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BACKGROUND: Nuclear Factor-Kappa B (NF-kB) is a family of transcription factors that are important in embryonic development, inflammation, epithelial-to-mesenchymal transition and cancer. The 65 kDa RelA subunit is the major transcriptional activator of the NF-kB pathways. Whole-body deficiency of RelA leads to massive apoptosis of liver hepatocytes and death in utero. To study the role of RelA in physiology and in disease states in a manner that circumvents this embryonic lethal phenotype, we have generated a mouse with RelA conditional knockout (CKO) alleles containing loxP sites that are deleted by activated Cre recombinase. RESULTS: We demonstrate that RelACKO/CKO mice are fertile, do not display any developmental defects and can be crossed with Cre-expressing mice to delete RelA in a temporal, tissue-specific manner. Our mating of RelACKO/CKO mice with Zp3-Cre transgenic led to embryonic lethality of RelA-deficient embryos. In contrast, mating of RelACKO/CKO mice with Col1α2-CreER mice allowed for the generation of double transgenics which could be stimulated with tamoxifen to induce fibroblast-specific RelA deletion in adulthood. CONCLUSIONS: Based on our collective data, we conclude that this novel RelACKO/CKO mouse allows for efficient deletion of RelA in a tissue-specific manner. This RelACKO/CKO mouse will be an invaluable tool for deciphering the mechanistic roles of RelA in various cells and tissues during development and in disease.
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OBJECTIVES: Dengue virus (DENV) infection is a significant risk to over a third of the human population that causes a wide spectrum of illness, ranging from sub-clinical disease to intermediate syndrome of vascular complications called dengue fever complicated (DFC) and severe, dengue hemorrhagic fever (DHF). Methods for discriminating outcomes will impact clinical trials and understanding disease pathophysiology. STUDY DESIGN: We integrated a proteomics discovery pipeline with a heuristics approach to develop a molecular classifier to identify an intermediate phenotype of DENV-3 infectious outcome. RESULTS: 121 differentially expressed proteins were identified in plasma from DHF vs dengue fever (DF), and informative candidates were selected using nonparametric statistics. These were combined with markers that measure complement activation, acute phase response, cellular leak, granulocyte differentiation and viral load. From this, we applied quantitative proteomics to select a 15 member panel of proteins that accurately predicted DF, DHF, and DFC using a random forest classifier. The classifier primarily relied on acute phase (A2M), complement (CFD), platelet counts and cellular leak (TPM4) to produce an 86% accuracy of prediction with an area under the receiver operating curve of >0.9 for DHF and DFC vs DF. CONCLUSIONS: Integrating discovery and heuristic approaches to sample distinct pathophysiological processes is a powerful approach in infectious disease. Early detection of intermediate outcomes of DENV-3 will speed clinical trials evaluating vaccines or drug interventions.
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Biomarcadores/análisis , Virus del Dengue/genética , Dengue/diagnóstico , Dengue Grave/diagnóstico , Reacción de Fase Aguda , Adulto , Biomarcadores/sangre , Activación de Complemento , Dengue/genética , Dengue/virología , Diagnóstico Precoz , Femenino , Humanos , Masculino , Fenotipo , Recuento de Plaquetas , Proteómica , Curva ROC , Dengue Grave/genética , Dengue Grave/virología , Tropomiosina/análisis , Carga Viral , Adulto Joven , alfa-Macroglobulinas/análisisRESUMEN
BACKGROUND: Development of thoracic aortic aneurysms is the most significant clinical phenotype in patients with Marfan syndrome. An inflammatory response has been described in advanced stages of the disease. Because the hallmark of vascular inflammation is local interleukin-6 (IL-6) secretion, we explored the role of this proinflammatory cytokine in the formation of aortic aneurysms and rupture in hypomorphic fibrillin-deficient mice (mgR/mgR). METHODS AND RESULTS: MgR/mgR mice developed ascending aortic aneurysms with significant dilation of the ascending aorta by 12 weeks (2.7 ± 0.1 and 1.3 ± 0.1 for mgR/mgR versus wild-type mice, respectively; P<0.001). IL-6 signaling was increased in mgR/mgR aortas measured by increases in IL-6 and SOCS3 mRNA transcripts (P<0.05) and in cytokine secretion of IL-6, MCP-1, and GM-CSF (P<0.05). To investigate the role of IL-6 signaling, we generated mgR homozygous mice with IL-6 deficiency (DKO). The extracellular matrix of mgR/mgR mice showed significant disruption of elastin and the presence of dysregulated collagen deposition in the medial-adventitial border by second harmonic generation multiphoton autofluorescence microscopy. DKO mice exhibited less elastin and collagen degeneration than mgR/mgR mice, which was associated with decreased activity of matrix metalloproteinase-9 and had significantly reduced aortic dilation (1.0 ± 0.1 versus 1.6 ± 0.2 mm change from baseline, DKO versus mgR/mgR, P<0.05) that did not affect rupture and survival. CONCLUSION: Activation of IL-6-STAT3 signaling contributes to aneurysmal dilation in mgR/mgR mice through increased MMP-9 activity, aggravating extracellular matrix degradation.
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Aorta/metabolismo , Aneurisma de la Aorta Torácica/etiología , Matriz Extracelular/metabolismo , Interleucina-6/metabolismo , Síndrome de Marfan/complicaciones , Proteínas de Microfilamentos/metabolismo , Animales , Aorta/patología , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/metabolismo , Aneurisma de la Aorta Torácica/patología , Aneurisma de la Aorta Torácica/prevención & control , Rotura de la Aorta/etiología , Rotura de la Aorta/metabolismo , Rotura de la Aorta/patología , Quimiocina CCL2/metabolismo , Colágeno/metabolismo , Dilatación Patológica , Modelos Animales de Enfermedad , Elastina/metabolismo , Fibrilina-1 , Fibrilinas , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interleucina-6/deficiencia , Interleucina-6/genética , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/deficiencia , Proteínas de Microfilamentos/genética , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Factores de Tiempo , Regulación hacia ArribaRESUMEN
OBJECTIVE: Dysregulated angiotensin II (Ang II) signaling induces local vascular interleukin-6 (IL-6) secretion, producing leukocyte infiltration and life-threatening aortic dissections. Precise mechanisms by which IL-6 signaling induces leukocyte recruitment remain unknown. T-helper 17 lymphocytes (Th17) have been implicated in vascular pathology, but their role in the development of aortic dissections is poorly understood. Here, we tested the relationship of IL-6-signal transducer and activator of transcription-3 signaling with Th17-induced inflammation in the formation of Ang II-induced dissections in C57BL/6 mice. APPROACH AND RESULTS: Ang II infusion induced aortic dissections and CD4(+)-interleukin 17A (IL-17A)-expressing Th17 cell accumulation in C57BL/6 mice. A blunted local Th17 activation, macrophage recruitment, and reduced incidence of aortic dissections were seen in IL-6(-/-) mice. To determine the pathological roles of Th17 lymphocytes, we treated Ang II-infused mice with IL-17A-neutralizing antibody or infused Ang II in genetically deficient IL-17A mice and found decreased aortic chemokine monocytic chemotactic protein-1 production and macrophage recruitment, leading to a reduction in aortic dissections. This effect was independent of blood pressure in IL-17A-neutralizing antibody experiment. Application of a cell-permeable signal transducer and activator of transcription-3 inhibitor to downregulate the IL-6 pathway decreased aortic dilation and Th17 cell recruitment. We also observed increased aortic Th17 infiltration and IL-17 mRNA expression in patients with thoracic aortic dissections. Finally, we found that Ang II-mediated aortic dissections occurred independent of blood pressure changes. CONCLUSIONS: Our results indicate that the IL-6-signal transducer and activator of transcription-3 signaling pathway converges on Th17 recruitment and IL-17A signaling upstream of macrophage recruitment, mediating aortic dissections.
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Angiotensina II , Aorta/inmunología , Aneurisma de la Aorta/inmunología , Disección Aórtica/inmunología , Mediadores de Inflamación/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Células Th17/inmunología , Disección Aórtica/inducido químicamente , Disección Aórtica/genética , Disección Aórtica/patología , Disección Aórtica/fisiopatología , Disección Aórtica/prevención & control , Animales , Anticuerpos Neutralizantes/administración & dosificación , Aorta/patología , Aneurisma de la Aorta/inducido químicamente , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/patología , Aneurisma de la Aorta/fisiopatología , Aneurisma de la Aorta/prevención & control , Presión Sanguínea , Quimiocina CCL2/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Mediadores de Inflamación/antagonistas & inhibidores , Interleucina-17/antagonistas & inhibidores , Interleucina-17/deficiencia , Interleucina-17/genética , Interleucina-6/deficiencia , Interleucina-6/genética , Activación de Linfocitos , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/metabolismo , Técnicas de Cultivo de TejidosRESUMEN
Secondary dengue viral infection can produce capillary leakage associated with increased mortality known as dengue hemorrhagic fever (DHF). Because the mortality of DHF can be reduced by early detection and intensive support, improved methods for its detection are needed. We applied multidimensional protein profiling to predict outcomes in a prospective dengue surveillance study in South America. Plasma samples taken from initial clinical presentation of acute dengue infection were subjected to proteomics analyses using ELISA and a recently developed biofluid analysis platform. Demographics, clinical laboratory measurements, nine cytokines, and 419 plasma proteins collected at the time of initial presentation were compared between the DF and DHF outcomes. Here, the subject's gender, clinical parameters, two cytokines, and 42 proteins discriminated between the outcomes. These factors were reduced by multivariate adaptive regression splines (MARS) that a highly accurate classification model based on eight discriminant features with an area under the receiver operator curve (AUC) of 0.999. Model analysis indicated that the feature-outcome relationship were nonlinear. Although this DHF risk model will need validation in a larger cohort, we conclude that approaches to develop predictive biomarker models for disease outcome will need to incorporate nonparametric modeling approaches.
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Dengue/diagnóstico , Dinámicas no Lineales , Proteínas/análisis , Proteómica , Dengue Grave/diagnóstico , Adolescente , Adulto , Área Bajo la Curva , Biomarcadores/sangre , Niño , Preescolar , Cromatografía en Gel , Citocinas/análisis , Dengue/sangre , Diagnóstico Diferencial , Análisis Discriminante , Diagnóstico Precoz , Electroforesis en Gel Bidimensional , Ensayo de Inmunoadsorción Enzimática , Fluorescencia , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Estudios Prospectivos , Proteómica/métodos , Medición de Riesgo , Factores de Riesgo , Dengue Grave/sangre , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Espectrometría de Masas en Tándem , Venezuela , Adulto JovenRESUMEN
BACKGROUND/AIMS: The role of adventitial fibroblasts in the vascular inflammation observed in the adventitia of large vessels in numerous cardiovascular diseases remains unclear. Our objective was to explore the contribution of these cells to angiotensin II (Ang II)-induced aortic inflammation and adventitial expansion. METHODS: Cytokine production by primary human aortic adventitial fibroblasts (AoAF) in tissue culture was detected using multiplex ELISA, and increases in cytokine mRNA following Ang II stimulation were quantitated by real-time PCR. The ability of AoAF-derived MCP-1 to attract monocytes was studied in vitro using Boyden assays, and the resulting effect of the monocyte-AoAF interaction on fibroblast proliferation was measured in vitro using proliferation and (3)H-thymidine incorporation assays. Ang II-induced fibroblast proliferation was measured in vivo using aortic digestion of single cells followed by flow cytometric quantification of fibroblast numbers as well as fibroblast and PCNA immunostaining. The ability of monocytes to induce AoAF proliferation was demonstrated in vivo using CCR2(+/+) wild-type monocyte adoptive transfer into Ang II-stimulated CCR2-null mice which can produce MCP-1 but have cells lacking the MCP-1 receptor - CCR2. RESULTS: AoAF constitutively secreted numerous proinflammatory cytokines, particularly IL-6 and MCP-1, whose gene expressions were further upregulated in response to Ang II stimulation. AoAF-derived MCP-1 was potent in recruiting THP-1 monocytes in vitro, and these monocytes stimulated AoAF proliferation based on a flow cytometric assessment of cell number and (3)H-thymidine incorporation in tissue culture. In vivo, Ang II induced fibroblast proliferation, increased fibroblast and PCNA adventitial staining, and blunted inflammatory responses in the CCR2(-/-) background. Injection of CCR2(+/+) monocytes into Ang II-treated CCR2(-/-) mice restored adventitial thickening which resulted in increased fibrosis secondary to adventitial fibroblast proliferation. CONCLUSIONS: Our results suggest that Ang II-stimulates AoAF to recruit monocytes via fibroblast-derived MCP-1, and the recruited monocytes further activate fibroblast proliferation, adventitial thickening, and additional cytokine production. This fibroblast-monocyte amplification loop may critically mediate hallmarks of adventitial inflammation common to many cardiovascular diseases.
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Angiotensina II/metabolismo , Aorta/inmunología , Tejido Conectivo/inmunología , Citocinas/metabolismo , Fibroblastos/inmunología , Mediadores de Inflamación/metabolismo , Inflamación/inmunología , Traslado Adoptivo , Animales , Aorta/metabolismo , Aorta/patología , Proliferación Celular , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiotaxis de Leucocito , Técnicas de Cocultivo , Tejido Conectivo/metabolismo , Tejido Conectivo/patología , Medios de Cultivo Condicionados/metabolismo , Citocinas/genética , Ensayo de Inmunoadsorción Enzimática , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis , Citometría de Flujo , Humanos , Inmunohistoquímica , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Interleucina-6/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/inmunología , Monocitos/metabolismo , Comunicación Paracrina , Reacción en Cadena de la Polimerasa , Receptores CCR2/deficiencia , Receptores CCR2/genética , Factores de TiempoRESUMEN
Vascular inflammation contributes to cardiovascular diseases such as aortic aneurysm and dissection. However, the precise inflammatory pathways involved have not been clearly defined. We have shown here that subcutaneous infusion of Ang II, a vasopressor known to promote vascular inflammation, into older C57BL/6J mice induced aortic production of the proinflammatory cytokine IL-6 and the monocyte chemoattractant MCP-1. Production of these factors occurred predominantly in the tunica adventitia, along with macrophage recruitment, adventitial expansion, and development of thoracic and suprarenal aortic dissections. In contrast, a reduced incidence of dissections was observed after Ang II infusion into mice lacking either IL-6 or the MCP-1 receptor CCR2. Further analysis revealed that Ang II induced CCR2+CD14hiCD11bhiF4/80- macrophage accumulation selectively in aortic dissections and not in aortas from Il6-/- mice. Adoptive transfer of Ccr2+/+ monocytes into Ccr2-/- mice resulted in selective monocyte uptake into the ascending and suprarenal aorta in regions of enhanced ROS stress, with restoration of IL-6 secretion and increased incidence of dissection. In vitro, coculture of monocytes and aortic adventitial fibroblasts produced MCP-1- and IL-6-enriched conditioned medium that promoted differentiation of monocytes into macrophages, induced CD14 and CD11b upregulation, and induced MCP-1 and MMP-9 expression. These results suggest that leukocyte-fibroblast interactions in the aortic adventitia potentiate IL-6 production, inducing local monocyte recruitment and activation, thereby promoting MCP-1 secretion, vascular inflammation, ECM remodeling, and aortic destabilization.
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Aneurisma de la Aorta/etiología , Disección Aórtica/etiología , Quimiocina CCL2/fisiología , Interleucina-6/fisiología , Receptores CCR2/fisiología , Traslado Adoptivo , Disección Aórtica/patología , Disección Aórtica/fisiopatología , Angiotensina II/administración & dosificación , Animales , Aneurisma de la Aorta/patología , Aneurisma de la Aorta/fisiopatología , Secuencia de Bases , Quimiocina CCL2/genética , Técnicas de Cocultivo , Tejido Conectivo/patología , Tejido Conectivo/fisiopatología , Cartilla de ADN/genética , Modelos Animales de Enfermedad , Humanos , Inflamación/etiología , Inflamación/patología , Inflamación/fisiopatología , Interleucina-6/deficiencia , Interleucina-6/genética , Macrófagos/efectos de los fármacos , Macrófagos/patología , Macrófagos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CCR2/deficiencia , Receptores CCR2/genética , Transducción de SeñalRESUMEN
Angiotensin II (A-II), the major effector peptide of the renin angiotensin system potently accelerates progression of atherosclerosis. To investigate its effects on vascular inflammatory mechanisms, we elucidated vascular cytokine expression during early lesion development in A-II-infused atherosclerosis-prone LDLR-/- mice. Male LDLR-/- mice were placed on a "Western" high-fat diet for 4 weeks, followed by sham or A-II infusion for 7 weeks. Equal blood pressures and elevations in serum lipids were seen in both groups. Mice were sacrificed when significant A-II-induced plaque development was first detectable, aortae were explanted and culture media assayed for secreted cytokines. Nine cytokines were significantly induced with interleukin-6 (IL-6) being the most highly secreted. Local IL-6 production was confirmed by in situ mRNA hybridization and immunostaining, where the most abundant IL-6 was found in the aortic adventitia, with lesser production by the medial and intimal layers. Immunofluorescence colocalization showed IL-6 expression by fibroblasts and activated macrophages. Activation of downstream IL-6 signaling mediated by the Jak-STAT3 pathway was demonstrated by inducible phospho-Tyr705-STAT3 formation in the adventitia and endothelium (of IL-6+/+ mice only). These findings define cytokine profiles in the A-II infusion model and demonstrate that IL-6, produced by activated macrophages and fibroblasts in the adventitia, induces the Jak-STAT3 pathway during early A-II-induced atherosclerosis.
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Angiotensina II/farmacología , Aterosclerosis/fisiopatología , Interleucina-6/genética , Quinasas Janus/metabolismo , Receptores de LDL/genética , Factor de Transcripción STAT3/metabolismo , Vasoconstrictores/farmacología , Animales , Aorta/fisiología , Aterosclerosis/metabolismo , Fibroblastos/fisiología , Interleucina-6/metabolismo , Macrófagos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Técnicas de Cultivo de Órganos , Fosforilación/efectos de los fármacos , ARN Mensajero/metabolismo , Receptores de LDL/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Tirosina/metabolismoRESUMEN
The vasoconstrictor angiotensin II (Ang II) accelerates atherosclerosis by inducing vascular gene expression programs, producing monocyte recruitment, and vascular remodeling. In vascular smooth muscle cells (VSMCs), Ang II signaling activates interleukin (IL)-6 expression, a cytokine producing acute-phase inflammation, mediated by the transcription factor nuclear factor kappaB (NF-kappaB). The classical NF-kappaB activation pathway involves cytoplasmic-to-nuclear translocation of the potent RelA transactivating subunit; however, because nuclear RelA is present in VSMCs, the mechanism by which NF-kappaB activity is controlled is incompletely understood. In this study, we focus on early activation steps controlling RelA activation. Although Ang II only weakly induces approximately 1.5-fold RelA nuclear translocation, RelA is nevertheless required because short interfering RNA-mediated RelA knockdown inhibits inducible IL-6 expression. We find instead that Ang II stimulation rapidly induces RelA phosphorylation at serine residue 536, a critical regulatory site in its transactivating domain. Chromatin immunoprecipitation assays indicate no significant changes in total RelA binding to the native IL-6 promoter, but an apparent increase in fractional binding of phospho-Ser536 RelA. Inactivation of RhoA by treatment with Clostridium botulinum exoenzyme C3 exotoxin or expression of dominant negative RhoA blocks Ang II-inducible RelA Ser536 phosphorylation and IL-6 expression. Finally, enhanced phospho-Ser536 RelA formation in the aortae of rats chronically infused with Ang II was observed. Together, these data indicate a novel mechanism for Ang II-induced NF-kappaB activation in VSMCs, mediated by RhoA-induced phospho-Ser536 RelA formation, IL-6 expression, and vascular inflammation.
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Angiotensina II/farmacología , Interleucina-6/genética , Músculo Liso Vascular/metabolismo , FN-kappa B/metabolismo , Regiones Promotoras Genéticas , Factor de Transcripción ReIA/metabolismo , Proteína de Unión al GTP rhoA/fisiología , Animales , Aorta/citología , Aorta/metabolismo , Interleucina-6/biosíntesis , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/metabolismo , FN-kappa B/fisiología , Fosforilación , Isoformas de Proteínas/metabolismo , Ratas , Factores de Tiempo , Transcripción Genética/efectos de los fármacos , Transcripción Genética/fisiologíaRESUMEN
Diet-induced changes in serum lipoproteins are a major risk factor for the development of atherosclerosis, the leading cause of mortality in Westernized countries. Atherosclerosis is now appreciated to be a systemic inflammatory disease where increased synthesis of inducible proteins by the liver, such as C-reactive protein (CRP) and others, may play roles in accelerating the disease process. To systematically investigate the genetic response of the liver to diet-induced atherosclerosis, we applied high-density microarray technology in a mouse model of atherosclerosis (LDLR-/- mouse). LDLR-/- mice and congenic (LDLR+/+) controls were placed on low-fat (LF) or high-fat (HF) Western-style diets. The Western diet produced sustained elevations in total cholesterol (2.5-fold for LDLR+/+, 5.0-fold LDLR-/-) relative to the respective LF groups. Tissues were harvested after 12 wk when significant atherosclerotic lesion development was first detectable by en face histomorphometry of oil red O-stained aortas. Diet, rather than genotype, was most highly associated with development of atherosclerotic lesions. Liver mRNA expression profiles of triplicate animals from each group were determined by high-density oligonucleotide microarrays; and genes with transcript levels influenced by genotype and diet were identified by two-way ANOVA. Approximately one-third of the 102 genes identified to be altered by diet [Pr(F) < 0.0005] were involved in lipid metabolism. In addition, we identified components of the alternative complement pathway, including C3, properdin, and factor D, for which mRNA levels were independently confirmed by quantitative real-time RT-PCR analysis, and C3 protein was demonstrated in aortic lesions by immunostaining. These findings suggest that induction of the alternative complement pathway may be an additional mechanism by which a high-fat/Western diet accelerates atherosclerosis.
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Arteriosclerosis/genética , Arteriosclerosis/patología , Vía Alternativa del Complemento/efectos de los fármacos , Grasas de la Dieta/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Animales , Arteriosclerosis/sangre , Arteriosclerosis/inducido químicamente , Complemento C3/análisis , Complemento C3/inmunología , Vía Alternativa del Complemento/genética , Vía Alternativa del Complemento/inmunología , Dieta , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Genotipo , Lípidos/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/sangre , Obesidad/inducido químicamente , Obesidad/genética , Obesidad/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptores de LDL/deficiencia , Receptores de LDL/genéticaRESUMEN
It is now well established that vascular inflammation is an independent risk factor for the development of atherosclerosis. In otherwise healthy patients, chronic elevations of circulating interleukin-6 or its biomarkers are predictors for increased risk in the development and progression of ischemic heart disease. Although multifactorial in etiology, vascular inflammation produces atherosclerosis by the continuous recruitment of circulating monocytes into the vessel wall and by contributing to an oxidant-rich inflammatory milieu that induces phenotypic changes in resident (noninflammatory) cells. In addition, the renin-angiotensin system (RAS) has important modulatory activities in the atherogenic process. Recent work has shown that angiotensin II (Ang II) has significant proinflammatory actions in the vascular wall, inducing the production of reactive oxygen species, inflammatory cytokines, and adhesion molecules. These latter effects on gene expression are mediated, at least in part, through the cytoplasmic nuclear factor-kappaB transcription factor. Through these actions, Ang II augments vascular inflammation, induces endothelial dysfunction, and, in so doing, enhances the atherogenic process. Our recent studies have defined a molecular mechanism for a biological positive-feedback loop that explains how vascular inflammation can be self-sustaining through upregulation of the vessel wall Ang II tone. Ang II produced locally by the inflamed vessel induces the synthesis and secretion of interleukin-6, a cytokine that induces synthesis of angiotensinogen in the liver through a janus kinase (JAK)/signal transducer and activator of transcription (STAT)-3 pathway. Enhanced angiotensinogen production, in turn, supplies more substrate to the activated vascular RAS, where locally produced Ang II synergizes with oxidized lipid to perpetuate atherosclerotic vascular inflammation. These observations suggest that one mechanism by which RAS antagonists prevent atherosclerosis is by reducing vascular inflammation. Moreover, antagonizing the vascular nuclear factor-kappaB and/or hepatic JAK/STAT pathways may modulate the atherosclerotic process.