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1.
Blood ; 117(22): 5963-74, 2011 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-21454454

RESUMO

TLR2, a functional, inflammatory-related receptor, is known to be expressed on megakaryocytes and platelets and to lead to infection and immune-mediated activation of platelets; however, the role of this receptor in megakaryocytes is not understood. Using Meg-01 cells and mouse megakaryocytes, we found that NFκB, ERK-MAPK, and PI3K/Akt pathways, known downstream pathways of TLRs, are activated by Pam3CSK4, a TLR2-specific ligand. In addition, transcription factors associated with megakaryocyte maturation, GATA-1, NF-E2, and mammalian target of rapamycin (mTOR), are all increased in the presence of Pam3CSK4. The effect of Pam3CSK4 on megakaryocyte maturation was verified by the increase in DNA content and adhesion to extracellular matrix proteins by TLR2-dependent stimulation. In addition, TLR2 stimulation resulted in an increase in reactive oxygen species (ROS) production. Gene expression and protein levels of GP1b, CD41, MCP-1, COX2, NFκB1, and TLR2 were up-regulated in megakaryocytes after TLR2 stimulation through NFκB, PI3K/Akt, and ERK-MAPK pathways. Treatment of wild-type mice with Pam3CSK4 resulted in a return to normal platelet levels and an increase in megakaryocyte maturation, which did not occur in the TLR2(-/-) mice. Therefore, inflammation, through TLR2, can increase maturation and modulate the phenotype of megakaryocytes, contributing to the interrelationship between inflammation and hemostasis.


Assuntos
Megacariócitos/metabolismo , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor 2 Toll-Like/fisiologia , Animais , Western Blotting , Adesão Celular , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Megacariócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/genética , Fosfatidilinositol 3-Quinases/genética , Ativação Plaquetária , Ploidias , Proteínas Proto-Oncogênicas c-akt/genética , RNA Mensageiro/genética , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
2.
F1000Res ; 1: 50, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-24358814

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are small RNAs that regulate gene expression by suppressing protein translation and may influence RNA expression. MicroRNAs are detected in extracellular locations such as plasma; however, the extent of miRNA expression in plasma its relation to cardiovascular disease is not clear and many clinical studies have utilized array-based platforms with poor reproducibility. METHODS AND RESULTS: Initially, to define distribution of miRNA in human blood; whole blood, platelets, mononuclear cells, plasma, and serum from 5 normal individuals were screened for 852 miRNAs using high-throughput micro-fluidic quantitative RT-PCR (qRT-PCR). In total; 609, 448, 658, 147, and 178 miRNAs were found to be expressed in moderate to high levels in whole blood, platelets, mononuclear cells, plasma, and serum, respectively, with some miRNAs uniquely expressed. To determine the cardiovascular relevance of blood miRNA expression, plasma miRNA (n=852) levels were measured in 83 patients presenting for cardiac catheterization. Eight plasma miRNAs were found to have over 2-fold increased expression in patients with significant coronary disease (≥70% stenosis) as compared to those with minimal coronary disease (less than 70% stenosis) or normal coronary arteries. Expression of miR-494, miR-490-3p, and miR-769-3p were found to have significantly different levels of expression. Using a multivariable regression model including cardiovascular risk factors and medications, hsa-miR-769-3p was found to be significantly correlated with the presence of significant coronary atherosclerosis. CONCLUSIONS: This study utilized a superior high-throughput qRT-PCR based method and found that miRNAs are found to be widely expressed in human blood with differences expressed between cellular and extracellular fractions. Importantly, specific miRNAs from circulating plasma are associated with the presence of significant coronary disease.

3.
J Am Coll Cardiol ; 58(3): 232-7, 2011 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-21737012

RESUMO

OBJECTIVES: The purpose of this study was to determine whether obese individuals with reduced adipose tissue inflammation exhibit a more favorable cardiovascular risk profile. BACKGROUND: Obesity is associated with a low-grade state of chronic inflammation that might be causally related to cardiometabolic disease. METHODS: With immunohistochemistry, we categorized obese individuals dichotomously as having inflamed fat (n = 78) or noninflamed fat (n = 31) on the basis of the presence (+) or absence (-) of macrophage crown-like structures (CLS) in subcutaneous abdominal fat biopsy samples. We compared their metabolic, vascular, and adipose tissue characteristics with lean subjects (n = 17). RESULTS: Inflamed CLS+ obese individuals displayed higher plasma insulin, homeostasis model assessment, triglycerides, glucose, blood pressure, high-sensitivity C-reactive protein, low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, and brachial artery flow-mediated dilation compared with lean subjects (p < 0.05). Adipose messenger ribonucleic acid expression of inflammatory genes including CD68, leptin, matrix metalloproteinase-9, CD163, and CD8A were significantly greater and vascular endothelial growth factor was lower in the CLS+ group (p < 0.05). In contrast, obese subjects with noninflamed fat exhibited a mixed clinical phenotype with lower insulin resistance, reduced proatherogenic gene expression, and preserved vascular function as in lean subjects. In multiple linear regression adjusting for age and sex, CLS status (beta = -0.28, p = 0.008) and waist circumference (beta = -0.25, p = 0.03) were independent predictors of flow-mediated dilation. CONCLUSIONS: These findings lend support to the novel concept that factors in addition to absolute weight burden, such as qualitative features of adipose tissue, might be important determinants of cardiovascular disease. Therapeutic modulation of the adipose phenotype might represent a target for treatment in obesity.


Assuntos
Doenças Cardiovasculares/sangue , Síndrome Metabólica/sangue , Obesidade/sangue , Obesidade/patologia , Fenótipo , Gordura Subcutânea Abdominal/patologia , Adulto , Glicemia/análise , Pressão Sanguínea , Índice de Massa Corporal , Artéria Braquial/fisiopatologia , Proteína C-Reativa/análise , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/fisiopatologia , Colesterol/sangue , Feminino , Humanos , Inflamação , Insulina/sangue , Macrófagos/patologia , Masculino , Síndrome Metabólica/complicações , Obesidade/complicações , Obesidade/fisiopatologia , Sobrepeso/patologia , Triglicerídeos/sangue
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