Arteriosclerosis, thrombosis, and vascular biology
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Arterioscler. Thromb. Vasc. Biol. · Dec 2009
Inhibition of prolyl hydroxylase domain-containing protein suppressed lipopolysaccharide-induced TNF-alpha expression.
Prolyl hydroxylase domain-containing proteins (PHDs) play pivotal roles in oxygen-sensing system through the regulation of alpha-subunit of hypoxia-inducible factor (HIF), a key transcription factor governing a large set of gene expression to adapt hypoxia. Although tissue hypoxia plays an essential role in maintaining inflammation, the role of PHDs in the inflammatory responses has not been clearly determined. Here, we investigated the role of PHDs in lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) induction in macrophages. ⋯ PHD inhibition by DMOG or RNA interference inhibited LPS-induced TNF-alpha upregulation in macrophages possibly through NF-kappaB inhibition, which is independent of HIF-1alpha accumulation. This study suggests that PHDs are positive regulators of LPS-induced inflammatory process, and therefore inhibition of PHD may be a novel strategy for the treatment of inflammatory diseases.
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Arterioscler. Thromb. Vasc. Biol. · Dec 2009
Matrix metalloproteinase-10 is upregulated by thrombin in endothelial cells and increased in patients with enhanced thrombin generation.
Thrombin is a multifunctional serine protease that promotes vascular proinflammatory responses whose effect on endothelial MMP-10 expression has not previously been evaluated. ⋯ Thrombin induces MMP-10 through a PAR-1-dependent mechanism mediated by ERK1/2, JNK, and AP-1 activation. Endothelial MMP-10 upregulation could be regarded as a new proinflammatory effect of thrombin whose pathological consequences in thrombin-related disorders and plaque stability deserve further investigation.
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Arterioscler. Thromb. Vasc. Biol. · Nov 2009
Comparative StudyPPARbeta/delta agonists modulate platelet function via a mechanism involving PPAR receptors and specific association/repression of PKCalpha--brief report.
Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is a nuclear receptor found in platelets. PPARbeta/delta agonists acutely inhibit platelet function within a few minutes of addition. As platelets are anucleated, the effects of PPARbeta/delta agonists on platelets must be nongenomic. Currently, the particular role of PPARbeta/delta receptors and their intracellular signaling pathways in platelets are not known. ⋯ These data provide evidence of a novel mechanism by which PPAR receptors influence platelet activity and thereby thrombotic risk.
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Arterioscler. Thromb. Vasc. Biol. · Sep 2009
Targeted metabolomic evaluation of arginine methylation and cardiovascular risks: potential mechanisms beyond nitric oxide synthase inhibition.
We examine the relationship of related posttranslational modification products of arginine methylation and coronary artery disease (CAD) phenotypes. ⋯ ADMA, SDMA, and the integrated quantification of arginine methylation (in the form of a methylation index) provided independent risk prediction for both significantly obstructive CAD and incident MACE in stable patients undergoing cardiac evaluation. These results suggest that factors beyond direct NOS inhibition contribute to the clinical associations between methylarginines and CAD outcomes.
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Arterioscler. Thromb. Vasc. Biol. · Aug 2009
Comparative StudyMatrix metalloproteinase-9 is essential for ischemia-induced neovascularization by modulating bone marrow-derived endothelial progenitor cells.
Both matrix metalloproteinases (MMPs) and endothelial progenitor cells (EPCs) have been implicated in the process of neovascularization. Here we show that the impaired neovascularization in mice lacking MMP-9 is related to a defect in EPC functions in vasculogenesis. ⋯ These findings suggest that MMP-9 deficiency impairs ischemia-induced neovascularization, and these effects may occur through a reduction in releasing the stem cell-active cytokine, and EPC mobilization, migration, and vasculogenesis functions.