Isoprenoids as mediators of the biological effects of statins
Open accessAbstract
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are potent inhibitors of cholesterol biosynthesis.Several large clinical trials have demonstrated the benefits of cholesterol lowering with these agents in the primary and secondary prevention of coronary heart disease.The overall clinical benefits observed with statin therapy, however, appear to be greater than what might be expected from changes in lipid profile alone, suggesting that the beneficial effects of statins may extend beyond their effects on serum cholesterol levels.Recent experimental and clinical evidence indicates that some of the cholesterol-independent, or so-called pleiotropic, effects of statins involve improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response in the vascular wall.Many of these cholesterolindependent effects reflect statins' ability to block the synthesis of important isoprenoid intermediates, which serve as lipid attachments for a variety of intracellular signaling molecules.In particular, the inhibition of small GTP-binding proteins Rho, Ras, and Rac, whose proper membrane localization and function are dependent upon isoprenylation, may play an important role in mediating the biological effects of statins. Pharmacological properties of statinsStatins bind to HMG-CoA reductase at nanomolar concentrations, leading to competitive displacement of the natural substrate, HMG-CoA, which binds at micromolar concentrations (1).In addition, inhibition of cholesterol biosynthesis is accompanied by an increase in hepatic LDL receptor, which promotes uptake and clearance of cholesterol from the bloodstream.While all statins inhibit hepatic HMG-CoA reductase to varying degrees, important structural differences exist among the statins that distinguish their lipophilicity, half-life, and potency (2).For example, one of the more potent newer statins, rosuvastatin, is relatively hydrophilic and has a greater number of bonding interactions with the catalytic site of HMG-CoA reductase compared with mevastatin, fluvastatin, simvastatin, cerivastatin, and atorvastatin (1, 3).The lipophilic statins would be expected to penetrate cell membranes more effectively than the more hydrophilic statins, causing more side effects but, at the same time, eliciting more pleiotropic effects.However, the observation that hydrophilic statins have pleiotropic effects similar to those of lipophilic statins calls into question whether there are really any cholesterol-independent effects of statins.Indeed, recent evidence suggests that some of the cholesterol-independent effects of these agents may be mediated by inhibition of hepatic HMG-CoA reductase, leading to subsequent reduction in circulating isoprenoid levels (4).This hypothesis may help explain why hydrophilic statins such as pravastatin and rosuvastatin are still able to exert cholesterol-independent benefits on the vascular wall without directly entering vascular wall cells.In this respect, the word "pleiotropic" probably does not reflect the hepatic versus nonhepatic effects of these agents. Clinical trials with statinsBecause serum cholesterol level is strongly associated with coronary heart disease (5), it has been generally assumed that cholesterol reduction by statins is the predominant, if not the only, mechanism underlying their beneficial effects in cardiovascular diseases.However, subgroup analysis of large clinical trials such as the 4S, WOSCOP, CARE, and HPS suggests that the clinical benefits of statins are not associated with base-line cholesterol levels or the degree of cholesterol reduction (6-9).Furthermore, in angiographic trials, clinical improvements with statins far exceed changes in the size of atherosclerotic lesions (10).It is quite likely that cholesterol lowering in these longterm trials stabilized atherosclerotic plaques and made them less prone to rupture.However, in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial, statins reduced recurrent ischemic events within 16 weeks following acute coronary ischemia (11).Although the serum LDL-cholesterol was decreased by 40%, this time frame was probably far too rapid for appreciable changes in lesion size and plaque stability to occur as a consequence of cholesterol reduction.An intriguing but perplexing result of large clinical trials with statins is the reduction in ischemic stroke ( 12).Although myocardial infarction is closely associated with serum cholesterol levels, neither the Framingham Heart Study nor the Multiple Risk Factor Intervention Isoprenoids as mediators of the biological effects of statins
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Statins inhibit synthesis of important isoprenoids such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are lipid attachments for the γ subunit of heterotrimeric G-proteins, Ras, and Ras-like proteins.
“Thus, the effects of statins are connected with the inhibition of the synthesis of important isoprenoids, e.g.farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are important lipid attachments for the γ subunit of heterotrimeric G-proteins [12] , guanosine triphosphatebinding protein Ras, and Ras-like proteins (Rho, Rab, Rac, Ral, or Rap) [12][13][14] .”
From Statins as antifungal agents (2011) · cites this paper as [13]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia
Shepherd, J., Cobbe, S. M., Ford, I., Isles, C. G., Lorimer, A. R., Macfarlane, P. W., McKillop, J. H., & Packard, C. J. (1995) · New England Journal of Medicine · doi:10.1056/nejm199511163332001 · Cited by 7,449 · see citing works
Sacks, F. M., Pfeffer, M. A., Moye, L. A., Rouleau, J. L., Rutherford, J. D., Cole, T. G., Brown, L., Warnica, J. W., Arnold, J. M. O., Wun, C.-C., et al. (1996) · New England Journal of Medicine · doi:10.1056/nejm199610033351401 · Cited by 7,439 · see citing works
Regulation of the mevalonate pathway
Goldstein, J. L., & Brown, M. S. (1990) · Nature · doi:10.1038/343425a0 · Cited by 5,394 · see citing works
Rho GTPases and signaling networksPreprint
Aelst, L. V., & D’Souza‐Schorey, C. (1997) · Genes & Development · doi:10.1101/gad.11.18.2295 · Cited by 2,358 · see citing works
Serum cholesterol, lipoproteins, and the risk of coronary heart disease. The Framingham study.
Kannel, W., Castelli, W., Gordon, T., & McNamara, P. M. (2020) · Annals of Internal Medicine · doi:10.7326/0003-4819-74-1-1 · Cited by 2,160 · see citing works
Molecular Bases of the Acute Coronary Syndromes
Libby, P. (1995) · Circulation · doi:10.1161/01.cir.91.11.2844 · Cited by 2,029 · see citing works
Statins and the risk of dementia
Jick, H., Zornberg, G. L., Jick, S. S., Seshadri, S. S., & Drachman, D. (2000) · The Lancet · doi:10.1016/s0140-6736(00)03155-x · Cited by 1,763 · see citing works
Structural mechanism for statin inhibition of HMG-CoA reductase
Istvan, E. S., & Deisenhofer, J. (2001) · Science · doi:10.1126/science.1059344 · Cited by 1,644 · see citing works
Ridker, P. M., Rifai, N., Clearfield, M., Downs, J. R., Weis, S. E., Miles, J. S., & Gotto, A. M. (2001) · New England Journal of Medicine · doi:10.1056/nejm200106283442601 · Cited by 1,557 · see citing works
Kureishi, Y., Luo, Z., Shiojima, I., Bialik, A., Fulton, D. J., Lefer, D. J., Sessa, W. C., & Walsh, K. X. (2000) · Nature Medicine · doi:10.1038/79510 · Cited by 1,438 · see citing works
Wolozin, B. L. (2000) · Archives of Neurology · doi:10.1001/archneur.57.10.1439 · Cited by 1,386 · see citing works
Effect of pravastatin on outcomes after cardiac transplantation
Kobashigawa, J. A., Katznelson, S., Laks, H., Johnson, J. A., Yeatman, L., Wang, X. M., Chia, D., Terasaki, P. I., Sabad, A., Cogert, G. A., et al. (1995) · New England Journal of Medicine · doi:10.1056/nejm199509073331003 · Cited by 1,301 · see citing works
Dimmeler, S., Aicher, A., Vasa‐Nicotera, M., Mildner-Rihm, C., Adler, K., Tiemann, M., Rütten, H., Fichtlscherer, S., Martin, H., & Zeiher, A. M. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13152 · Cited by 1,206 · see citing works
Dimmeler, S., Aicher, A., Vasa‐Nicotera, M., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200113152 · Cited by 1,025 · see citing works
Vasa‐Nicotera, M., Fichtlscherer, S., Adler, K., Aicher, A., Martin, H., Zeiher, A. M., & Dimmeler, S. (2001) · Circulation · doi:10.1161/hc2401.092816 · Cited by 1,007 · see citing works
Crisby, M., Fredrikson, G. N., Shah, P. K., Yano, J., Zhu, J., & Nilsson, J. Å. (2001) · Circulation · doi:10.1161/01.cir.103.7.926 · Cited by 999 · see citing works
Endres, M., Laufs, U., Huang, Z., Nakamura, T., Huang, P. L., Moskowitz, M. A., & Liao, J. K. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.15.8880 · Cited by 957 · see citing works
Self-citationBrown, B., Zhao, X., Sacco, D., & Albers, J. (1993) · Circulation · doi:10.1161/01.cir.87.6.1781 · Cited by 886 · see citing works
New insights into the pharmacodynamic and pharmacokinetic properties of statins
Corsini, A., Bellosta, S., Baetta, R., Fumagalli, R., Paoletti, R., & Bernini, F. (1999) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(99)00045-5 · Cited by 796 · see citing works
HMG-CoA reductase inhibitor mobilizes bone marrow–derived endothelial progenitor cells
Llevadot, J., Murasawa, S., Kureishi, Y., Uchida, S., Masuda, H., Kawamoto, A., Walsh, K., Isner, J. M., & Asahara, T. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13131 · Cited by 701 · see citing works
HMG-CoA reductase inhibitor mobilizes bone marrow–derived endothelial progenitor cells
Llevadot, J., Murasawa, S., Kureishi, Y., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200113131 · Cited by 611 · see citing works
Aikawa, M., Aikawa, E. R., Sugiyama, S., Voglic, S. J., Fukumoto, Y., Furukawa, Y., Shiomi, M., Schöen, F. J., & Libby, P. (2001) · Circulation · doi:10.1161/01.cir.103.2.276 · Cited by 587 · see citing works
Serum Cholesterol in Young Men and Subsequent Cardiovascular Disease
Klag, M. J., Ford, D. E., Mead, L. A., He, J., Whelton, P. K., Liang, K., & Levine, D. M. (1993) · New England Journal of Medicine · doi:10.1056/nejm199302043280504 · Cited by 518 · see citing works
Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy
Takemoto, M., Node, K., Nakagami, H., Liao, Y., Grimm, M. F., Takemoto, Y., Kitakaze, M., & Liao, J. K. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13350 · Cited by 485 · see citing works
Self-citationMcTaggart, F., Buckett, L. K., Davidson, R. G., Holdgate, G. A., McCormick, A., Schneck, D. W., Smith, G., & Warwick, M. J. (2001) · The American Journal of Cardiology · doi:10.1016/s0002-9149(01)01454-0 · Cited by 413 · see citing works
Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of fracture among older women
Chan, K. A., Andrade, S. E., Boles, M., Buist, D. S. M., Chase, G. A., Donahue, J. G., Goodman, M. J., Gurwitz, J. H., LaCroix, A. Z., & Platt, R. G. (2000) · The Lancet · doi:10.1016/s0140-6736(00)02400-4 · Cited by 393 · see citing works
Waßmann, S., Laufs, U., Bäumer, A. T., Müller, K., Konkol, C., Sauer, H., Böhm, M., & Nickenig, G. (2001) · Molecular Pharmacology · doi:10.1124/mol.59.3.646 · Cited by 340 · see citing works
Denoyelle, C. (2001) · Carcinogenesis · doi:10.1093/carcin/22.8.1139 · Cited by 317 · see citing works
Essig, M., Nguyen, G., Prié, D., Escoubet, B., Sraer, J., & Friedlander, G. (1998) · Circulation Research · doi:10.1161/01.res.83.7.683 · Cited by 316 · see citing works
Neuroprotection mediated by changes in the endothelial actin cytoskeleton
Laufs, U., Endres, M., Stagliano, N. E., Amin‐Hanjani, S., Chui, D.-S., Yang, S.-X., Simoncini, T., Yamada, M., Aikawa, E. R., Allen, P. G., et al. (2000) · Journal of Clinical Investigation · doi:10.1172/jci9639 · Cited by 282 · see citing works
Self-citationLow-Density Lipoprotein Cholesterol and the Risk of Dementia With Stroke
Moroney, J. T. (1999) · JAMA · doi:10.1001/jama.282.3.254 · Cited by 222 · see citing works
Hernández‐Perera, O., Pérez‐Sala, D., Soria, E., & Lamas, S. (2000) · Circulation Research · doi:10.1161/01.res.87.7.616 · Cited by 187 · see citing works
Cholesterol and Alzheimer’s disease
Simons, M., Keller, P., Dichgans, J., & Schulz, J. (2001) · Neurology · doi:10.1212/wnl.57.6.1089 · Cited by 166 · see citing works
HMG-CoA reductase inhibitor therapy and stroke risk reduction: an analysis of clinical trials data
Crouse, J. R., Byington, R. P., & Furberg, C. D. (1998) · Atherosclerosis · doi:10.1016/s0021-9150(98)00014-8 · Cited by 111 · see citing works
THE MRC/BHF HEART PROTECTION STUDY: PRELIMINARY RESULTS
Owen, O. G. (2002) · International Journal of Clinical Practice · doi:10.1111/j.1742-1241.2002.tb11192.x · Cited by 95 · see citing works
Statins as antioxidant therapy for preventing cardiac myocyte hypertrophy
Takemoto, M., Node, K., Nakagami, H., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200113350 · Cited by 72 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Points of control in inflammation
Nathan, C. (2002) · Nature · doi:10.1038/nature01320 · Cited by 2,738 · see citing works
Statin Therapy, LDL Cholesterol, C-Reactive Protein, and Coronary Artery Disease
Nissen, S. E., Tuzcu, E. M., Schoenhagen, P., Crowe, T., Sasiela, W. J., Tsai, J., Orazem, J., Magorien, R. D., O'Shaughnessy, C., & Ganz, P. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa042000 · Cited by 1,325 · see citing works
Contrast-Induced Acute Kidney Injury
McCullough, P. A., Choi, J. P., Feghali, G. A., SCHUSSLER, J. M., Stoler, R., Vallabahn, R. C., & Mehta, A. N. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2016.05.099 · Cited by 1,070 · see citing works
Statin therapy and autoimmune disease: from protein prenylation to immunomodulation
Greenwood, J., Steinman, L., & Zamvil, S. S. (2006) · Nature reviews. Immunology · doi:10.1038/nri1839 · Cited by 685 · see citing works
THE CARDIAC FIBROBLAST: Therapeutic Target in Myocardial Remodeling and Failure
Brown, R. D., Ambler, S. K., Mitchell, M. D., & Long, C. S. (2005) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.45.120403.095802 · Cited by 643 · see citing works
Mevalonate pathway: A review of clinical and therapeutical implications
Buhaescu, I., & Izzedine, H. (2007) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2007.03.016 · Cited by 620 · see citing works
Association of Nitrotyrosine Levels With Cardiovascular Disease and Modulation by Statin Therapy
Shishehbor, M. H., Aviles, R. J., Brennan, M.-L., Fu, X., Goormastic, M., Pearce, G. L., Gokce, N., Keaney, J. F., Penn, M. S., Sprecher, D. L., et al. (2003) · JAMA · doi:10.1001/jama.289.13.1675 · Cited by 464 · see citing works
Duivenvoorden, R., Tang, J., Cormode, D. P., Mieszawska, A. J., Izquierdo‐Garcia, D., Ozcan, C., Otten, M. J., Zaidi, N., Lobatto, M. E., van Rijs, S. M., et al. (2014) · Nature Communications · doi:10.1038/ncomms4065 · Cited by 444 · see citing works
Liao, J. K., Seto, M., & Noma, K. (2007) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e318070d1bd · Cited by 402 · see citing works
Self-citationKruppel-Like Factor 2 as a Novel Mediator of Statin Effects in Endothelial Cells
SenBanerjee, S., Mir, S. S., Lin, Z., Hamik, A., Atkins, G. B., Das, H., Banerjee, P., Kumar, A., & Jain, M. K. (2005) · Circulation · doi:10.1161/circulationaha.104.525774 · Cited by 348 · see citing works
Breast Cancer Growth Prevention by Statins
Campbell, M. J., Esserman, L. J., Zhou, Y., Shoemaker, M., Lobo, M., Borman, E., Baehner, F. L., Kumar, A. S., Adduci, K., Marx, C., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-4061 · Cited by 349 · see citing works
Cholesterol in Alzheimer's disease
Shobab, L. A., Hsiung, G. R., & Feldman, H. (2005) · The Lancet Neurology · doi:10.1016/s1474-4422(05)70248-9 · Cited by 332 · see citing works
Role of Cholesterol in the Development and Progression of Breast Cancer
Llaverı́as, G., Danilo, C., Mercier, I., Daumer, K. M., Capozza, F., Williams, T. M., Sotgia, F., Lisanti, M. P., & Frank, P. G. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2010.11.005 · Cited by 329 · see citing works
Sterol regulatory element binding protein 1 couples mechanical cues and lipid metabolism
Bertolio, R., Napoletano, F., Mano, M., Maurer‐Stroh, S., Fantuz, M., Zannini, A., Bicciato, S., Sorrentino, G., & Sal, G. D. (2019) · Nature Communications · doi:10.1038/s41467-019-09152-7 · Cited by 296 · see citing works
Diverse compounds mimic Alzheimer disease–causing mutations by augmenting Aβ42 production
Kukar, T. L., Murphy, M. P., Eriksen, J. L., Sagi, S. A., Weggen, S., Smith, T. E., Ladd, T. B., Khan, M. A., Kache, R., Beard, J. D., et al. (2005) · Nature Medicine · doi:10.1038/nm1235 · Cited by 284 · see citing works
Aktaş, O., Waiczies, S., Тихоновна, С. А., Dörr, J. R., Seeger, B., Prozorovski, T., Sallach, S., Endres, M., Brocke, S., Nitsch, R., et al. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20021425 · Cited by 282 · see citing works
C‐Reactive Protein (CRP)‐Lowering Agents
Prasad, K. (2006) · Cardiovascular Drug Reviews · doi:10.1111/j.1527-3466.2006.00033.x · Cited by 271 · see citing works
Toxicity of statins on rat skeletal muscle mitochondria
Kaufmann, P., Török, M., Zahno, A., Waldhauser, K. M., Brecht, K., & Krähenbühl, S. (2006) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-006-6235-z · Cited by 263 · see citing works
Statins and the vascular endothelial inflammatory response
Greenwood, J., & Mason, J. C. (2007) · Trends in Immunology · doi:10.1016/j.it.2006.12.003 · Cited by 263 · see citing works
Statins Exert Endothelial Atheroprotective Effects via the KLF2 Transcription Factor
Parmar, K. M., Nambudiri, V. E., Dai, G., Larman, H. B., Gimbrone, M. A., & García‐Cardeña, G. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.c500144200 · Cited by 253 · see citing works
The vulnerable atherosclerotic plaque
Aikawa, M., & Libby, P. (2004) · Cardiovascular Pathology · doi:10.1016/s1054-8807(04)00004-3 · Cited by 242 · see citing works
Hewitt, R. E., Lissina, A., Green, A. E., Slay, E. S., Price, D. A., & Sewell, A. K. (2004) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2005.02665.x · Cited by 241 · see citing works
Statins for the treatment of dementia
McGuinness, B., Craig, D., Bullock, R. A., Malouf, R. S., & Passmore, P. (2014) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd007514.pub3 · Cited by 232 · see citing works
Mechanisms of plaque stabilization with statins
Libby, P., & Aikawa, M. (2003) · The American Journal of Cardiology · doi:10.1016/s0002-9149(02)03267-8 · Cited by 225 · see citing works
Evidence for Statin Pleiotropy in Humans
Liu, P., Liu, Y.-W., Lin, L.-J., Chen, J.-H., & Liao, J. K. (2008) · Circulation · doi:10.1161/circulationaha.108.813311 · Cited by 226 · see citing works
Self-citationFluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer
Garwood, E. R., Kumar, A. S., Baehner, F. L., Moore, D. H., Au, A., Hylton, N. M., Flowers, C. I., Garber, J. E., Lesnikoski, B., Hwang, E. S., et al. (2009) · Breast Cancer Research and Treatment · doi:10.1007/s10549-009-0507-x · Cited by 215 · see citing works
Dunn, S. E., Youssef, S., Goldstein, M. J., Prod’homme, T., Weber, M. S., Zamvil, S. S., & Steinman, L. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20051129 · Cited by 213 · see citing works
Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial
Bjarnadottir, O., Romero, Q., Bendahl, P.-O., Jirström, K., Rydén, L., Loman, N., Uhlén, M., Johannesson, H., Rose, C., Grabau, D., et al. (2013) · Breast Cancer Research and Treatment · doi:10.1007/s10549-013-2473-6 · Cited by 230 · see citing works
Kolavennu, V., Zeng, L., Peng, H., Wang, Y., & Danesh, F. R. (2007) · Diabetes · doi:10.2337/db07-1241 · Cited by 201 · see citing works
Statins for the prevention of dementia
McGuinness, B., Craig, D., Bullock, R., & Passmore, P. (2009) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd003160.pub2 · Cited by 193 · see citing works
New Insights Into Molecular Mechanisms of Diabetic Kidney Disease
Badal, S. S., & Danesh, F. R. (2014) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2013.10.047 · Cited by 180 · see citing works
Scirica, B. M., Morrow, D. A., Cannon, C. P., Ray, K. K., Sabatine, M. S., Jarolim, P., Shui, A., McCabe, C. H., & Braunwald, E. (2006) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2006.03.034 · Cited by 181 · see citing works
Statin-Associated Myopathy: Emphasis on Mechanisms and Targeted Therapy
Vinci, P., Panizon, E., Tosoni, L. M., Cerrato, C., Pellicori, F., Mearelli, F., Biasinutto, C., Fiotti, N., Girolamo, F. G. D., & Biolo, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111687 · Cited by 180 · see citing works
Yeganeh, B., Wiecheć, E., Ande, S. R., Sharma, P. K., Moghadam, A. R., Post, M., Freed, D. H., Hashemi, M. M., Shojaei, S., Zeki, A. A., et al. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.02.007 · Cited by 168 · see citing works
Atherosclerosis and osteoporosis: age-dependent degenerative processes or related entities?
Anagnostis, P. G., Karagiannis, A. I., Kakafika, A. I., Τζιόμαλος, Κ., Athyros, V. G., & Mikhailidis, D. P. (2008) · Osteoporosis International · doi:10.1007/s00198-008-0648-5 · Cited by 171 · see citing works
Steinmetz, E. F., Buckley, C., Shames, M. L., Ennis, T. L., VanVickle-Chavez, S. J., Mao, D., Goeddel, L. A., Hawkins, C. J., & Thompson, R. W. (2005) · Annals of Surgery · doi:10.1097/01.sla.0000150258.36236.e0 · Cited by 169 · see citing works
Kinlay, S. (2007) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2007.01.083 · Cited by 166 · 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
Sidaway, J. E., Davidson, R. G., McTaggart, F., Orton, T. C., Scott, R. C., Smith, G. J., & Brunskill, N. J. (2004) · Journal of the American Society of Nephrology · doi:10.1097/01.asn.0000138236.82706.ee · Cited by 154 · see citing works
Simvastatin triggers mitochondria-induced Ca2+ signaling alteration in skeletal muscle
Sirvent, P., Mercier, J., Vassort, G., & Lacampagne, A. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.02.070 · Cited by 154 · see citing works
Emerging role of myeloperoxidase and oxidant stress markers in cardiovascular risk assessment
Brennan, M., & Hazen, S. L. (2003) · Current Opinion in Lipidology · doi:10.1097/00041433-200308000-00003 · Cited by 153 · see citing works
Ramasubbu, K., Estep, J. D., White, D. L., Deswal, A. M., & Mann, D. L. (2008) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2007.10.009 · Cited by 151 · see citing works
Role of Rac1–mineralocorticoid-receptor signalling in renal and cardiac disease
Nagase, M., & Fujita, T. (2013) · Nature Reviews Nephrology · doi:10.1038/nrneph.2012.282 · Cited by 150 · see citing works
Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?
Abeles, A. M., & Pillinger, M. H. (2006) · Arthritis & Rheumatism · doi:10.1002/art.21521 · Cited by 149 · see citing works
Osteoporosis and atherosclerosis: biological linkages and the emergence of dual-purpose therapies
Hamerman, D. (2005) · QJM · doi:10.1093/qjmed/hci077 · Cited by 143 · see citing works
Statins as potential therapeutic agents in neuroinflammatory disorders
Stüve, O., Youssef, S., Steinman, L., & Zamvil, S. S. (2003) · Current Opinion in Neurology · doi:10.1097/01.wco.0000073942.19076.d1 · Cited by 141 · see citing works
Chitosan-Coated Nanoparticles: Effect of Chitosan Molecular Weight on Nasal Transmucosal Delivery
Bruinsmann, F. A., Pigana, S., Aguirre, T. A. S., Souto, G. D., Pereira, G. G., Bianchera, A., Fasiolo, L. T., Colombo, G., Marques, M. D. S., Pohlmann, A. R., et al. (2019) · Pharmaceutics · doi:10.3390/pharmaceutics11020086 · Cited by 140 · see citing works
Désiré, L., Bourdin, J., Loiseau, N., Peillon, H., Picard, V., Oliveira, C. D., Bachelot, F., Leblond, B., Taverne, T., Beausoleil, E., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507913200 · Cited by 134 · see citing works
Regulation of Macrophage Cholesterol Efflux through Hydroxymethylglutaryl-CoA Reductase Inhibition
Argmann, C., Edwards, J. Y., Sawyez, C. G., O’Neil, C. H., Hegele, R. A., Pickering, J. G., & Huff, M. W. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m502761200 · Cited by 129 · see citing works
Fong, C. W. (2014) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2014.08.037 · Cited by 128 · see citing works
Cholesterol, Cholesterol-Lowering Medication Use, and Breast Cancer Outcome in the BIG 1-98 Study
Borgquist, S., Giobbie‐Hurder, A., Ahern, T. P., Garber, J. E., Colleoni, M. A., Láng, I., Debled, M., Ejlertsen, B., von Moos, R., Smith, I., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2016.70.3116 · Cited by 128 · see citing works
Statin‐induced muscle damage and atrogin‐1 induction is the result of a geranylgeranylation defect
Cao, P., Hanai, J., Tanksale, P., Imamura, S., Sukhatme, V. P., & Lecker, S. H. (2009) · The FASEB Journal · doi:10.1096/fj.08-128843 · Cited by 118 · see citing works
Shinohara, M., Sato, N., Kurinami, H., Takeuchi, D., Takeda, S., Shimamura, M., Yamashita, T., Uchiyama, Y., Rakugi, H., & Morishita, R. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.102277 · Cited by 117 · see citing works
Simvastatin induces impairment in skeletal muscle while heart is protected
Sirvent, P., Bordenave, S., Vermaelen, M., Roels, B., Vassort, G., Mercier, J., Raynaud, E., & Lacampagne, A. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.10.108 · Cited by 116 · see citing works
New pharmacological treatments for improving renal outcomes in diabetes
Declèves, A., & Sharma, K. (2010) · Nature Reviews Nephrology · doi:10.1038/nrneph.2010.57 · Cited by 114 · see citing works
Simvastatin Inhibits Airway Hyperreactivity: Implications for the Mevalonate Pathway and Beyond
Zeki, A. A., Franzi, L. M., Last, J. A., & Kenyon, N. J. (2009) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200901-0018oc · Cited by 115 · 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
Emerging views of statin pleiotropy and cholesterol lowering
Yu, D., & Liao, J. K. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab032 · Cited by 110 · see citing works
Self-citationBourdon, J. A., Halappanavar, S. S., Saber, A. T., Jacobsen, N. R., Williams, A., Wallin, H., Vogel, U. B., & Yauk, C. L. (2012) · Toxicological Sciences · doi:10.1093/toxsci/kfs119 · Cited by 107 · see citing works
The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins
Murphy, C., Deplazes, E., Cranfield, C. G., & Garcia, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228745 · Cited by 109 · see citing works
Ahn, K. S., Sethi, G., & Aggarwal, B. B. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.4.2507 · Cited by 105 · see citing works
Effects of lovastatin on breast cancer cells: a proteo-metabonomic study
Klawitter, J., Shokati, T., Moll, V., Christians, U., & Klawitter, J. (2010) · Breast Cancer Research · doi:10.1186/bcr2485 · Cited by 102 · see citing works
Shimizu, K., Aikawa, M., Takayama, K., Libby, P., & Mitchell, R. N. (2003) · Circulation · doi:10.1161/01.cir.0000092949.67153.74 · Cited by 99 · see citing works
Statins: a role in breast cancer therapy?
Borgquist, S., Bjarnadottir, O., Kimbung, S., & Ahern, T. P. (2018) · Journal of Internal Medicine · doi:10.1111/joim.12806 · Cited by 93 · see citing works
Ghavami, S., Mutawe, M. M., Sharma, P. K., Yeganeh, B., McNeill, K. D., Klonisch, T. C., Unruh, H. W., Kashani, H. H., Schaafsma, D., Łoś, M., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016523 · Cited by 95 · see citing works
Zimmet, P., & Thomas, C. (2003) · Journal of Internal Medicine · doi:10.1046/j.1365-2796.2003.01170.x · Cited by 94 · see citing works
Statins downregulate myeloperoxidase gene expression in macrophages
Kumar, A. P., & Reynolds, W. F. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.204 · Cited by 94 · see citing works
Nagashima, T., Okazaki, H., Yudoh, K., Matsuno, H., & Minota, S. (2006) · Arthritis & Rheumatism · doi:10.1002/art.21564 · Cited by 93 · see citing works
Atorvastatin attenuates angiotensin II-induced inflammatory actions in the liver
Moreno, M., Ramalho, L. N. Z., Sancho‐Bru, P., Ruiz‐Ortega, M., Ramalho, F. S., Abraldeṣ, J. G., Colmenero, J., Domínguez, M., Egido, J., Arroyo, V., et al. (2008) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00462.2007 · Cited by 93 · see citing works
Statins for the treatment of dementia
McGuinness, B., O’Hare, J., Craig, D., Bullock, R. A., Malouf, R. S., & Passmore, P. (2010) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd007514.pub2 · Cited by 92 · see citing works
Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins
Sirvent, P., Fabre, O., Bordenave, S., Hillaire-Buys, D., Raynaud De Mauverger, E., Lacampagne, A., & Mercier, J. (2012) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2012.01.008 · Cited by 90 · see citing works
Statin myopathy: Incidence, risk factors, and pathophysiology
Sewright, K. A., Clarkson, P. M., & Thompson, P. D. (2007) · Current Atherosclerosis Reports · doi:10.1007/s11883-007-0050-3 · Cited by 90 · see citing works
Liang, K., Yin, S., Ting, C.-T., Lin, S., Hsueh, C., Chen, C.-Y., & Hsu, S. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.06.034 · Cited by 89 · see citing works
Mullen, P. J., Lüscher, B., Scharnagl, H., Krähenbühl, S., & Brecht, K. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.12.007 · Cited by 88 · see citing works
Senokuchi, T., Matsumura, T., Sakai, M., Yano, M., Taguchi, T., Matsuo, T., Sonoda, K., Kukidome, D., Imoto, K., Nishikawa, T., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m412531200 · Cited by 88 · see citing works
The role of statins in the differentiation and function of bone cells
Chamani, S., Liberale, L., Mobasheri, L., Montecucco, F., Al‐Rasadi, K., Jamialahmadi, T., & Sahebkar, A. (2021) · European Journal of Clinical Investigation · doi:10.1111/eci.13534 · Cited by 85 · see citing works
Therapeutic targets in pulmonary arterial hypertension
Rhodes, C. J., Davidson, A., Gibbs, J. S. R., Wharton, J., & Wilkins, M. R. (2008) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2008.10.002 · Cited by 85 · see citing works
Ghavami, S., Mutawe, M. M., Hauff, K. D., Stelmack, G. L., Schaafsma, D., Sharma, P. K., McNeill, K. D., Hynes, T. S., Kung, S. K. P., Unruh, H. W., et al. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2009.12.005 · Cited by 79 · see citing works
Atorvastatin Reduces Plasma Levels of Chemokine (CXCL10) in Patients with Crohn's Disease
Grip, O., & Janciauskiene, S. M. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005263 · Cited by 80 · see citing works
Bocci, G., Fioravanti, A., Orlandi, P., Bernardini, N., Collecchi, P., Tacca, M. D., & Danesi, R. (2005) · British Journal of Cancer · doi:10.1038/sj.bjc.6602720 · Cited by 75 · see citing works
ROCKs as therapeutic targets in cardiovascular diseases
Rikitake, Y., & Liao, J. K. (2005) · Expert Review of Cardiovascular Therapy · doi:10.1586/14779072.3.3.441 · Cited by 75 · see citing works
Self-citationThe 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
Paintlia, A. S., Paintlia, M. K., Singh, A. K., & Singh, I. (2008) · Molecular Pharmacology · doi:10.1124/mol.107.044230 · Cited by 73 · see citing works
Khattri, S., & Zandman‐Goddard, G. (2013) · Immunologic Research · doi:10.1007/s12026-013-8409-8 · Cited by 72 · see citing works
Wang, S. Y., Lee, S.-R., Guo, S., Kim, W. J., Montaner, J., Wang, X., & Lo, E. H. (2006) · Stroke · doi:10.1161/01.str.0000226923.48905.39 · Cited by 71 · see citing works
Immunomodulation by statins: mechanisms and potential impact on autoimmune diseases
Chow, S. C. (2009) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-009-0038-5 · Cited by 69 · see citing works
Singh, I., Paintlia, A. S., Khan, M., Stanislaus, R., Paintlia, M. K., Haq, E., Singh, A. K., & Contreras, M. A. (2004) · Brain Research · doi:10.1016/j.brainres.2004.06.059 · Cited by 69 · see citing works
Schaafsma, D., Dueck, G., Ghavami, S., Kroeker, A., Mutawe, M. M., Hauff, K. D., Xu, F. Y., McNeill, K. D., Unruh, H. W., Hatch, G. M., et al. (2010) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2010-0052oc · Cited by 68 · see citing works
Zhang, X., Tao, Y., Troiani, L., & Markovic‐Plese, S. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100580 · Cited by 68 · see citing works
Statins in the treatment of central nervous system autoimmune disease
Weber, M. S., Youssef, S., Dunn, S. E., Prod’homme, T., Neuhaus, O., Stüve, O., Greenwood, J., Steinman, L., & Zamvil, S. S. (2006) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2006.06.006 · Cited by 67 · see citing works
Poulsen, S. S., Saber, A. T., Mortensen, A., Szarek, J., Wu, D., Williams, A., Andersen, O., Jacobsen, N. R., Yauk, C. L., Wallin, H., et al. (2015) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2015.01.011 · Cited by 67 · see citing works
Simvastatin enhances hippocampal long-term potentiation in C57BL/6 mice
Mans, R. A., Chowdhury, N., Cao, D., McMahon, L. L., & Li, L. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.12.062 · Cited by 67 · see citing works
The Nonlipid Effects of Statins on Endothelial Function
Beckman, J. A., & Creager, M. A. (2006) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2006.03.003 · Cited by 67 · see citing works
Effects of statins on the vasculature
Sowers, J. R. (2003) · The American Journal of Cardiology · doi:10.1016/s0002-9149(02)03269-1 · Cited by 67 · see citing works
Therapy of Pulmonary Hypertension: The Evolution from Vasodilators to Antiproliferative Agents
Rubin, L. J. (2002) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.2208008 · Cited by 67 · see citing works
Statins and breast cancer stage and mortality in the Women’s Health Initiative
Desai, P. M., Lehman, A., Chlebowski, R. T., Kwan, M. L., Arun, M., Manson, J. E., Lavasani, S. M., Wasswertheil-Smoller, S., Sarto, G. E., LeBoff, M. S., et al. (2015) · Cancer Causes & Control · doi:10.1007/s10552-015-0530-7 · Cited by 66 · see citing works
Effects of HMG-CoA reductase inhibitors (statins) on progression of kidney disease
Fried, L. F. (2008) · Kidney International · doi:10.1038/ki.2008.231 · Cited by 65 · see citing works
Pharmacogenomics and Pharmacogenetics of Cholesterol-Lowering Therapy
Schmitz, G., & Drobnik, W. (2003) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2003.088 · Cited by 64 · see citing works
Igarashi, J., Miyoshi, M., Hashimoto, T., Kubota, Y., & Kosaka, H. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707114 · Cited by 64 · see citing works
Inflammation and atherosclerosis
Shishehbor, M. H., & Bhatt, D. L. (2004) · Current Atherosclerosis Reports · doi:10.1007/s11883-004-0102-x · Cited by 63 · see citing works
- Authors
- Liao, J. K.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Liao, James K.
- ORCID
- Liao, James K.
- Venue
- Journal of Clinical Investigation
- Published
- 2002-08-01
- Volume
- 110
- Issue
- 3
- Pages
- 285-288
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W4235797558
- Cited by
- 352
- References
- 35
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 11 · 2020: 8 · 2019: 11 · 2018: 9 · 2017: 11 · 2016: 14 · 2015: 15 · 2014: 16 · 2013: 13 · 2012: 16
- FWCI
- 23.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- statins, terpenoids, pleiotropy, cholesterol-independent effects, HMG-CoA reductase inhibition, cholesterol biosynthesis, isoprenylation, small GTPases, Rho, Ras, Rac, endothelial function, atherosclerotic plaque stability, oxidative stress, inflammation, thrombogenicity, statin adverse effects
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
