Mechanisms of Statin-mediated Inhibition of Small G-protein Function

Cordle, Andrew; Koenigsknecht-Talboo, Jessica; Wilkinson, Brandy; Limpert, Allison; Landreth, Gary

doi:10.1074/jbc.m505268200

Cited by 235Protein Kinase Regulation and GTPase SignalingAlzheimer's disease research and treatmentsSphingolipid Metabolism and Signaling

Mechanisms of Statin-mediated Inhibition of Small G-protein Function

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Cordle, Andrew, Koenigsknecht-Talboo, Jessica, Wilkinson, Brandy, Limpert, Allison, Landreth, Gary·2005·Journal of Biological Chemistry

DOI 10.1074/jbc.m505268200

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Abstract

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been reported to reduce the risk of Alzheimer disease. We have shown previously that statins inhibit a beta-amyloid (Abeta)-mediated inflammatory response through mechanisms independent of cholesterol reduction. Specifically, statins exert anti-inflammatory actions through their ability to prevent the isoprenylation of members of the Rho family of small G-proteins, resulting in the functional inactivation of these G-proteins. We report that statin treatment of microglia results in perturbation of the cytoskeleton and morphological changes due to alteration in Rho family function. Statins also block Abeta-stimulated phagocytosis through inhibition of Rac action. Paradoxically, the statin-mediated inactivation of G-protein function was associated with increased GTP loading of Rac and RhoA, and this effect was observed in myeloid lineage cells and other cell types. Statin treatment disrupted the interaction of Rac with its negative regulator the Rho guanine nucleotide dissociation inhibitor (RhoGDI), an interaction that is dependent on protein isoprenylation. We propose that lack of negative regulation accounts for the increased GTP loading. Isoprenylation of Rac is also required for efficient interaction with the plasma membrane, and we report that statin treatment dramatically reduces the capacity of Rac to interact with membranes. These results suggest a mechanism by which statins inhibit the actions of Rho GTPases and attenuate Abeta-stimulated inflammation.

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Statins act as inhibitors of some G-protein actions and Ras or Ras-like signaling, affecting several important bioprocesses.
“Thus, statins act as inhibitors of some G-protein actions and Ras or Ras-like signaling, which affect several important bioprocesses [15] .”
From Statins as antifungal agents (2011) · cites this paper as [15]
Statins induce apoptosis-like cell death in filamentous fungi.
“Beyond to the harmful effects on membrane fluidity and the synthesis of important isoprenoids for cell signaling and vital processes (such as cell proliferation and differentiation), and protein prenylation [16] , statins induce apoptosis-like cell death in filamentous fungi [15,30,31] .”
From Statins as antifungal agents (2011) · cites this paper as [15]

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LXR Regulation of Brain Cholesterol: From Development to Disease
Courtney, R., & Landreth, G. E. (2016) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2016.03.018 · Cited by 176 · see citing works
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Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension
Oka, M., Fagan, K. A., Jones, P. L., & McMurtry, I. F. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.239 · Cited by 177 · see citing works
The roles of NADPH oxidase and phospholipases A2in oxidative and inflammatory responses in neurodegenerative diseases
Sun, G. Y., Horrocks, L. A., & Farooqui, A. A. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04670.x · Cited by 169 · see citing works
Pleiotropic effects of statins: A focus on cancer
Ahmadi, M., Amiri, S., Pecic, S., Machaj, F., Rosik, J., Łoś, M., Alizadeh, J., Mahdian, R., Rosa, S. C. D. S., Schaafsma, D., et al. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165968 · Cited by 159 · see citing works
HMG-CoA Reductase Inhibitors Bind to PPARα to Upregulate Neurotrophin Expression in the Brain and Improve Memory in Mice
Roy, A., Jana, M., Kundu, M., Corbett, G. T., Rangaswamy, S. B., Mishra, R. K., Luan, C., Gonzalez, F. J., & Pahan, K. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.022 · Cited by 160 · see citing works
Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells
Alizadeh, J., Zeki, A. A., Mirzaei, N., Tewary, S., Moghadam, A. R., Głogowska, A., Nagakannan, P., Eftekharpour, E., Wiecheć, E., Gordon, J. W., et al. (2017) · Scientific Reports · doi:10.1038/srep44841 · Cited by 142 · see citing works
HMG-CoA reductase inhibition induces IL-1β release through Rac1/PI3K/PKB-dependent caspase-1 activation
Kuijk, L. M., Beekman, J. M., Koster, J., Waterham, H. R., Frenkel, J., & Coffer, P. J. (2008) · Blood · doi:10.1182/blood-2008-03-144667 · Cited by 138 · see citing works
Diverse Roles of Rho Family GTPases in Neuronal Development, Survival, and Death
Linseman, D. (2008) · Frontiers in Bioscience · doi:10.2741/2710 · Cited by 134 · see citing works
Lipid-lowering drug use is associated with reduced prevalence of atrial fibrillation in patients with left ventricular systolic dysfunction
Hanna, I. R., Heeke, B., Bush, H., Brosius, L., King-Hageman, D., Dudley, S. C., Beshai, J. F., & Langberg, J. J. (2006) · Heart Rhythm · doi:10.1016/j.hrthm.2006.05.010 · Cited by 132 · see citing works
Statins, Risk of Dementia, and Cognitive Function: Secondary Analysis of the Ginkgo Evaluation of Memory Study
Bettermann, K., Arnold, A. M., Williamson, J. D., Rapp, S. R., Sink, K. M., Toole, J. F., Carlson, M. C., Yaşar, S., DeKosky, S. T., & Burke, G. L. (2011) · Journal of Stroke and Cerebrovascular Diseases · doi:10.1016/j.jstrokecerebrovasdis.2010.11.002 · Cited by 132 · see citing works
Fibrillar β-Amyloid-stimulated Intracellular Signaling Cascades Require Vav for Induction of Respiratory Burst and Phagocytosis in Monocytes and Microglia
Wilkinson, B. L., Koenigsknecht-Talboo, J., Grommes, C., Lee, C. Y. D., & Landreth, G. E. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m600627200 · Cited by 131 · see citing works
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Alzheimer's Disease: cholesterol, membrane rafts, isoprenoids and statins
Reid, P., Urano, Y., Kodama, T., & Hamakubo, T. (2007) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2007.00054.x · Cited by 129 · see citing works
Lipoprotein receptors and cholesterol in APP trafficking and proteolytic processing, implications for Alzheimer's disease
Marzolo, M.-P., & Bu, G. (2009) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2008.10.005 · Cited by 122 · see citing works
A yeast-based screen reveals that sulfasalazine inhibits tetrahydrobiopterin biosynthesis
Chidley, C., Haruki, H., Pedersen, M. G., Muller, E., & Johnsson, K. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.557 · Cited by 122 · see citing works
Cholesterol and statins in Alzheimer's disease: Current controversies
Fonseca, A. C. R. G., Resende, R., Oliveira, C. R., & Pereira, C. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.09.013 · Cited by 112 · see citing works
Atorvastatin prevents hippocampal cell death, neuroinflammation and oxidative stress following amyloid-β1–40 administration in mice: Evidence for dissociation between cognitive deficits and neuronal damage
Piermartiri, T., Figueiredo, C. P., Rial, D., Duarte, F. S., Bezerra, S. C., Mancini, G., Bem, A. F. D., Prediger, R. D., & Tasca, C. I. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.08.030 · Cited by 106 · see citing works
Isoprenoids, small GTPases and Alzheimer's disease
Hooff, G. P., Wood, W. G., Müller, W. E., & Eckert, G. P. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.03.014 · Cited by 102 · see citing works
Comparison of biochemical effects of statins and fish oil in brain: The battle of the titans
Farooqui, A. A., Ong, W., Horrocks, L. A., Chen, P., & Farooqui, T. (2007) · Brain Research Reviews · doi:10.1016/j.brainresrev.2007.09.004 · Cited by 100 · see citing works
Endothelial cell barrier protection by simvastatin: GTPase regulation and NADPH oxidase inhibition
Chen, W., Pendyala, S., Natarajan, V., Garcia, J. G. N., & Jacobson, J. R. (2008) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00428.2007 · Cited by 100 · see citing works
Role of the Rho GTPase Rac in the activation of the phagocyte NADPH oxidase
Pick, E. (2014) · Small GTPases · doi:10.4161/sgtp.27952 · Cited by 98 · see citing works
Oxidative and nitrosative stress in the maintenance of myocardial function
Zhang, Y., Tocchetti, C. G., Krieg, T., & Moens, A. L. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.07.010 · Cited by 96 · see citing works
Statins inhibit C-reactive protein-induced chemokine secretion, ICAM-1 upregulation and chemotaxis in adherent human monocytes
Montecucco, F., Burger, F., Pelli, G., Poku, N. K., Berlier, C., Steffens, S., & Mach, F. (2009) · Lara D. Veeken · doi:10.1093/rheumatology/ken466 · Cited by 96 · see citing works
Alzheimer’s Disease and Cholesterol: The Fat Connection
Canevari, L., & Clark, J. B. (2006) · Neurochemical Research · doi:10.1007/s11064-006-9200-1 · Cited by 93 · see citing works
Statins alter neutrophil migration by modulating cellular Rho activity–a potential mechanism for statins-mediated pleotropic effects?
Maher, B. M., Dhonnchu, T. N., Burke, J. P., Soo, A., Wood, A. E., & Watson, R. W. G. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.0608382 · Cited by 93 · see citing works
Pathologic role of glial nitric oxide in adult and pediatric neuroinflammatory diseases
Ghasemi, M., & Fatemi, A. S. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.06.002 · Cited by 95 · see citing works
Small GTP-binding proteins and their regulators in cardiac hypertrophy
Lezoualc’h, F., Metrich, M., Hmitou, I., Duquesnes, N., & Morel, É. (2008) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2008.01.011 · Cited by 91 · see citing works
Simvastatin prevents the inflammatory process and the dopaminergic degeneration induced by the intranigral injection of lipopolysaccharide
Hernández-Romero, M. C., Argüelles, S., Villarán, R. F., de Pablos, R. M., Delgado‐Cortés, M. J., Santiago, M., Herrera, A. J., Cano, J., & Machado, A. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05148.x · Cited by 91 · see citing works
Simvastatin regulates oligodendroglial process dynamics and survival
Miron, V. E., Rajasekharan, S., Jarjour, A. A., Zamvil, S. S., Kennedy, T. E., & Antel, J. P. (2006) · Glia · doi:10.1002/glia.20441 · Cited by 91 · see citing works
Statins induce regulatory T cell recruitment via a CCL1 dependent pathway.
Mira, E., León, B., Barber, D. F., Jiménez-Baranda, S., Goya, I., Almonacid, L., Márquez, G., Zaballos, A., Martínez-A., C., Stein, J. V., et al. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.5.3524 · Cited by 88 · see citing works
In vitro synergistic interactions of the effects of various statins and azoles against some clinically important fungi: Synergistic interactions between statins and azoles
Nyilasi, I., Kocsubé, S., Krizsán, K., Galgóczy, L., Pesti, M., Papp, T., & Vágvölgyi, C. (2010) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.2010.01972.x · Cited by 83 · see citing works
A Pivotal Role for Interleukin-4 in Atorvastatin-associated Neuroprotection in Rat Brain
Clarke, R. M., Lyons, A., O'Connell, F., Deighan, B. F., Barry, C. E., Anyakoha, N., Nicolaou, A., & Lynch, M. A. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m707442200 · Cited by 85 · see citing works
Deciphering the signaling networks underlying simvastatin-induced apoptosis in human cancer cells: evidence for non-canonical activation of RhoA and Rac1 GTPases
Zhu, Y., Casey, P. J., Kumar, A. P., & Pervaiz, S. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.103 · Cited by 85 · see citing works
Statin synergizes with LPS to induce IL-1β release by THP-1 cells through activation of caspase-1
Kuijk, L. M., Mandey, S. H. L., Schellens, I. M. M., Waterham, H. R., Rijkers, G. T., Coffer, P. J., & Frenkel, J. (2008) · Molecular Immunology · doi:10.1016/j.molimm.2007.12.008 · Cited by 84 · see citing works
Bcl-2 upregulation and neuroprotection in guinea pig brain following chronic simvastatin treatment
Franke, C., Nöldner, M., Abdel-Kader, R. M., Johnson‐Anuna, L. N., Wood, W. G., Müller, W. E., & Eckert, G. P. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.10.004 · Cited by 83 · see citing works
Cholesterol-independent neuroprotective and neurotoxic activities of statins: Perspectives for statin use in Alzheimer disease and other age-related neurodegenerative disorders
Butterfield, D. A., Barone, E., & Mancuso, C. (2011) · Pharmacological Research · doi:10.1016/j.phrs.2011.04.007 · Cited by 80 · see citing works
“Noting that inflammatory processes occur in several neurodegenerative disorders, such as Alzheimer disease, statin-mediated inhibition of Rho GTPases seems to attenuate betaamyloid (Aβ) peptide-stimulated inflammation in microglia [8].”
Background
Atorvastatin reduces vascular endothelial growth factor (VEGF) expression in human non‐small cell lung carcinomas (NSCLCs) via inhibition of reactive oxygen species (ROS) production
Chen, J., Liu, B., Yuan, J., Yang, J., Zhang, J., An, Y., Tie, L., Pan, Y., & Li, X. (2011) · Molecular Oncology · doi:10.1016/j.molonc.2011.11.003 · Cited by 81 · see citing works
Red mold rice ameliorates impairment of memory and learning ability in intracerebroventricular amyloid β‐infused rat by repressing amyloid β accumulation
Lee, C., Kuo, T., Wang, J., & Pan, T. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21428 · Cited by 81 · see citing works
Simvastatin protects neurons from cytotoxicity by up‐regulating Bcl‐2 mRNA and protein
Johnson‐Anuna, L. N., Eckert, G. P., Franke, C., Igbavboa, U., Müller, W. E., & Wood, W. G. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04375.x · Cited by 79 · see citing works
Rac1-dependent secretion of platelet-derived CCL5 regulates neutrophil recruitment via activation of alveolar macrophages in septic lung injury
Hwaiz, R. A., Rahman, M., Syk, I., Zhang, E., & Thorlacius, H. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.4a1214-603r · Cited by 79 · see citing works
Actin cytoskeleton remodeling governs aquaporin‐4 localization in astrocytes
Nicchia, G. P., Rossi, A., Mola, M. G., Procino, G., Frigeri, A., & Svelto, M. (2008) · Glia · doi:10.1002/glia.20724 · Cited by 75 · see citing works
The beneficial effects of HMG-CoA reductase inhibitors in the processes of neurodegeneration
Saravi, S. S. S., Saravi, S. S. S., Arefidoust, A., & Dehpour, A. R. (2017) · Metabolic Brain Disease · doi:10.1007/s11011-017-0021-5 · Cited by 75 · see citing works
Statins induce differentiation and cell death in neurons and astroglia
März, P., Otten, U., & Miserez, A. R. (2006) · Glia · doi:10.1002/glia.20422 · Cited by 74 · see citing works
Isoprenoids and Alzheimer's disease: A complex relationship
Cole, S. L., & Vassar, R. J. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.11.007 · Cited by 70 · see citing works
Effects of Simvastatin on Cholesterol Metabolism and Alzheimer Disease Biomarkers
Serrano‐Pozo, A., Vega, G. L., Lütjohann, D., Locascio, J. J., Tennis, M. K., Deng, A., Atri, A., Hyman, B. T., Irizarry, M. C., & Growdon, J. H. (2010) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e3181d61fea · Cited by 70 · see citing works
Atorvastatin Inhibits T Cell Activation through 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase without Decreasing Cholesterol Synthesis
Blank, N., Schiller, M. R., Krienke, S., Busse, F., Schätz, B., Ho, A. D., Kalden, J. R., & Lorenz, H. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.6.3613 · Cited by 69 · see citing works
Targeting and localized signalling by small GTPases
ten Klooster, J. P., & Hordijk, P. L. (2006) · Biology of the Cell · doi:10.1042/bc20060071 · Cited by 68 · see citing works
Identification of AnnexinA1 as an Endogenous Regulator of RhoA, and Its Role in the Pathophysiology and Experimental Therapy of Type-2 Diabetes
Purvis, G. S. D., Collino, M., Loiola, R. A., Baragetti, A., Chiazza, F., Brovelli, M., Sheikh, M. H., Collotta, D., Cento, A. S., Mastrocola, R., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00571 · Cited by 70 · see citing works
Suppressive effect of simvastatin on interferon-β-induced expression of CC chemokine ligand 5 in microglia
Nakamichi, K., Saiki, M., Kitani, H., Kuboyama, Y., Morimoto, K., Takayama‐Ito, M., & Kurane, I. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2006.08.044 · Cited by 68 · see citing works
Prevention of stroke and dementia by statin therapy: Experimental and clinical evidence of their pleiotropic effects
Miida, T., Takahashi, A., & Ikeuchi, T. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2006.09.003 · Cited by 66 · see citing works
Impact of HMG-CoA reductase inhibition on brain pathology
Zipp, F., Waiczies, S., Aktaş, O., Neuhaus, O., Hemmer, B., Schraven, B., Nitsch, R., & Hartung, H. (2007) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2007.05.001 · Cited by 65 · see citing works
The HMG-CoA reductase inhibitor, atorvastatin, attenuates the effects of acute administration of amyloid-β1–42 in the rat hippocampus in vivo
Clarke, R. M., O'Connell, F., Lyons, A., & Lynch, M. A. (2006) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.07.031 · Cited by 63 · see citing works
Regulation of Rac1 by Simvastatin in Endothelial Cells
Kou, R., Sartoretto, J. L., & Michel, T. M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808664200 · Cited by 62 · see citing works
Protein Prenylation and Synaptic Plasticity: Implications for Alzheimer’s Disease
Hottman, D. A., & Li, L. (2014) · Molecular Neurobiology · doi:10.1007/s12035-013-8627-z · Cited by 62 · see citing works
Rho GTPases in the Physiology and Pathophysiology of Peripheral Sensory Neurons
Kalpachidou, T., Spiecker, L., Kress, M., & Quarta, S. (2019) · Cells · doi:10.3390/cells8060591 · Cited by 62 · see citing works
Selective Inhibition of Growth of Tuberous Sclerosis Complex 2 –Null Cells by Atorvastatin Is Associated with Impaired Rheb and Rho GTPase Function and Reduced mTOR/S6 Kinase Activity
Finlay, G. A., Malhowski, A. J., Liu, Y., Fanburg, B. L., Kwiatkowski, D. J., & Toksoz, D. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1394 · Cited by 62 · see citing works
Delineation of cell death mechanisms induced by synergistic effects of statins and erlotinib in non-small cell lung cancer cell (NSCLC) lines
Otahal, A., Aydemir, D., Tomasich, E., & Minichsdorfer, C. (2020) · Scientific Reports · doi:10.1038/s41598-020-57707-2 · Cited by 58 · see citing works
Red mold rice extract represses amyloid beta peptide-induced neurotoxicity via potent synergism of anti-inflammatory and antioxidative effect
Lee, C.-L., Wang, J., & Pan, T. (2008) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-008-1480-8 · Cited by 60 · see citing works
Inhibition of serotonin-induced mitogenesis, migration, and ERK MAPK nuclear translocation in vascular smooth muscle cells by atorvastatin
Li, M., Liu, Y., Dutt, P., Fanburg, B. L., & Toksoz, D. (2007) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00133.2007 · Cited by 60 · see citing works
Simvastatin Suppresses Self‐Renewal of Mouse Embryonic Stem Cells by Inhibiting RhoA Geranylgeranylation
Lee, M., Cho, Y. S., & Han, Y. (2007) · Stem Cells · doi:10.1634/stemcells.2006-0753 · Cited by 59 · see citing works
Targeting Rho GTPase Signaling for Cancer Therapy
Mardilovich, K., Olson, M. F., & Baugh, M. D. (2012) · Future Oncology · doi:10.2217/fon.11.143 · Cited by 59 · see citing works
Simvastatin Prevents Coronary Microvascular Remodeling in Renovascular Hypertensive Pigs
Zhu, X.-Y., Daghini, E., Chade, A., Claudio Napoli, A., Ritman, E. L., Lerman, A., & Lerman, L. O. (2007) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006090976 · Cited by 58 · see citing works
Statin treatment affects cytokine release and phagocytic activity in primary cultured microglia through two separable mechanisms
Churchward, M. A., & Todd, K. G. (2014) · Molecular Brain · doi:10.1186/s13041-014-0085-7 · Cited by 57 · see citing works
Biocatalyzed Synthesis of Statins: A Sustainable Strategy for the Preparation of Valuable Drugs
Hoyos, P., Pace, V., & Alcántara, A. R. (2019) · Catalysts · doi:10.3390/catal9030260 · Cited by 58 · see citing works
Roles of Cholesterol and Lipids in the Etiopathogenesis ofAlzheimer′s Disease
Rojo, L. E., Sjöberg-Herrera, M. K., Hernández, P., Zambrano, C. A., & Maccioni, R. B. (2006) · BioMed Research International · doi:10.1155/jbb/2006/73976 · Cited by 57 · see citing works
Inhibition of Rho and Rac Geranylgeranylation by Atorvastatin Is Critical for Preservation of Endothelial Junction Integrity
Xiao, H., Qin, X., Ping, D., & Zuo, K. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059233 · Cited by 55 · see citing works
Systematic review of the in vitro effects of statins on oral and perioral microorganisms
Ting, M., Whitaker, E. J., & Albandar, J. M. (2015) · European Journal Of Oral Sciences · doi:10.1111/eos.12239 · Cited by 57 · see citing works
Combined inhibition of the mevalonate pathway with statins and zoledronic acid potentiates their anti-tumor effects in human breast cancer cells
Göbel, A., Thiele, S., Browne, A. J., Rauner, M., Zinna, V. M., Hofbauer, L. C., & Rachner, T. D. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.03.004 · Cited by 54 · see citing works
Dominant-Negative α-Subunit of Farnesyl- and Geranyltransferase Inhibits Glucose-Stimulated, but Not KCl-Stimulated, Insulin Secretion in INS 832/13 Cells
Veluthakal, R., Kaur, H., Goalstone, M. L., & Kowluru, A. (2006) · Diabetes · doi:10.2337/db06-0668 · Cited by 51 · see citing works
Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption
Lampi, M. C., Faber, C. J., Huynh, J., Bordeleau, F., Zanotelli, M. R., & Reinhart‐King, C. A. (2016) · PLoS ONE · doi:10.1371/journal.pone.0147033 · Cited by 48 · see citing works
Zoledronate-induced S phase arrest and apoptosis accompanied by DNA damage and activation of the ATM/Chk1/cdc25 pathway in human osteosarcoma cells
Iguchi, T., Miyakawa, Y., Saito, K., Nakabayashi, C., Nakanishi, M., Saya, H., Ikeda, Y., & Kizaki, M. (2007) · International Journal of Oncology · doi:10.3892/ijo.31.2.285 · Cited by 50 · see citing works
Statin's Excitoprotection Is Mediated by sAPP and the Subsequent Attenuation of Calpain-Induced Truncation Events, Likely via Rho-ROCK Signaling
Ma, T., Zhao, Y., Kwak, Y. D., Yang, Z.-M., Thompson, R., Luo, Z., Xu, H., & Liao, F. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.6150-08.2009 · Cited by 48 · see citing works
Simvastatin Inhibits Staphylococcus aureus Host Cell Invasion through Modulation of Isoprenoid Intermediates
Horn, M. P., Knecht, S. M., Rushing, F. L., Birdsong, J. A., Siddall, P., Johnson, C. M., Abraham, T. N., Brown, A., Volk, C. B., Gammon, K., et al. (2008) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.137927 · Cited by 48 · see citing works
Effect of simvastatin on proinflammatory cytokines production during lipopolysaccharide-induced inflammation in rats.
Nežić, L., Škrbić, R., Dobrić, S., Stojiljković, M. P., Šatara, S. S., Milovanovic, Z. A., & Stojaković, N. (2009) · PubMed · Cited by 47 · see citing works
Induction of RISK by HMG-CoA reductase inhibition affords cardioprotection after myocardial infarction
Vilahur, G., Casaní, L., Peña, E., Durán, X., Juan‐Babot, O., & Badimón, L. (2009) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2009.02.009 · Cited by 45 · see citing works
Isoprenoids and Related Pharmacological Interventions: Potential Application in Alzheimer’s Disease
Li, L., Zhang, W., Cheng, S., Cao, D., & Parent, M. A. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8253-1 · Cited by 45 · see citing works
Effects of lovastatin on Rho isoform expression, activity, and association with guanine nucleotide dissociation inhibitors
Turner, S. J., Zhuang, S., Zhang, T., Boss, G. R., & Pilz, R. B. (2007) · Biochemical Pharmacology · doi:10.1016/j.bcp.2007.08.031 · Cited by 45 · see citing works
Immunomodulatory and Anti-Inflammatory Activities of Statins
Mira, E., & Mañes, S. (2009) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/187153009789044383 · Cited by 45 · see citing works
Statins and the Squalene Synthase Inhibitor Zaragozic Acid Stimulate the Non-Amyloidogenic Pathway of Amyloid-β Protein Precursor Processing by Suppression of Cholesterol Synthesis
Kojro, E., Füger, P., Prinzen, C., Kanarek, A. M., Rat, D., Endres, K., Fahrenholz, F., & Postina, R. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-091621 · Cited by 45 · see citing works
Susceptibility of clinically important dermatophytes against statins and different statin-antifungal combinations
Nyilasi, I., Kocsubé́, S., Krizsán, K., Galgóczy, L., Papp, T., Pesti, M., Nagy, K., & Vágvölgyi, C. (2013) · Medical Mycology · doi:10.3109/13693786.2013.828160 · Cited by 44 · see citing works
Modulation of Rho-Rock signaling pathway protects oligodendrocytes against cytokine toxicity via PPAR-α-dependent mechanism
Paintlia, A. S., Paintlia, M. K., Singh, A. K., & Singh, I. (2013) · Glia · doi:10.1002/glia.22537 · Cited by 43 · see citing works
Activation of PPAR‐γ and PTEN cascade participates in lovastatin‐mediated accelerated differentiation of oligodendrocyte progenitor cells
Paintlia, A. S., Paintlia, M. K., Singh, A. K., Orak, J. K., & Singh, I. (2010) · Glia · doi:10.1002/glia.21039 · Cited by 43 · see citing works
Simvastatin enhances Rho/actin/cell rigidity pathway contributing to mesenchymal stem cells’ osteogenic differentiation
Ho, M., Tai, I., Wang, Y.-H., Chen, C., Chuang, S., & Chang, J. (2015) · International Journal of Nanomedicine · doi:10.2147/ijn.s84273 · Cited by 42 · see citing works
Statins inhibit aminoglycoside accumulation and cytotoxicity to renal proximal tubule cells
Antoine, D. J., Srivastava, A., Pirmohamed, M., & Park, B. K. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.09.021 · Cited by 42 · see citing works
Epithelial cell migration as a potential therapeutic target in early lung cancer
Millar, F. R., Janes, S. M., & Giangreco, A. (2017) · European Respiratory Review · doi:10.1183/16000617.0069-2016 · Cited by 42 · see citing works
Immune regulatory effects of simvastatin on regulatory T cell-mediated tumour immune tolerance
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3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate β-Amyloid-Induced Microglial Inflammatory Responses
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Self-citation
Statins Reduce Amyloid-β Production through Inhibition of Protein Isoprenylation
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Self-citation
Simvastatin inhibits protein isoprenylation in the brain
Ostrowski, S. M., Johnson, K., Siefert, M. E., Shank, S. S., Sironi, L., Wolozin, B. L., Landreth, G. E., & Ziady, A. G. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.04.053 · Cited by 27 · see citing works
Self-citation
3-Hydroxy-3-Methylglutaryl-CoenzymeAReductase InhibitorsAttenuate-Amyloid-InducedMicroglial InflammatoryResponses
Landreth, G. E. (2005)
Self-citation
Neurobiology of Disease 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate �-Amyloid-Induced Microglial Inflammatory Responses
Cordle, A., & Gary, L. (2013)
Self-citation

Authors: Cordle, A., Koenigsknecht-Talboo, J., Wilkinson, B., Limpert, A., & Landreth, G.
Affiliations: Case Western Reserve University (US)
Corresponding author: Landreth, Gary
ORCID: Cordle, Andrew
Wilkinson, Brandy
Limpert, Allison
Landreth, Gary
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2005-10
Volume: 280
Issue: 40
Pages: 34202-34209
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m505268200
OpenAlex: W2015034968
Cited by: 235
References: 64
Citations by year: 2026: 4 · 2025: 1 · 2024: 1 · 2023: 6 · 2022: 6 · 2021: 9 · 2020: 3 · 2019: 8 · 2018: 9 · 2017: 8 · 2016: 10 · 2015: 15 · 2014: 9 · 2013: 14 · 2012: 10
FWCI: 8.91
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 5470 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Institute on Aging (AG-20202, R01AG020202, R01AG016740, AG-16740)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
Keywords: statins, Rho GTPases, Rac, RhoA, isoprenylation, amyloid-beta, Alzheimer's disease, microglia, inflammation, RhoGDI, GTP loading, membrane association, cytoskeleton, phagocytosis
MeSH terms: Alzheimer Disease, Animals, Cell Line, Cytoskeleton, Guanosine Triphosphate, Humans, Inflammation, Monocytes, Phagocytosis, Protein Prenylation, Microglia, Hydroxymethylglutaryl-CoA Reductase Inhibitors, rho GTP-Binding Proteins, Mice

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