Adesão de Célula Vascular/efeitos dos fármacosAssuntos
Apoptose , Rejeição de Enxerto/patologia , Transplante de Coração/patologia , Heme Oxigenase (Desciclizante)/metabolismo , Doença Aguda , Adulto , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Feminino , Rejeição de Enxerto/enzimologia , Transplante de Coração/imunologia , Heme Oxigenase-1 , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Proteínas de MembranaAssuntos
Apoptose/fisiologia , Rejeição de Enxerto/imunologia , Transplante de Coração/imunologia , Heme Oxigenase (Desciclizante)/metabolismo , Doença Aguda , Biópsia , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Rejeição de Enxerto/enzimologia , Rejeição de Enxerto/patologia , Transplante de Coração/patologia , Heme Oxigenase-1 , Humanos , Proteínas de MembranaRESUMO
OBJECTIVE: To examine the relation between plasma concentrations of interleukin-18 (IL-18), the interferon gamma inducing factor, and clinical instability of coronary artery disease. DESIGN AND SETTING: Observational study in a university hospital. PATIENTS: 11 patients with unstable angina and negative troponin I, 21 patients with acute non-Q wave myocardial infarction (MI), 21 patients with acute Q wave MI, 9 patients with stable angina, and 11 controls. MAIN OUTCOME MEASURES: Plasma IL-18 concentrations and their relation to clinical instability and myocardial dysfunction. RESULTS: Plasma concentrations of IL-18 were significantly increased in the unstable angina and MI groups in comparison with the stable angina and control groups (p < 0.01). No difference in IL-18 concentrations were found between patients with unstable angina, patients with non-Q wave MI, and patients with Q wave MI. Plasma IL-18 concentrations significantly correlated with decreased left ventricular ejection fraction (p = 0.01). CONCLUSIONS: Plasma IL-18 concentrations are increased in patients with acute coronary syndromes and correlate with the severity of myocardial dysfunction.
Assuntos
Doença da Artéria Coronariana/sangue , Interleucina-18/sangue , Doença Aguda , Idoso , Biomarcadores/sangue , Doença da Artéria Coronariana/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico/fisiologia , SíndromeRESUMO
BACKGROUND: Shed membrane microparticles circulate in the peripheral blood of nonischemic (NI) patients and patients with myocardial infarction (MI). We investigated whether or not these microparticles would affect endothelium-dependent responses. METHODS AND RESULTS: Rat aortic rings with endothelium were exposed for 24 hours to circulating microparticles isolated from 7 patients with NI syndromes and 19 patients with acute MI. Endothelium-dependent relaxations to acetylcholine were not affected by high concentrations of microparticles from NI patients (P=0.80). However, significant impairment was observed in preparations exposed to microparticles from patients with MI at low and high concentrations, corresponding to 0.7-fold and 2-fold circulating plasma levels (P=0.05 and 0.001, respectively). Impairment was not affected by diclofenac (P=0.47), nor by the cell-permeable superoxide dismutase mimetic Mn(III)tetra(4-benzoic acid) porphyrin chloride (P=0.33), but it was abolished by endothelium removal or by N(omega)monomethyl-L-arginine. Relaxations to the calcium ionophore ionomycin were decreased in rings exposed to microparticles from MI patients (P=0.05 and 0.009 for low and high concentrations, respectively), but microparticles from NI patients had no effect (P=0.81). Finally, high concentrations of microparticles from MI patients affected neither endothelium-independent relaxation to sodium nitroprusside (P=0.59) nor expression of the endothelial nitric oxide synthase (P=0.43). CONCLUSIONS: Circulating microparticles from patients with MI selectively impair the endothelial nitric oxide transduction pathway and, therefore, could contribute to the general vasomotor dysfunction observed after MI, even in angiographically normal arteries.
Assuntos
Membrana Celular/metabolismo , Endotélio Vascular/metabolismo , Infarto do Miocárdio/sangue , Adulto , Animais , Aorta , Estruturas da Membrana Celular/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Diclofenaco/farmacologia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Técnicas In Vitro , Ionóforos/farmacologia , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo III , Tamanho da Partícula , Ratos , Ratos Wistar , Vasoconstritores/farmacologia , Vasodilatadores/antagonistas & inibidores , Vasodilatadores/farmacologia , Sistema Vasomotor/efeitos dos fármacos , Sistema Vasomotor/metabolismo , ômega-N-Metilarginina/farmacologiaRESUMO
Atherosclerosis is an inflammatory disease of large arteries that is initiated through the activation of endothelium by proinflammatory mediators. CD40 receptor stimulation has been implicated in the pathogenesis of atherosclerosis. One of the most important atheroprotective stimuli is the viscous drag (shear stress) generated by the streaming blood acting on the endothelial monolayer. Here, we demonstrate that shear stress prevents CD40 ligand-induced endothelial cell activation, and we identify upregulation of TNF receptor-associated factor-3 (TRAF-3) as a potent CD40-inhibitory mechanism. Shear stress specifically upregulates TRAF-3 in cultured endothelial cells. Moreover, in the endothelial cells overlying human atherosclerotic plaques, TRAF-3 expression is upregulated in areas with high shear stress. Overexpression of TRAF-3 inhibits endothelial expression of proinflammatory cytokines and tissue factor and blocks DNA-binding activity of the transcription factor AP-1; it thereby prevents CD40-induced endothelial activation. Thus, upregulation of TRAF-3 represents a novel mechanism for preserving the functional integrity of the endothelial monolayer.
Assuntos
Antígenos CD40/metabolismo , Proteínas/metabolismo , Regulação para Cima , Sequência de Bases , Northern Blotting , Western Blotting , Primers do DNA , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Humanos , Transdução de Sinais , Fator 3 Associado a Receptor de TNFRESUMO
Atherosclerosis is a disease of the arterial wall that seems to be tightly modulated by the local inflammatory balance. Whereas a large body of evidence supports a role for proinflammatory mediators in disease progression, the understanding of the role of the antiinflammatory component in the modulation of plaque progression is only at its beginning. TGF-beta1, -beta2, and -beta3 are cytokines/growth factors with broad activities on cells and tissues in the cardiovascular system and have been proposed to play a role in the pathogenesis of atherosclerosis. However, no study has examined the direct role of TGF-beta in the development and composition of advanced atherosclerotic lesions. In the present study, we show that inhibition of TGF-beta signaling using a neutralizing anti-TGF-beta1, -beta2, and -beta3 antibody accelerates the development of atherosclerotic lesions in apoE-deficient mice. Moreover, inhibition of TGF-beta signaling favors the development of lesions with increased inflammatory component and decreased collagen content. These results identify a major protective role for TGF-beta in atherosclerosis.
Assuntos
Arteriosclerose/etiologia , Arteriosclerose/metabolismo , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Aorta/metabolismo , Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Arteriosclerose/patologia , Peso Corporal/efeitos dos fármacos , HDL-Colesterol/sangue , Colágeno/metabolismo , Progressão da Doença , Imuno-Histoquímica , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta1 , Fator de Crescimento Transformador beta2 , Fator de Crescimento Transformador beta3RESUMO
BACKGROUND: Interleukin (IL)-18 is a potent proinflammatory cytokine with potential atherogenic properties. Its expression and role in atherosclerosis, however, are unknown. METHODS AND RESULTS: In the present study, we examined stable and unstable human carotid atherosclerotic plaques retrieved by endarterectomy for the presence of IL-18 using reverse transcription-polymerase chain reaction (PCR), Western blot, and immunohistochemical techniques. IL-18 was highly expressed in the atherosclerotic plaques compared with control normal arteries and was localized mainly in plaque macrophages. IL-18 receptor was also upregulated in plaque macrophages and endothelial cells, suggesting potential biological effects. To examine the role of IL-18 in atherosclerosis, we determined the relation between IL-18 mRNA expression and signs of plaque instability using real-time quantitative PCR. Interestingly, significantly higher levels of IL-18 mRNA were found in symptomatic (unstable) plaques than asymptomatic (stable) plaques (P<0.01). CONCLUSIONS: These results suggest, for the first time, a major role for IL-18 in atherosclerotic plaque destabilization leading to acute ischemic syndromes.