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(Journal of Leukocyte Biology. 2001;69:959-962.)
© 2001 by Society for Leukocyte Biology

Statins suppress THP-1 cell migration and secretion of matrix metalloproteinase 9 by inhibiting geranylgeranylation

Birming Wong^*, William C. Lumma, Anthony M. Smith, John T. Sisko, Samuel D. Wright^* and Tian-Quan Cai^*

Departments of
^* Lipid Biochemistry and
Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey

Correspondence: Tian-Quan Cai, Merck Research Laboratories, Department of Lipid Biochemistry, RY80W-250, 126 East Lincoln Avenue, Rahway, NJ 07065.

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Macrophages secrete matrix metalloproteinase 9 (MMP-9), an enzyme that weakens the fibrous cap of atherosclerotic plaques, predisposing them to plaque rupture and subsequent ischemic events. Recent work indicates that statins strongly reduce the possibility of heart attack. Furthermore, these compounds appear to exert beneficial effects not only by lowering plasma low-density-lipoprotein cholesterol but also by directly affecting the artery wall. To evaluate whether statins influence the proinflammatory responses of monocytic cells, we studied their effects on the chemotactic migration and MMP-9 secretion of human monocytic cell line THP-1. Simvastatin dose dependently inhibited THP-1 cell migration mediated by monocyte chemoattractant protein 1, with a 50% inhibitory concentration of about 50 nM. It also inhibited bacterial lipopolysaccharide-stimulated secretion of MMP-9. The effects of simvastatin were completely reversed by mevalonate and its derivatives, farnesylpyrophosphate and geranylgeranyl pyrophosphate, but not by ubiquinone. Additional studies revealed similar but more profound inhibitory effects with L-839,867, a specific inhibitor of geranylgeranyl transferase. However, -hydroxyfarnesyl phosphonic acid, an inhibitor of farnesyl transferase, had no effect. C3 exoenzyme, a specific inhibitor of the prenylated small signaling Rho proteins, mimicked the inhibitory effects of simvastatin and L-839,867. These data supported the role of geranylgeranylation in the migration and MMP-9 secretion of monocytes.

Key Words: monocytes • inhibitors • HMG-CoA reductase

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Agents that inhibit 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (statins) are widely used in the treatment of patients with hypercholesterolemia. Such agents improve the survival of patients with coronary heart disease in hypercholesterolemic individuals [¹ , ² ]. Although the benefits of statins are primarily attributed to their lipid-lowering effects, accumulating evidence suggests the possibility of other beneficial effects independent from serum cholesterol levels. For example, statins have been found to reduce neointimal thickening in normocholesterolemic rabbits [³ ], infarct size in normocholesterolemic mice [⁴ ], and atherosclerotic lesions in mice deficient in apolipoprotein E, without altering plasma lipid levels [⁵ ].

The inhibition of HMG-CoA reductase blocks the production of mevalonic acid, a precursor for both cholesterol and several isoprenoid intermediates. Some of these intermediates, such as farnesylpyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), are substrates for the posttranslational isoprenylation of various proteins involved in cell signaling [⁶ , ⁷ ]. Results from several recent studies indicated that some of the direct effects of HMG-CoA reductase inhibitors on the vascular wall are mediated by the inhibition of isoprenoid but not cholesterol synthesis [^{8 9 10} ]. For example, inhibitors of HMG-CoA reductase were found to enhance the expression of nitric oxide synthase [⁸ ] and fibrinolytic activity in endothelial cells [⁹ ] and to induce apoptosis in smooth muscle cells [¹⁰ ]. All these effects appear to be linked to a reduction of isoprenoid but not cholesterol synthesis [^{8 9 10} ].

Monocyte recruitment and secretion of matrix metalloproteinases (MMPs) are crucial for many inflammatory processes, including the initiation and progression of atherosclerotic lesions [¹¹ , ¹² ]. We showed that simvastatin, an HMG-CoA reductase inhibitor, inhibited chemotactic migration and MMP-9 secretion in human monocytic THP-1 cells. These data demonstrate an important anti-inflammatory role for statins in monocytes. Additional studies with a newly developed specific inhibitor for geranylgeranyl transferase revealed similar but much more profound anti-inflammatory activities.

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Reagents
Bacterial lipopolysaccharide (LPS) from Salmonella minnesota strain R595 was obtained from List Biological Laboratories, Inc. (Campbell, CA). Recombinant human MMP-9 and monocyte chemoattractant protein-1 (MCP-1) were purchased from R&D Systems (Minneapolis, MN). Sheep anti-human MMP-9 was obtained from Biodesign International (Kennebunkport, ME). Biotinylated monoclonal anti-human MMP-9 was purchased from Oncogene Research Products (Cambridge, MA). CellTiter 96 AQ_ueous One solution was obtained from Promega (Madison, WI). Disposable 96-well chemotaxis chambers were purchased from Neuroprobe, Inc. (Gaithersburg, MD). Superblock was obtained from Pierce (Rockford, IL). Streptavidin-conjugated alkaline phosphatase was purchased from Bio-Rad (Hercules, CA). Heat-inactivated fetal calf serum (FCS) and RPMI 1640 medium were obtained from Life Technologies (Gaithersburg, MD). -Hydroxyfarnesyl phosphonic acid (HFPA), FPP, GGPP, penicillin G, and streptomycin were purchased from Sigma (St Louis, MO). Attophos was obtained from JBL Scientific, Inc. (San Luis Obispo, CA). Recombinant C3 exoenzyme was purchased from Upstate Biotechnology (Lake Placid, NY). L-839,867, a specific inhibitor for geranylgeranyl transferase, was synthesized at Merck [¹³ ].

Cell culture
Human THP-1 monocytic leukemia cells were obtained from the American Type Culture Collection (Rockville, MD). Cells were maintained in RPMI 1640 medium with 10% heat-inactivated FCS, 50 U/mL of penicillin G, and 50 µg/mL of streptomycin sulfate in an atmosphere containing 5% CO₂ and 95% air. Before assay, cultured cells were harvested and washed once with phosphate-buffered saline and then resuspended in the assay medium (RPMI 1640 medium with 0.5% heat-inactivated FCS, 50 U/mL of penicillin G, and 50 µg/mL of streptomycin sulfate). All reagents used in the experiments were diluted in the same assay medium. Cells were seeded at a density of 1.5 x 10⁴ cells/well into 96-well plates with a final volume of 250 µL/well. They were treated with compounds for 1 h before the addition of either LPS or assay medium. After a 48-h incubation at 37°C, plates were centrifuged at 500 g for 5 min. A 150-µL/well conditioned cell medium was then harvested from each well. Media from triplicate samples were pooled and assayed for MMP-9 concentrations.

Cell migration assay
The migration of THP-1 cells was studied using a ChemoTx 96-well disposable chamber (Neuroprobe, Inc., Gaithersburg, MD) and quantitated using the AQ_ueous cell proliferation assay kit (Promega). Briefly, cells suspended in the assay medium (RPMI 1640 medium with 0.5% heat-inactivated FCS, 50 U/mL of penicillin G, and 50 µg/mL of streptomycin sulfate) at 10⁶ cells/mL were incubated with various doses of compounds. After overnight (16 h) incubation at 37°C, 50 µL of treated cells were transferred on to the top of the chemotaxis chamber, a 96-well framed filter with 8-µm pores. The lower chamber, a 96-well plate, contained 30 µL/well of the assay medium with or without MCP-1. For total cell determination, 30 µL of a serial dilution of cells were placed directly into the lower chamber. Incubation was continued for 90 min at 37°C, after which the nonmigrating cells on the origin side (i.e., top) of the filter were removed by gentle wiping with a cell harvester and flushed with phosphate-buffered saline. Plates were centrifuged at 500 g for 5 min. After centrifugation, filters were removed. To determine the number of cells that migrated to the lower chamber, 5 µL/well of medium were removed from each well, and the same amount of AQ_ueous One solution was added. Plates were incubated for 2 h at 37°C. Formazan formation was measured using a multiwell SpectraFluor plate reader (Tecan U.S. Inc., Research Triangle Park, NC) at 492 nm. Results were expressed in arbitrary absorbance units. Each sample was assayed in triplicate.

MMP-9 assay
MMP-9 was quantitated using sandwich enzyme-linked immunosorbent assays with commercially available antibodies, as described previously [¹⁴ ]. Antibodies against human MMP-9 used in the assay do not show detectable cross-reactivity with MMP-1, -2, or -3.

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
HMG-CoA reductase inhibitor reduces the migration of THP-1 cells
The migration of THP-1 cells was studied with a ChemoTx 96-well disposable chamber in the presence of MCP-1, a well-characterized chemoattractant of monocytic cells. As expected, MCP-1 caused a dose-dependent increase in the migration of THP-1 cells (data not shown). At 25 ng/mL of MCP-1, 14,167 ± 2,397 cells/well migrated to the bottom chamber. This represented a 6.8-fold increase in comparison with the control value of 2,081 ± 384 cells/well (n =4). Pretreatment of THP-1 cells with simvastatin resulted in a dose-dependent inhibition of cell migration mediated by MCP-1 (Fig. 1 ). At 2 µM, simvastatin inhibited the migration of THP-1 cells by > 85%. The concentration needed for a half maximal inhibition is about 50 nM. The simvastatin-mediated reduction of THP-1 cell migration apparently is not caused by cell toxicity, because parallel studies showed that simvastatin fails to significantly change the ability of cells to convert 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt into formazan (data not shown; for assay details, see reference 14).

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Figure 1. HMG-CoA reductase inhibitor reduces migration of THP-1 cells. THP-1 cells at 106 cells/mL were mixed with indicated concentrations of simvastatin. After overnight incubation, treated cells were transferred to a chemotaxis chamber. The migration of cells toward MCP-1 (25 ng/mL) during a 90-min incubation was determined as described in Materials and Methods. Data are presented as percentages of control of a representative experiment repeated three times.

Reversal effects of mevalonate metabolites
To determine which mevalonate metabolites may be important for the inhibitory effect of simvastatin, several mevalonate derivatives were tested. Mevalonate derivatives alone failed to significantly affect the cell migration (data not shown). Coincubation of mevalonate (100 µM), FPP (15 µM), or GGPP (15 µM) with simvastatin (1 µM) completely reversed the inhibitory effect of simvastatin (Fig. 2 ). In contrast, coincubation of ubiquinone (50 µM) with simvastatin failed to reverse the effect.

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Figure 2. Reversal effects of mevalonate metabolites on migration of THP-1 cells. THP-1 cells at 106 cells/mL were mixed with medium (Control), simvastatin [Simva (S); 1 µM], or simvastatin plus indicated metabolites [mevalonate (S +Meva), 100 µM; FPP (S +FPP), 15 µM; GGPP (S +GGPP), 15 µM; ubiquinone (S + Ubiqu), 50 µM). After overnight incubation, treated cells were transferred to a chemotaxis chamber. Migration of cells toward MCP-1 (25 ng/mL) was determined. Data are presented as percentages of control of a representative experiment repeated three times.

Role of geranylgeranylation in cell migration
Because FPP and GGPP both may be used for posttranslational modification of signaling molecules [¹⁵ ], we tested the involvement of these two molecules in regulating migration by using a specific inhibitor for farnesyl transferase or geranylgeranyl transferase. As shown in Figure 3A , the inhibition of farnesyl transferase with a known specific inhibitor, HFPA, at concentrations up to 30 µM, failed to significantly affect migration. In contrast, inhibition of geranylgeranyl transferase using a specific inhibitor, L-839,867, at 1 nM dramatically reduced cell migration. The inhibitory effect mediated by L-839,867 was dose dependent (Fig. 3B) . A nearly complete inhibition was observed at concentrations of < 1 nM. Although certain mevalonate derivatives reversed the inhibitory effects of simvastatin (Fig. 2) , our additional studies showed that none of these derivatives were able to reverse the inhibitory effect of L-839,867 (data not shown). These data demonstrate the involvement of protein geranylgeranylation in cell migration.

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Figure 3. Effects of farnesyl and geranylgeranyl transferase inhibitors on migration of THP-1 cells. THP-1 cells at 106 cells/mL were mixed with (A) medium, HFPA (30 µM), or L-839,867 (1 nM), or (B) indicated concentrations of L-839,867. After overnight incubation, treated cells were transferred to a chemotaxis chamber. Migration of cells toward MCP-1 (25 ng/mL) was determined. Data are presented as percentages of control of a representative experiment repeated three times.

Among isoprenylated proteins, the Rho and Rab proteins are known to be the most geranylgeranylated [¹⁶ ]. To determine whether the inhibitory effect of simvastatin or L-839,867 resulted from an inhibition of prenylation of Rho proteins, cell migration was measured in the presence of C3 exoenzyme, a specific inhibitor of the Rho proteins [¹⁷ ]. As shown in Figure 4 , the addition of C3 exoenzyme (5 µg/mL) dramatically reduced cell migration.

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Figure 4. Inhibitor of Rho proteins reduces migration of THP-1 cells. THP-1 cells at 106 cells/mL were mixed with C3 exoenzyme (5 µg/mL). After overnight incubation, treated cells were transferred to a chemotaxis chamber. Migration of cells toward MCP-1 (25 ng/mL) was determined. Data are presented as percentages of control of a representative experiment repeated three times.

Role of geranylgeranylation in MMP-9 secretion
In addition to migration, the secretion of proinflammatory molecules is crucial for macrophage-mediated inflammatory responses. We next investigated the effects of the inhibition of geranylgeranylation on the secretion of MMP-9, a well-known proinflammatory molecule. THP-1 cells were initially maintained in a medium with 10% FCS and then transferred to a medium with 0.5% FCS in the presence of increasing concentrations of L-839,867, a specific inhibitor of geranylgeranyl transferase. As we previously reported [¹⁴ ], the production of MMP-9 in THP-1 cells is entirely dependent on stimulation. The incubation of THP-1 cells with LPS led to a dose-dependent secretion of MMP-9 (data not shown). At 1 ng/mL of LPS, THP-1 cells secreted 21.2 ± 4.8 ng/mL of MMP-9 (equivalent to 0.354 ±0.08 pg/cell; n =8). The treatment of cells with L-839,867 resulted in a dose-dependent inhibition of the secretion of MMP-9 (Fig. 5 ).

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Figure 5. Geranylgeranyl transferase inhibitor reduces secretion of MMP-9 from THP-1 cells. THP-1 cells (1.5 x104 cells/well) were plated in a 96-well plate and mixed with increasing concentrations of L-839,867. After 60 min of incubation at 37°C, LPS (1 ng/mL) and 0.25% normal human plasma were added, and plates were incubated for another 48 h at 37°C. Culture media were harvested, and MMP-9 concentrations were determined by enzyme-linked immunosorbent assay. Data are presented as percentages of control of a representative experiment repeated three times.

Additional studies showed that the treatment of cells with HFPA, a specific inhibitor of farnesyl transferase, failed to inhibit the secretion of MMP-9 (data not shown). The treatment of cells with simvastatin also inhibited the secretion of MMP-9, but to a much smaller extent than that with L-839,867 (data not shown).

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this study, we demonstrated an important role for protein geranylgeranylation in regulating chemotactic migration and MMP-9 secretion of human monocytic THP-1 cells. We showed that the treatment of THP-1 cells with simvastatin, an inhibitor of HMG-CoA reductase, reduced MCP-1-mediated migration and LPS-induced MMP-9 secretion. Further, by using various mevalonate metabolites, we showed that the inhibitory effects of simvastatin are reversed by the presence of mevalonate, FPP, and GGPP, but not ubiquinone. Finally, we reported similar but much more potent inhibitory effects with L-839,867, a specific inhibitor of geranylgeranyl transferase, but not with HFPA, a specific inhibitor of farnesyl transferase. Recently, several groups have reported statin effects on vascular cells, including smooth muscle cells and endothelial cells. It was found that the statin affects nitric oxide synthase expression [⁸ ], fibrinolytic activity [⁹ ], apoptosis [¹⁰ ], and plasminogen activator inhibitor-1 expression [¹⁸ ], and that all these may be linked to protein geranylgeranylation. In a similar fashion, another recent study showed that the treatment of fluvastatin reduces the secretion of MMP-9 from mouse and human macrophages [¹⁹ ]. Together with our data, these observations suggest that statins may use a common mechanism, that is, the reduction of geranylgeranylation, to influence several functional processes in various cell types.

The isoprenylated small guanosine triphosphate (GTP) proteins Rho and Rab are major substrates for posttranslational modification by geranylgeranyl transferase [¹⁶ ]. Upon geranylgeranylation, these signaling molecules are activated and play an important role in many functional processes, including the regulation of membrane traffic, exocytic and endocytic transport processes [²⁰ ], actin stress-fiber formation, focal adhesion assembly, and reorganization of the actin cytoskeleton [²¹ , ²² ]. It is conceivable that the blockade of prenylation may prevent the activation of these signaling molecules and thus suppress the corresponding cell functions. Consistent with this notion, we showed that C3 exoenzyme, a specific inhibitor for the Rho proteins, also inhibits the migration and MMP-9 secretion of THP-1 cells. Because C3 exoenzyme may block the activation of several Rho protein family members [¹⁷ ], further studies are needed to elucidate which specific Rho molecule contributes to migration and MMP-9 secretion.

Monocyte recruitment and secretion of MMP-9 are crucial for the initiation and progression of atherosclerosis [¹¹ , ¹² ]. Statin-mediated reduction of monocyte migration and MMP-9 secretion could potentially play an important role in lowering the incidence of coronary heart disease. Although the data presented here have not yet been linked directly to in vivo statin effects, the effective concentration of simvastatin is quite low and in the range that could be expected to occur in vivo. For example, at 16 nM, simvastatin reduces THP-1 migration by 40%. Such concentrations presumably are attainable in patients taking statin therapy.

Increasing attention has been directed in recent years to the development of prenyl transferase inhibitors in an attempt to block tumor cell proliferation [²³ , ²⁴ ]. It is interesting that studies on the potential anti-inflammatory effects of prenyl transferase inhibitors have been limited. The data presented in this article show that L-839,867, an inhibitor of geranylgeranyl transferase, is very effective in inhibiting monocyte proinflammatory responses. At 1 nM concentration, it completely blocks the migration of THP-1 cells. Our results suggest that inhibitors of geranylgeranyl transferase could potentially be used as anti-inflammatory agents.

 
We thank Dr. Anne Hermanowski-Vosatka for critical reading of the manuscript.

Received September 18, 2000; revised January 13, 2001; accepted January 16, 2001.

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

1
1. . Scandinavian Simvastatin Survival Study Group (1994) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet 344,1383-1389[Medline]
2
2. Shepherd, J., Cobbe, S. M., Ford, I., Isles, C. G., Lorimer, A. R., MacFarlane, P. W., McKillop, J. H., Packard, C. J. (1995) Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia N. Engl. J. Med. 333,1301-1307[Abstract/Free Full Text]
3
3. Soma, M. R., Donetti, E., Parolini, C., Mazzini, G., Ferrari, C., Fumagalli, R., Paoletti, R. (1993) HMG CoA reductase inhibitors: in vivo effects on carotid intimal thickening in normocholesterolemic rabbits Arterioscl. Thromb. 13,571-578[Abstract/Free Full Text]
4
4. Endres, M., Laufs, U., Huang, Z., Nakamura, T., Huang, P., Moskowitz, M. A., Liao, J. K. (1998) Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase Proc. Natl. Acad. Sci. USA 95,8880-8885[Abstract/Free Full Text]
5
5. Sparrow, C. P., Burton, C. A., Hernandez, M., Mundt, S., Hassing, H., Patel, S., Rosa, R., Hermanowski-Vosatka, A., Wanf, P. R., Zhang, D., Peterson, L., Detmers, P. A., Chao, Y. S., Wright, S. D. (2001) Simvastatin has anti-inflammatory and anti-atherosclerotic activities independent of plasma cholesterol-lowering Arterioscl. Thromb. Vasc. Biol. 21,115-121[Abstract/Free Full Text]
6
6. Goldstein, J. L., Brown, M. S. (1990) Regulation of the mevalonate pathway Nature 343,425-430[Medline]
7
7. Casey, P. J. (1995) Protein lipidation in cell signaling Science 268,221-225[Abstract/Free Full Text]
8
8. Laufs, U., Liao, J. K. (1998) Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase J. Biol. Chem. 273,24266-24271[Abstract/Free Full Text]
9
9. Essig, M., Nguyen, G., Prie, D., Escoubet, B., Sraer, J. D., Friedlander, G. (1998) 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranylgeranylation and Rho proteins Circ. Res. 83,683-690[Abstract/Free Full Text]
10
10. Guijarro, C., Blanco-Colio, L. M., Ortego, M., Alonso, C., Ortiz, A., Plaza, J. J., Diaz, C., Hernandez, G., Edigo, J. (1998) 3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture Circ. Res. 83,490-500[Abstract/Free Full Text]
11
11. Libby, P., Geng, Y. J., Aikawa, M., Schoenbeck, U., Mach, F., Clinton, S. K., Sukhova, G. K., Lee, R. T. (1996) Macrophages and atherosclerotic plaque stability Curr. Opin. Lipidol. 7,330-335[Medline]
12
12. Ross, R. (1999) Atherosclerosis—an inflammatory disease N. Engl. J. Med. 340,115-126[Free Full Text]
13
13. Huber, H. E., Abrams, M., Graham, S., Hartman, G., Lobell, R., Lumma, W., Nahas, D., Robinson, R., Sisko, J., Heimbrook, D. C. (2000) Biochemical evaluation of specific geranylgeranyltransferase inhibitors, In Proc Am. Assoc. Cancer Res. San Francisco, CA 41,446
14
14. Shu, H., Wong, B., Zhou, G., Li, Y., Berger, J., Woods, J. W., Wright, S. D., Cai, T. Q. (2000) Activation of PPAR or reduces secretion of matrix metalloproteinase 9 but not interleukin 8 from human monocytic THP-1 cells Biochem. Biophys. Res. Commun. 267,345-349[Medline]
15
15. Casey, P. J., Seabra, M. C. (1996) Protein prenyltransferases J. Biol. Chem. 271,5289-5292[Free Full Text]
16
16. Adamson, P., Marshall, C. J., Hall, A., Tilbrook, P. A. (1992) Post-translational modifications of p21rho proteins J. Biol. Chem. 267,20033-20038[Abstract/Free Full Text]
17
17. Aktories, K., Braun, U., Rosener, S., Just, I., Hall, A. (1989) The rho gene product expressed in E. coli is a substrate of botulinum ADP-ribosyltransferase C3 Biochem. Biophys. Res. Commun. 158,209-213[Medline]
18
18. Bourcier, T., Libby, P. (2000) HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells Arterioscl. Thromb. Vasc. Biol. 20,556-562[Abstract/Free Full Text]
19
19. Bellosta, S., Via, D., Canavesi, M., Pfister, P., Fumagalli, R., Paoletti, R., Bernini, F. (1998) HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages Arterioscl. Thromb. Vasc. Biol. 18,1671-1678[Abstract/Free Full Text]
20
20. Zerial, M., Stenmark, H. (1993) Rab GTPases in vesicular transport Curr. Opin. Cell Biol. 5,613-620[Medline]
21
21. Van Aelst, L., D’Souza-Schorey, C. (1997) Rho GTPases and signaling networks Genes Dev 11,2295-2322[Free Full Text]
22
22. Hall, A. (1998) Rho GTPases and the actin cytoskeleton Science 279,509-514[Abstract/Free Full Text]
23
23. Casey, P. J., Seabra, M. C. (1996) Protein prenyltransferases J. Biol. Chem. 271,5289-5292
24
24. Tamanoi, F. (1993) Inhibitors of Ras farnesyltransferases Trends Biochem. Sci. 18,349-353[Medline]

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				L. M. Pierini, R. J. Eddy, M. Fuortes, S. Seveau, C. Casulo, and F. R. Maxfield Membrane Lipid Organization Is Critical for Human Neutrophil Polarization J. Biol. Chem., March 14, 2003; 278(12): 10831 - 10841. [Abstract] [Full Text] [PDF]

				P.O Bonetti, L.O Lerman, C Napoli, and A Lerman Statin effects beyond lipid lowering--are they clinically relevant? Eur. Heart J., February 1, 2003; 24(3): 225 - 248. [Full Text] [PDF]

				W. Palinski and C. Napoli Unraveling Pleiotropic Effects of Statins on Plaque Rupture Arterioscler. Thromb. Vasc. Biol., November 1, 2002; 22(11): 1745 - 1750. [Full Text] [PDF]

				V. Portik-Dobos, M. P. Anstadt, J. Hutchinson, M. Bannan, and A. Ergul Evidence for a Matrix Metalloproteinase Induction/Activation System in Arterial Vasculature and Decreased Synthesis and Activity in Diabetes Diabetes, October 1, 2002; 51(10): 3063 - 3068. [Abstract] [Full Text] [PDF]

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