Inhibition of Rho/Rho-kinase signaling downregulates plasminogen activator inhibitor-1 synthesis in cultured human monocytes

Ishibashi, Toshiyuki; Nagata, Kenji; Ohkawara, Hiroshi; Sakamoto, Takayuki; Yokoyama, Keiko; Shindo, Joji; Sugimoto, Koichi; Sakurada, Sotaro; Takuwa, Yoh; Teramoto, Tamio; Maruyama, Yukio

doi:10.1016/s0167-4889(02)00201-x

Cited by 32 publications

(25 citation statements)

References 41 publications

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“…1C) and PBMC (Fig. 1D), clearly contradicts earlier observations of reduced Rho activation in myeloid (19) and lymphoma cells (20), as determined by similar GTP-binding assays. Because the latter reports applied longer incubations (at least 48 h) with HMGCRI, we next performed a kinetic with atorvastatin in PBMC.…”

Section: Increased Rho Gtp Loading In T Cells Following Ggpp Depletionsupporting

confidence: 76%

Geranylgeranylation but Not GTP Loading Determines Rho Migratory Function in T Cells

Waiczies

Bendix

Prozorovski

et al. 2007

The Journal of Immunology

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Rho GTPases orchestrate signaling pathways leading to cell migration. Their function depends on GTP loading and isoprenylation by geranylgeranyl pyrophosphate (GGpp). In this study, we show that in human T cells, geranylgeranylation—and not GTP loading—is necessary for RhoA-mediated downstream events. As a result of GGpp depletion with the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin, RhoA was sequestered from the membrane to the cytosol and, notwithstanding increased GTP loading, the constitutive activation of its substrate Rho-associated coiled-coil protein kinase-1 was blocked. In line with this, T cells expressing increased GTP-RhoA failed to form an intact cytoskeleton and to migrate toward a chemokine gradient. In vivo treatment with atorvastatin in the rodent model of multiple sclerosis markedly decreased the capacity of activated T cells to traffic within the brain, as demonstrated by multiphoton analysis. Thus, tethering of RhoA to the membrane by GGpp is determinant for T cell migration and provides a mechanism for preventing T cell infiltration into inflamed compartments by 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors,

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Section: Increased Rho Gtp Loading In T Cells Following Ggpp Depletionsupporting

confidence: 76%

Geranylgeranylation but Not GTP Loading Determines Rho Migratory Function in T Cells

Waiczies

Bendix

Prozorovski

et al. 2007

The Journal of Immunology

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“…We also showed that both hydrophilic and lipophilic statins suppress molecular expression, including tissue factor and plasminogen activator inhibitor-1, by depletion of cellular geranylgeranylpyrophosphate (GGPP) 16,[26][27][28] . Taken together with other reports [29][30][31] , our previous study clearly demonstrated the exact mechanism of the pleiotropic effect that statins rapidly blocks the activation of unprocessed GDP-RhoA by inhibiting geranylgeranylation 9) .…”

Section: Discussionmentioning

confidence: 95%

RhoA and Rac1 Changes in the Atherosclerotic Lesions of WHHLMI Rabbits

Ohkawara¹,

Ishibashi²,

Shiomi

et al. 2009

JAT

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Aim:The activation of RhoA and Rac1 is crucial for the pathogenesis of atherosclerosis. This study investigated the changes of unprocessed and mature forms of RhoA and Rac1 in the progression of atherosclerosis. Methods: Unprocessed and geranylgeranylated forms of RhoA and Rac1 in aortic atherosclerotic lesions were separated by the Triton X-114 partition method using Watanabe heritable hyperlipidemic (WHHLMI) rabbits prone to myocardial infarction. The activation of RhoA and Rac1 was determined by membrane translocation and pull-down assays. Results: The levels of unprocessed RhoA and Rac1 of the aortas were higher at 7 months than 3 months, accompanied by increased levels of total RhoA and Rac1. Membrane-bound RhoA and Rac1 levels of the aortas at 7 months were significantly increased compared with those at 3 months, consistent with the results of GTP-loading. Unprocessed and activated forms of RhoA and Rac1 had gradually decreas at 15 and 24 months compared to 7 months. Conclusions: We show evidence of marked increases in unprocessed RhoA and Rac1 with enhanced activities in the progression of atherosclerosis in WHHLMI rabbits. This is important for better understanding of the pathogenesis of hyperlipidemia-dependent atherosclerosis.

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“…For example, statins increase endothelial nitric oxide synthase expression, 14 decrease smooth muscle cell proliferation, 15 reduce matrix metalloproteinase activity and tissue factor production by macrophages, 16,17 increase fibrinolytic activity, 18 and have immunomodulatory and antiinflammatory actions such as increasing resistance to complement 19 and decreasing dendritic cell maturation. 20 Many of these effects are reversed only with geranylgeranyl pyrophosphate and not with farnesyl pyrophosphate, suggesting that inhibition of Rho isoprenylation by statins is the predominant mechanism by which statins exert their antiatherogenic activities.…”

Section: Discussionmentioning

confidence: 99%

“…12 Extending our data to the clinical situation, the differential response of the volunteers suggests that individual patients will benefit to different degrees from the pleiotropic effects of statins, independently of the lipid-lowering effect. The increase in nonisoprenylated inactive form of RhoA in PBMCs has been linked to the atheroprotective effects of statins on these cells, such as downregulation of plasminogen activator inhibitor-1 synthesis, 18 decreased transcription of matrix metalloproteinases and adhesion molecules in monocytes, 16 decreased monocyte-endothelial cell interactions, 23 and inhibition of activation and proliferation of T lymphocytes. 24 The most responsive patients will be expected to benefit from lipidlowering and from pleiotropic atheroprotective effect of statins.…”

Section: Discussionmentioning

confidence: 99%

Monitoring the Cellular Effects of HMG-CoA Reductase Inhibitors In Vitro and Ex Vivo

Cicha

Schneiderhan‐Marra

Yılmaz

et al. 2004

ATVB

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Objective-Inhibition of 3hydroxy3methylglutaryl-coenzyme A (HMG-CoA) reductase by statins and the subsequent reduction in Rho protein isoprenylation inactivates these important signaling molecules. The purpose of this study was to directly monitor statin effects on Rho proteins. Methods and Results-We used biphasic Triton X-114 system, 1-dimensional isoelectric focusing, and 2D-electrophoresis for the separation of modified and nonmodified Rho proteins. These methods were evaluated in human fibroblasts treated with simvastatin. 2D-electrophoresis, which proved to be the most sensitive method, revealed 2 major spots of identical molecular weight but different isoelectric points, with the more basic spot representing the carboxymethylated form of RhoA. In control cells, 90% of RhoA was fully modified (carboxymethylated). After treatment with simvastatin, a significant shift toward the unmethylated form was observed, representing inhibition of isoprenylation, which is a prerequisite to further modification. Similar shifts were observed for Rac1 and Cdc42. In freshly isolated peripheral blood mononuclear cells, a shift toward nonmodified RhoA was observed after treatment with atorvastatin in vitro and in vivo. There was a significant increase in unmethylated RhoA in statin-treated individuals versus control individuals. Key Words: RhoA Ⅲ isoprenylation Ⅲ carboxymethylation Ⅲ HMG-CoA reductase Ⅲ statins T herapy with 3hydroxy3methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) is associated with lipid-lowering and plaque-stabilizing effects, resulting from their interference with cholesterol biosynthesis. However, recent experimental and clinical evidence indicate that the beneficial effects of statins extend beyond cholesterol reduction, involving improved plaque composition, decreased inflammation, and ameliorated endothelial function. 1,2 These pleiotropic effects are mediated by the ability of statins to interfere directly with the posttranslational modification of signaling proteins, particularly small GTP-binding proteins of the Ras and Rho families. Because the membrane localization and function of Ras and Rho depend on the attachment of isoprenoid intermediates to these proteins, by inhibiting protein isoprenylation, statin treatment leads to accumulation of the inactive forms of Ras and Rho in the cytoplasm. Although farnesylation of Ras proteins and geranylgeranylation of Rho proteins are equally affected by statins, many of the beneficial cardiovascular effects of statins are thought to be a result of their interference with Rho protein signaling. 3 As interference with the geranylgeranyl modification of Rho proteins is one of the earliest steps related to the direct cellular actions of statins, it appears desirable to determine the relative amount of modified versus nonmodified protein. Some of the isoprenylated proteins, such as Ras proteins, can be separated from their nonmodified form by high-resolution SDS-polyacrylamide gel electrophoresis (SDS-PAGE). 4 However, for Rho family prot...

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Inhibition of Rho/Rho-kinase signaling downregulates plasminogen activator inhibitor-1 synthesis in cultured human monocytes

Cited by 32 publications

References 41 publications

Geranylgeranylation but Not GTP Loading Determines Rho Migratory Function in T Cells

Geranylgeranylation but Not GTP Loading Determines Rho Migratory Function in T Cells

RhoA and Rac1 Changes in the Atherosclerotic Lesions of WHHLMI Rabbits

Monitoring the Cellular Effects of HMG-CoA Reductase Inhibitors In Vitro and Ex Vivo

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