guanosine-triphosphate and Arteriosclerosis

3-Hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are competitive inhibitors of the rate-limiting enzyme in cholesterol synthesis. Several clinical trials have shown a marked reduction in cholesterol levels associated with decreased cardiovascular mortality in patients treated with statins. However, more recent observations have suggested that the clinical benefits of statins may be, at least in part, independent of the effect of statins on cholesterol synthesis. These so-called pleiotropic or cholesterol-independent effects of statins could be the result of reduction in the formation of intermediaries in the mevalonate pathway as statins, by inhibiting L-mevalonic acid synthesis, also prevent the production of isoprenoids in the cholesterol biosynthetic pathway. Isoprenoids serve as important lipid attachments for the posttranslational modification of a variety of proteins such as small GTP-binding proteins of the Ras superfamily implicated in intracellular signaling. The list of different pleitropic effects of statins is still growing and includes, among others, direct effects of statins on modulating endothelial function, decreasing oxidative stress and, more recently, anti-inflammatory and immunomodulatory actions of statins. For instance, statins decrease T cell activation, the recruitment of inflammatory cells into atherosclerotic lesions, and inhibit IFN-gamma expression of MHC II on antigen-presenting cells. This review article summarizes the anti-inflammatory and immunomodulatory effects of statins and thus provides a new rationale to use statins as a new class of immunosuppressive agents.

Topics: Adjuvants, Immunologic; Animals; Arteriosclerosis; Cell Line; Cholesterol; Clinical Trials as Topic; Guanosine Triphosphate; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Interferon-gamma; Mevalonic Acid; Models, Biological; T-Lymphocytes; Transplantation

In the process of atherosclerosis, platelet activating factor (PAF) promotes the infiltration of inflammatory cells into atherosclerotic plaque by modulating their cytoskeleton. Here, we examined whether Rho family proteins are involved in PAF-induced cytoskeletal reorganization in THP-1 macrophages. PAF stimulation rapidly induced cell elongation, accompanied by filopodia formation. The inhibition of Rho family proteins by the overexpression of Rho-GDI attenuated the PAF-mediated morphological changes. Both RhoA and Cdc42 were activated in response to PAF. Inhibition of RhoA or Cdc42 by dominant negative mutants abrogated morphological changes induced by PAF. Collectively, PAF regulates cytoarchitecture through Rho family proteins in macrophages.

Topics: Adenoviridae; Arteriosclerosis; beta-Galactosidase; cdc42 GTP-Binding Protein; Cell Line, Tumor; Cytoskeleton; Gene Transfer Techniques; Guanine Nucleotide Dissociation Inhibitors; Guanosine Triphosphate; Humans; Immunoblotting; Inflammation; Macrophages; Platelet Activating Factor; Pseudopodia; rac1 GTP-Binding Protein; rho GTP-Binding Proteins; rho-Specific Guanine Nucleotide Dissociation Inhibitors; rhoA GTP-Binding Protein; Time Factors; Up-Regulation

To determine the effects of green tea polyphenols(GTP) on advanced glycation end products (AGEs)-induced proliferation and expression of p44/42 mitogen-activated protein kinase (MAPK) of rat vascular smooth muscle cells (VSMCs). Rat aortic VSMCs isolated and cultured in vitro were stimulated with AGEs in the presence or absence of GTP at different concentrations, followed by quantitative analysis of the cell proliferation with colorimetric assay. The p44/42 MAPK activity was evaluated by immunoblotting technique using anti-p44/42 phospho-MAPK antibody.. Compared with the control cells(without GTP treatment), GTP dose-dependently inhibited AGE-stimulated VSMC proliferation (P<0.05), and the p44/42 MAPK activity was significantly enhanced. The effects of AGEs were antagonized by GTP (372+/-41 vs 761+/-56, P<0.05).. GTP can inhibit the AGE-induced proliferation and p44/42 MAPK expression of rat VSMCs.

Topics: Animals; Arteriosclerosis; Cells, Cultured; Flavonoids; Glycation End Products, Advanced; Guanosine Triphosphate; Male; Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenols; Polyphenols; Rats; Rats, Sprague-Dawley; Tea

Temporal gradients in fluid shear stress have been shown to induce a proatherogenic phenotype in endothelial cells. The biomechanical mechanism(s) that enables the endothelium to respond to fluid shear stress requires rapid activation and signal transduction. The small G protein Ras has been identified as an early link between rapid mechanotransduction events and the effects of shear stress on downstream signal-transduction cascades. The aim of this study was to elucidate the upstream mechanotransduction signaling events mediating the rapid activation of Ras by fluid shear stress in human endothelial cells.. Direct measurement of Ras-bound GTP and GDP showed that fluid-flow activation of Ras was rapid (10-fold within 5 seconds) and dose dependent on shear stress magnitude. Treatment with protein tyrosine kinase inhibitors or pertussis toxin did not significantly affect flow-induced Ras activation. However, activation was inhibited by transient transfection with antisense to Galpha(q) or the Gbetagamma scavenger beta-adrenergic receptor kinase carboxy terminus. Transfection with several Gbetagamma subunit isoforms revealed flow-induced Ras activation was most effectively enhanced by Gbeta1gamma2.. These results suggest that the rapid, shear-induced activation of Ras is mediated by Galpha(q) through the activity of Gbetagamma subunits in human vascular endothelial cells.

Topics: Adaptation, Physiological; Arteriosclerosis; beta-Adrenergic Receptor Kinases; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Endothelial Cells; Endothelium, Vascular; Enzyme Activation; Enzyme Inhibitors; GTP-Binding Protein alpha Subunits, Gq-G11; Guanosine Diphosphate; Guanosine Triphosphate; Humans; MAP Kinase Signaling System; Oligodeoxyribonucleotides, Antisense; Pertussis Toxin; Protein Subunits; Proto-Oncogene Proteins p21(ras); Recombinant Fusion Proteins; Rheology; Stress, Mechanical; Transfection