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Pleiotropic Effects of Statins: Lipid Reduction and Beyond

Division of Endocrinology, Diabetes and Hypertension, Departments of Medicine and Cell Biology, State University of New York Health Science Center, Brooklyn, New York 11203; and Veterans Affairs Medical Center, Brooklyn, New York 11209

Address all correspondence and requests for reprints to: James R. Sowers, M.D., F.A.C.P., Professor of Medicine and Cell Biology, Director of Endocrinology, Diabetes and Hypertension Division, State University of New York Health Science Center at Brooklyn, 450 Clarkson Avenue, Box 1205, Brooklyn, New York 11203. E-mail: . jsowers{at}netmail.hscbklyn.edu

Abstract

There is accumulating evidence that statins have beneficial effects that are independent of their classical actions on lipoproteins. These effects include reductions in inflammation in the vasculature, kidney, and bone. Potential beneficial effects of these agents include enhancement of nitric oxide production in vasculature and the kidney. These agents appear to reduce bone fractures and may improve insulin sensitivity and reduce the likelihood of persons progressing from impaired glucose tolerance to type II diabetes. Potential beneficial pleiotropic effects of statins are covered in this review.

THE 3-HYDROXY-3-METHYLGLUTARYL COENZYME A (HMG-CoA) reductase inhibitors (statins) have multiple actions above and beyond that of cholesterol lowering. These pleiotropic actions include direct effects on vascular tissue, kidney, bone, and glucose metabolism. Clinical trials and animal studies (in vivo and in vitro) have shown that these agents reduce cardiovascular disease (CVD) risks and events (1, 2, 3), progression of nephropathy (4), development of diabetes (5), and fracture rates (6); these are benefits that go beyond lipid lowering alone. Potential beneficial effects are due to the positive impact on vascular and glomerular nitric oxide (NO) production and attenuation of vascular inflammation. Effects on bone, including fracture reduction, are thought to be mediated by direct action on bone formation. Finally, potential reduction in the development of diabetes as observed in the West of Scotland Coronary Prevention Study (WOSCOPS) (5) may relate to the improvement in insulin sensitivity. Actions of statins on vascular, glomerular, bone, and insulin-sensitive tissue will be discussed in this review.

Impact on CVD

Statins have been shown in primary (1, 2) and secondary prevention (3, 7, 8) trials to significantly reduce fatal and nonfatal CVD events. Cardiovascular benefits of statins have been conventionally attributed to reduction of LDL-cholesterol (9). However, subanalyses of large clinical trials suggest that statins also have direct cardioprotective effects. For example, in WOSCOPS (1), the time-to-event curves began to diverge within 6 months of initiating therapy, an effect that is earlier than predicted from cholesterol lowering alone. Clinical trials have also shown larger significant CVD benefits associated with only minimal changes in luminal dimensions on angiography, benefits that cannot be explained by simple plaque regression (10). Statins also increase myocardial perfusion and reduce recurrent anginal episodes after acute coronary events (11). Potential mechanisms that may mediate these effects include modulation of endothelial function, plaque stabilization, attenuated atherogenesis, and anti-inflammatory and antithrombotic action.

Statins and plaque stabilization.

Most acute coronary events are due to disruption of unstable atherosclerotic plaques, which result in thrombotic occlusion. These vulnerable lesions occur in moderately stenotic vessels and are characterized by a lipid-rich core and excess activated inflammatory cells (12). Macrophages release matrix metalloproteases that degrade plaque matrix connective tissue, weaken the fibrous cap, and render them susceptible for rupture (12). Statins have been shown to decrease the levels of metalloproteases, oxidized-LDL (ox-LDL), core lipid content, and macrophages and to increase collagen content in plaque matrix, actions that increase plaque stability (13).

Statins and endothelial function.

Statins have beneficial effects on vascular endothelium (14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27), and many of these effects are mediated by the inhibition of small molecular weight G-proteins of the Ras superfamily (Ras and Rho). These small molecular weight G-proteins are involved in cell proliferation, differentiation, apoptosis, migration, contraction, and regulation of gene transcription. Activated Ras/Rho proteins are key components in signal-transducing kinase cascades involved in NO production and glucose metabolism. Thus, inhibition of these proteins can critically affect various cellular processes. The anchoring of these small G-proteins to cell membranes requires prenylation; Ras proteins are farnesylated, whereas Rho proteins are geranylgeranylated. Small G-proteins exist in an inactive GDP-bound cytosolic form, and upon cellular activation they exchange GTP and translocate to the active-membrane form (Fig. 1). Lack of protein isoprenylation leads to cytosolic sequestration and loss of biological activity. Statins, in addition to lowering cholesterol by inhibiting HMG-CoA reductase enzyme, also reduce cellular isoprenoid intermediates such as dolichol, ubiquinone, farnesol, and geranylgeraniol (Fig. 2). Statins, by inhibiting isoprenylation, effectively lower membrane levels and activity of Ras/Rho proteins and thus improve vascular function.

View larger version (27K): [in this window] [in a new window]   Figure 1. Effects of statins on small G-proteins.

View larger version (24K): [in this window] [in a new window]   Figure 2. Cholesterol biosynthesis and mevalonate pathway. Bisphosphonates exert inhibitory effect a step distal to that of statins.

eNOS resides in the caveolae and produces small amounts of NO on demand in a transient fashion that is both calcium- and calmodulin-dependent. In the caveolae, eNOS is bound to the caveolar protein, caveolin that inhibits its activity. Elevations in cytoplasmic calcium promote binding of calmodulin to eNOS that subsequently displaces caveolin, thus activating eNOS (Fig. 3). In addition to undergoing regulatory posttranslational modifications, eNOS is regulated by a serine-threonine kinase, Akt. Akt is activated by insulin/IGF-I binding to endothelial and vascular smooth muscle cells (VSMCs) (20). Phosphorylation by Akt increases the affinity of eNOS to calmodulin and enhances the activity of eNOS. Statins activate Akt and thus increase NO production (21). Statins also decrease cellular caveolin levels and attenuate the inhibition of eNOS by caveolin, resulting in increased NO production (22). In addition to affecting posttranslational regulatory mechanisms, statins increase eNOS transcription, stability, and protein level (23). These class effects of statins contribute to improved NO-mediated vascular relaxation.

View larger version (23K): [in this window] [in a new window]   Figure 3. Effects of statin on the endothelium.

Statins also modulate the release and action of vasoconstrictors (e.g. endothelin and angiotensin II) (27, 28). Clinical studies show that hypercholesterolemic men have exaggerated hypertensive responses to infused Ang II, and this response is reversed by statins (29). In a study using double transgenic rat model harboring the human renin and angiotensin genes, cervistatin improved survival, decreased blood pressure, and reduced cardiac hypertrophy (30). Statins also have a direct effect on endothelin-1 (ET-1) production (Fig. 3). These agents reduce, in a dose- and time-dependent fashion, the expression of ET-1 in endothelial cells. This reduction is maintained even in the presence of ox-LDL (27). Because ET-1 is a powerful vasoconstrictor, decreasing ET-1 levels potentially reduces vascular resistance and improves blood flow in coronary and systemic vascular beds.

The anti-inflammatory actions of statins.

The vascular inflammatory response is a complex process that leads to thrombus formation, angiogenesis, neointimal thickening, and atherosclerosis (12). Markers of inflammation such as C-reactive protein, IL-6, TNF-, and monocyte-chemotactic protein-1 (MCP-1) have, in varying degrees, been proposed as CVD risk factors (12). Recent evidence indicates that statins decrease C-reactive protein levels in just 6 wk of treatment, independent of LDL cholesterol reduction, and suggests that statins possess anti-inflammatory actions (31, 32).

Augmented expression of adhesion molecules on leukocytes (e.g. CD11b) and endothelial cells (e.g. P-selectin, intracellular adhesion molecule, ICAM-1) is necessary and critical in the early vascular response to injury. Cytokines, in addition to enhancing cellular adhesion, promote chemotaxis and stimulate vascular proliferation. Statins affect many of these events in the inflammatory cascade by inhibiting receptor-dependent activation of signal-transducing cascades. In a rat model of coronary inflammation, pravastatin reduces MCP-1 expression, monocyte infiltration, and proliferation (33). Simvastatin reduces leukocyte rolling, adherence, and transmigration in a rodent model of NO deficiency and attenuates endothelial adhesion molecule (34) and monocyte CD11b expression (35) in the absence of lipid lowering (Fig. 4). Statin therapy reduced the levels of soluble P-selectin in patients with acute coronary syndromes (36). In another rat model associated with elevated serum levels of TNF- and IL-1ß, cerivastatin has been shown to reduce serum levels of these markers and improve survival rate (37). Statins also mediate the suppression of cytokine and adhesion molecule expression by reducing NF-B activity in inflammatory and vascular cells (33). These observations underlie the importance of statins in attenuating the inflammatory process and the consequent impact on CVD risk reduction.

View larger version (29K): [in this window] [in a new window]   Figure 4. Effects of statins on inflammation and glucose metabolism.

Oxidative stress is a result of altered balance in the relative concentrations of oxidants and antioxidants. Ox-LDL is deleterious to endothelial and VSMCs; it activates macrophages, induces release of various cytokines, and increases endothelial adhesiveness resulting in vascular injury and inflammation. Statins as potent antioxidants and antiatherosclerotic agents are attractive therapeutic options for preserving normal vascular function and blood flow. In several human and animal studies, various statins have been shown to: 1) inhibit the uptake and generation of ox-LDL (38), 2) attenuate vascular and endothelial superoxide anion formation by inhibition of NADH oxidases via Rho-dependent mechanisms (39, 40); and 3) preserve the relative levels of vitamin E, vitamin C, and endogenous antioxidants such as ubiquinone and glutatione in LDL particles (41, 42, 43). Thus, statins not only decrease oxidants but also restore antioxidants, thereby possibly reducing the level of oxidative stress in the vascular milieu, which may explain some of the observed clinical beneficial effects.

Statins and thrombosis.

Statins have been shown to play a role in altering the levels of several key elements in the process of thrombosis. Different statins have varying effects on prothrombotic factors, such as tissue factor, tissue factor pathway inhibitor, platelet aggregation, blood and plasma viscosity, fibrinogen, plasminogen activator inhibitor 1 (PAI-1), and lipoprotein (a) (44). Cellular expression of tissue factor in human macrophages is suppressed by lipophilic statins (45). Statins normalize thrombin generation in hypercholesterolemic patients and reduce platelet aggregation (46). Furthermore, decreases in platelet aggregation after statin therapy may be partially related to relative reductions in the cholesterol to phospholipid content in the platelet membrane (47).

Elevated fibrinogen levels and plasma viscosity may contribute to increased risk for CVD events in patients with and without established coronary artery disease (20, 46). Conflicting results exist on the effects of statins on fibrinogen levels and blood viscosity (48, 49, 50). Elevated plasminogen activator inhibitor 1 levels are associated with prothrombotic states, and statins reduce these levels (51); however, this effect is not a class effect. Further studies are needed to explain the apparent conflicting results.

Statins and vasculogenesis.

Statins, in addition to modulating endothelial and vascular function, may mediate neovascularization (vasculogenesis) and collectively contribute to the reduction in recurrent CVD events. Increased vasculogenesis has been demonstrated in rabbits treated with simvastatin via the activation of vascular Akt (21). Statins mobilize endothelial progenitor cells (EPCs) from the bone marrow that play a role in maintenance vasculogenesis (52). Increased EPCs are seen immediately after a coronary event (53) and line the endothelium of myocardial vessels (54). Indeed, statin therapy is associated with enhanced EPCs in patients with coronary artery disease (55).

Statins and kidneys

Statins have been shown to attenuate renal injury in both in vivo and in vitro studies. Renal injury initiates inflammatory cascades that involve similar cellular events as seen in vascular tissue. Statins inhibit key events in this process that alter the progression of renal injury. In hyperglycemic insulin-deficient diabetic rats, pravastatin ameliorates the structural and functional changes of diabetic nephropathy (56). Although the pathogenesis of diabetic nephropathy is complex and multifactorial, statins have been demonstrated to decrease TGF-ß production and suppress the enhanced Ras-dependent activation of MAPK cascade (Fig. 4). Lovastatin has similar action on glomerular disease in obese insulin-resistant rats (57). In another model of renal injury due to overexpression of Ang II, cerivastatin decreased systolic blood pressure, albuminuria, and cortical necrosis (28). These changes were associated with reduced infiltration of inflammatory cells, diminished expression of adhesion molecules, and lower levels of transcription factor (NF-B) activity (Fig. 4). In rats with glomerulonephritis, simvastatin decreased mesangial cell proliferation and monocyte/macrophage infiltration (58). Statins have been shown to inhibit the proliferative actions of platelet-derived growth factor (59) and TGF-ß (56). Cytokines released during renal injury activate NF-B and growth-regulating pathways in mesangial and tubular cells. Statins both decrease the levels of cytokines and inhibit the NF-B-dependent gene activation, such as MCP-1 and IL-6. In humans, statins also decrease urinary albumin excretion in patients with nephrotic syndrome and in patients with type II diabetes (4). Thus, statins modulate glomerular mesangial and interstitial inflammatory process independent of lipid reduction. Clinical relevance of these observations is yet to be determined by the ongoing interventional studies.

Statins and glucose metabolism

A retrospective analysis of the WOSCOPS examining the development of new diabetes mellitus revealed that pravastatin therapy reduced the risk of developing diabetes by 30%. This prevention in the onset of diabetes was associated with significant reduction in triglyceride levels, but upon further analyses the reduction in triglycerides did not account for the effect of statins on the development of diabetes (5). Recent advances in understanding the cellular actions of statins may explain mechanisms that mediate the statin effect on insulin sensitivity. Statins may affect substrate delivery to insulin-sensitive tissues or modulate insulin-activated signaling cascades that mediate glucose uptake. Insulin increases skeletal muscle perfusion and substrate delivery by enhancing eNOS activity. As described previously, statins also increase eNOS expression, which may result in increased capillary recruitment and glucose disposal (60). Insulin activates a series of kinase cascades that involve PI3K and Akt, resulting in the translocation of glucose transporters to cell membrane and enhanced glucose uptake (60). This cascade is inhibited by circulating cytokines (TNF- and IL-6) (60). Statins, like insulin, activate PI3K and Akt, which may play a role in glucose uptake. Statins, in addition to decreasing cytokine levels, also inhibit the cellular cascades such as Rho-kinase that inactivate the insulin receptor and signaling (20). NO is a potential intermediary, because it has been shown to stimulate skeletal muscle glucose uptake (61). Further studies (in vivo and in vitro) are needed to better understand the favorable effect of statin on glucose metabolism and insulin sensitivity.

Statins and bone remodeling

Effects of statins on bone remodeling were suggested by the finding that nitrogen-containing bisphosphonates exert their cytotoxic effects on osteoclasts by interfering with the mevalonate pathway, a step further downstream from the site of action of statins (62) (Fig. 2). Murine osteoclast formation in cultures was inhibited by both lovastatin and alendronate (a nitrogen-containing bisphosphonate). Furthermore, rabbit osteoclast formation and activity are also inhibited by lovastatin and by alendronate and reversed by mevalonate and geranylgeraniol, respectively (63). These findings suggest that statins, via their effects on osteoclasts, possibly inhibit bone resorption.

Statins were also shown to stimulate bone formation in several studies. In vitro, statins increase the number of osteoblasts and the amount of new bone formation in mouse skull bones (63). Similar effects were also seen in vivo when simvastatin or lovastatin was injected sc over the skull bone of mice. Furthermore, oral administration of simvastatin to rats increased trabecular bone volume and the rate of new bone formation (64). These findings were confirmed by further studies; for example, transdermal lovastatin (65) and cerivastatin were shown to increase bone mass in rodents at doses similar to the dose used in humans in the treatment of hypercholesterolemia (66). All of these findings illustrate positive effects of statins on bone remodeling in the form of inhibition of bone resorption and stimulation of bone formation. The question remains whether statins would emerge as a treatment for osteoporosis that could increase bone formation and reduce fractures. Several published studies, mostly observational, have evaluated the association of statin use and fracture risk (67, 68, 69, 70, 71); one reanalyzed data from a randomized controlled study (the LIPID trial) (72). These studies showed inconsistent results; for example, upon analysis of the General Practice Research Database, Meier et al. (6) reported a risk of hip fracture to be reduced almost by half among statin users (relative risk, 0.55; 95% confidence interval, 0.44–0.66). However, reanalysis of the General Practice Research Database using age- and gender-matched controls for each of the 218,062 patients with fractures showed no relationship between statin use and nonspine fractures (67). The adjusted relative risk for hip fracture among older women in this group was 0.80. This uncertainty regarding the effects of statins on fracture risk needs to be addressed in randomized controlled trials in the future. However, the exciting possibility of a newer generation of statin with a stronger affinity to bone, which could lower both CVD and fracture risks, remains to be seen.

Conclusion

In summary, accumulating evidence from basic research and clinical trials indicates that statins have pleiotropic effects that may largely account for the clinical benefits observed. These agents have been shown to stabilize unstable plaques, improve vascular relaxation, and promote new vessel formation. Statins reduce glomerular injury, renal disease progression, insulin resistance, and bone resorption. These actions are mediated, in part, by the effects on small G-proteins, modulation of signaling cascades, transcription, and gene expression. The clinical relevance of these effects is beginning to be recognized, and ongoing studies will be able to answer these many questions in the near future.

Acknowledgments

We acknowledge Ms. Paddy McGowan for her usual excellent work in preparing this manuscript.

Footnotes

This work was supported by grants from the NIH (RO1-HL-63904–01), a Veterans Affairs Merit Review, and the American Diabetes Association (to J.R.S.).

Abbreviations: CVD, Cardiovascular disease; eNOS, endothelial NO synthase; EPC, endothelial progenitor cell; ET-1, endothelin-1; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; iNOS, inducible form of NO synthase; MCP-1, monocyte-chemotactic protein-1; NO, nitric oxide; ox-LDL, oxidized-LDL; WOSCOPS, West of Scotland Coronary Prevention Study.

Received September 27, 2001.

Accepted December 5, 2001.

References

1. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ 1995 Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 333:1301–1307[Abstract/Free Full Text]
2. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto Jr AM 1998 Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 279:1615–1622[Abstract/Free Full Text]
3. 1994 Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344:1383–1389
4. Tonolo G, Melis MG, Formato M, Angius MF, Carboni A, Brizzi P, Ciccarese M, Cherchi GM, Maioli M 2000 Additive effects of Simvastatin beyond its effects on LDL cholesterol in hypertensive type 2 diabetic patients. Eur J Clin Invest 30:980–987[CrossRef][Medline]
5. Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, Isles C, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, Shepherd J, Gaw A 2001 Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 103:357–362[Abstract/Free Full Text]
6. Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H 2000 HMG-CoA reductase inhibitors and the risk of fractures. JAMA 283:3205–3210[Abstract/Free Full Text]
7. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E 1996 The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 335:1001–1009[Abstract/Free Full Text]
8. 1998 Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. N Engl J Med 339:1349–1357
9. Holme I 1990 An analysis of randomized trials evaluating the effect of cholesterol reduction on total mortality and coronary heart disease incidence. Circulation 82:1916–1924[Abstract/Free Full Text]
10. Jukema JW, Bruschke AV, van Boven AJ, Reiber JH, Bal ET, Zwinderman AH, Jansen H, Boerma GJ, van Rappard FM, Lie KI, on behalf of the REGRESS Study Group Interuniversity Cardiology Institute Utrecht Netherlands 1995 Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation 91:2528–2540[Abstract/Free Full Text]
11. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators 2001 Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study, a randomized controlled trial. JAMA 285:1711–1718[Abstract/Free Full Text]
12. Tedgui A, Mallat Z 2001 Antiinflammatory mechanisms in the vascular wall. Circulation Res 88:877–887[Abstract/Free Full Text]
13. Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J 2001 Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation 103:926–933[Abstract/Free Full Text]
14. Perticone F, Ceravolo R, Maio R, Cloro C, Candigliota M, Scozzafava A, Mongiardo A, Mastroroberto P, Chello M, Mattioli PL 2000 Effects of atorvastatin and vitamin C on endothelial function of hypercholesterolemic patients. Atherosclerosis 152:511–518[CrossRef][Medline]
15. Mital S, Zhang X, Zhao G, Bernstein RD, Smith CJ, Fulton DL, Sessa WC, Liao JK, Hintze TH 2000 Simvastatin upregulates coronary vascular endothelial nitric oxide production in conscious dogs. Am J Physiol Heart Circ Physiol 279:H2649–H2657
16. Alvarez De Sotomayor M, Herrera MD, Marhuenda E, Andriantsitohaina R 2000 Characterization of endothelial factors involved in the vasodilatory effect of simvastatin in aorta and small mesenteric artery of the rat. Br J Pharmacol 131:1179–1187[CrossRef][Medline]
17. Laufs U, La Fata V, Plutzky J, Liao JK 1998 Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 97:1129–1135[Abstract/Free Full Text]
18. Amin-Hanjani S, Stagliano NE, Yamada M, Huang PL, Liao JK, Moskowitz MA 2001 Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. Stroke 32: 980–986
19. Tamai O, Matsuoka H, Itabe H, Wada Y, Kohno K, Imaizumi T 1997 Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans. Circulation 95:76–82[Abstract/Free Full Text]
20. McFarlane SI, Banerji M, Sowers JR 2001 Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 86:713–718[Free Full Text]
21. Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa WC, Walsh K 2000 The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 6:1004–1010[CrossRef][Medline]
22. Feron O, Dessy C, Desager JP, Balligand JL 2001 Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance. Circulation 103:113–118[Abstract/Free Full Text]
23. Laufs U, Liao JK 1998 Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 273:24266–24271[Abstract/Free Full Text]
24. Lefer DJ, Scalia R, Jones SP, Sharp BR, Hoffmeyer MR, Farvid AR, Gibson MF, Lefer AM 2001 HMG-CoA reductase inhibition protects the diabetic myocardium from ischemia-reperfusion injury. FASEB J 15:1454–1456[Free Full Text]
25. Muniyappa R, Srinivas PR, Ram JL, Sowers JR 2001 Glucose-induced inhibition of inducible nitric oxide synthase in vascular smooth muscle cells: role of protein kinase Cß II and Rho. J Diabet Complications 15:22[CrossRef]
26. Muniyappa R, Xu R, Ram JL, Sowers JR 2000 Inhibition of Rho protein stimulates iNOS expression in rat vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 278:H1762–H1768
27. Hernandez-Perera O, Perez-Sala D, Soria E, Lamas S 2000 Involvement of Rho GTPases in the transcriptional inhibition of preproendothelin-1 gene expression by simvastatin in vascular endothelial cells. Circ Res 87:616–622[Abstract/Free Full Text]
28. Park JK, Muller DN, Mervaala EM, Dechend R, Fiebeler A, Schmidt F, Bieringer M, Schafer O, Lindschau C, Schneider W, Ganten D, Luft FC, Haller H 2000 Cerivastatin prevents angiotensin II-induced renal injury independent of blood pressure- and cholesterol-lowering effects. Kidney Int 58:1420–1430[CrossRef][Medline]
29. Nickenig G, Baumer AT, Temur Y, Kebben D, Jockenhovel F, Bohm M 1999 Statin-sensitive dysregulated AT1 receptor function and density in hypercholesterolemic men. Circulation 100:2131–2134[Abstract/Free Full Text]
30. Dechend R, Fiebler A, Lindschau C, Bischoff H, Muller D, Park JK, Dietz R, Haller H, Luft FC 2001 Modulating angiotensin II-induced inflammation by HMG Co-A reductase inhibition. Am J Hypertens 14:55S–61S
31. Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S 2001 Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation 103:1933–1935[Abstract/Free Full Text]
32. Albert MA, Danielson E, Rifai N, Ridker PM, PRINCE Investigators 2001 Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 286:64–70[Abstract/Free Full Text]
33. Egashira K, Ni W, Inoue S, Kataoka C, Kitamoto S, Koyanagi M, Takeshita A 2000 Pravastatin attenuates cardiovascular inflammatory and proliferative changes in a rat model of chronic inhibition of nitric oxide synthesis by its cholesterol-lowering independent actions. Hypertens Res 23:353–358[Medline]
34. Pruefer D, Scalia R, Lefer AM 1999 Simvastatin inhibits leukocyte-endothelial cell interactions and protects against inflammatory processes in normocholesterolemic rats. Arterioscler Thromb Vasc Biol 19:2894–2900[Abstract/Free Full Text]
35. Weber C, Erl W, Weber KS, Weber PC 1997 HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol 30:1212–1217[Abstract]
36. Murphy RT, Foley JB, Mulvihill N, Crean P, Walsh MJ 2001 Impact of preexisting statin use on adhesion molecule expression in patients presenting with acute coronary syndromes. Am J Cardiol 87:446–448[CrossRef][Medline]
37. Ando H, Takamura T, Ota T, Nagai Y, Kobayashi K 2000 Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis. J Pharmacol Exp Ther 294:1043–1046[Abstract/Free Full Text]
38. Aviram M, Dankner G, Cogan U, Hochgraf E, Brook JG 1992 Lovastatin inhibits low-density lipoprotein oxidation and alters its fluidity and uptake by macrophages: in vitro and in vivo studies. Metabolism 41:229–235[CrossRef][Medline]
39. Wagner AH, Kohler T, Ruckschloss U, Just I, Hecker M 2000 Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol 20:61–69[Abstract/Free Full Text]
40. Wassmann S, Laufs U, Baumer AT, Muller K, Ahlbory K, Linz W, Itter G, Rosen R, Bohm M, Nickenig G 2001 HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension 37:1450–1457[Abstract/Free Full Text]
41. Blaha V, Zadak Z, Solichova D, Bratova M, Havel E 1998 Hypocholesterolemic effect of pravastatin is associated with increased content of antioxidant vitamin-E in cholesterol fractions. Acta Medica 41:87–90
42. Laaksonen R, Jokelainen K, Laakso J, Sahi T, Harkonen M, Tikkanen MJ, Himberg JJ 1996 The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle. Am J Cardiol 77:851–854[CrossRef][Medline]
43. Suzumura K, Kasahara E, Ohnishi Y, Chien KC, Inoue M 2000 Fluvastatin normalizes the decreased turnovers of glutathione and ascorbic acid in Watanabe heritable hyperlipidaemic rabbits. Clin Exp Pharmacol Physiol 27: 709–714
44. Rosenson RS, Tangney CC 1998 Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA 279:1643–1650[Abstract/Free Full Text]
45. Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E 1997 Statins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol 17:265–272[Abstract/Free Full Text]
46. Mayer J, Eller T, Brauer P, Solleder EM, Schafer RM, Keller F, Kochsiek K 1992 Effects of long-term treatment with lovastatin on the clotting system and blood platelets. Ann Hematol 64:196–201[CrossRef][Medline]
47. Standley PR, Ali S, Bapna C, Sowers JR 1993 Increased platelet cytosolic calcium responses to low density lipoprotein in type II diabetes with and without hypertension. Am J Hypertens 6:938–943[Medline]
48. Beigel Y, Fuchs J, Snir M, Green P, Lurie Y, Djaldetti M 1991 Lovastatin therapy in hypercholesterolemia: effect on fibrinogen, hemorrheologic parameters, platelet activity, and red blood cell morphology. J Clin Pharmacol 31:512–517[Abstract]
49. Jay RH, Rampling MW, Betteridge DJ 1990 Abnormalities of blood rheology in familial hypercholesterolaemia: effects of treatment. Atherosclerosis 85:249–256[CrossRef][Medline]
50. Tsuda Y, Satoh K, Kitadai M, Takahashi T, Izumi Y, Hosomi N 1996 Effects of pravastatin sodium and simvastatin on plasma fibrinogen level and blood rheology in type II hyperlipoproteinemia. Atherosclerosis 122:225–233[CrossRef][Medline]
51. Wada H, Mori Y, Kaneko T, Wakita Y, Minamikawa K, Ohiwa M, Tamaki S, Yokoyama N, Kobayashi T, Deguchi K, Shirakawa S, Suzuki K 1992 Hypercoagulable state in patients with hypercholesterolemia: effects of pravastatin. Clin Ther 14:829–834[Medline]
52. Llevadot J, Murasawa S, Kureishi Y, Uchida S, Masuda H, Kawamoto A, Walsh K, Isner JM, Asahara T 2001 HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells. J Clin Invest 108:399–405[CrossRef][Medline]
53. Shintani S, Murohara T, Ikeda H, Ueno T, Honma T, Katoh A, Sasaki Ki, Shimada T, Oike Y, Imaizumi T 2001 Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 103:2776–2779[Abstract/Free Full Text]
54. Gunsilius E, Duba HC, Petzer AL, Kahler CM, Grunewald K, Stockhammer G, Gabl C, Dirnhofer S, Clausen J, Gastl G 2000 Evidence from a leukaemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells. Lancet 355:1688–1691[CrossRef][Medline]
55. Vasa M, Fichtlscherer S, Adler K, Aicher A, Martin H, Zeiher AM, Dimmeler S 2001 Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 103:2885–2890[Abstract/Free Full Text]
56. Yokota T, Utsunomiya K, Murakawa Y, Kurata H, Tajima N 1999 Mechanism of preventive effect of HMG-CoA reductase inhibitor on diabetic nephropathy. Kidney Int 71:178–181
57. O’Donnell MP, Kasiske BL, Kim Y, Schmitz PG, Keane WF 1993 Lovastatin retards the progression of established glomerular disease in obese Zucker rats. Am J Kidney Dis 22:83–89[Medline]
58. Yoshimura A, Inui K, Nemoto T, Uda S, Sugenoya Y, Watanabe S, Yokota N, Taira T, Iwasaki S, Ideura T 1998 Simvastatin suppresses glomerular cell proliferation and macrophage infiltration in rats with mesangial proliferative nephritis. J Am Soc Nephrol 9:2027–2039[Abstract]
59. Grandaliano G, Biswas P, Choudhury GG, Abboud HE 1993 Simvastatin inhibits PDGF-induced DNA synthesis in human glomerular mesangial cells. Kidney Int 44:503–508[Medline]
60. Le Roith D, Zick Y 2001 Recent advances in our understanding of insulin action and insulin resistance. Diabetes Care 24:588–597[Abstract/Free Full Text]
61. Balon TW, Nadler JL 1997 Evidence that nitric oxide increases glucose transport in skeletal muscle. J Appl Physiol 82:359–363[Abstract/Free Full Text]
62. Luckman SP, Hughes DE, Coxon FP, Graham R, Russell G, Rogers MJ 1998 Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 13:581–589[CrossRef][Medline]
63. Fisher JE, Rogers MJ, Halasy JM, Luckman SP, Hughes DE, Masarachia PJ, Wesolowski G, Russell RG, Rodan GA, Reszka AA 1999 Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci USA 96:133–138[Abstract/Free Full Text]
64. Mundy G, Garrett R, Harris S, Chan J, Chen D, Rossini G, Boyce B, Zhao M, Gutierrez G 1999 Stimulation of bone formation in vitro and in rodents by statins. Science 286:1946–1949[Abstract/Free Full Text]
65. Whang K, Zhao M, Oiao M, Rossini G, Horn D, Garrett JR, Mundy GR, Chen D 2000 Administration of lovastatin locally in low doses in a novel delivery system induces prolonged bone formation. J Bone Miner Res 15:S225 (Abstract)
66. Wilkie D, Bowman, Lyga A, Bagi CM, Miller SC, Ranges CE, Carley W 2000 Cerivastatin increases cortical bone formation in OVX rats. J Bone Miner Res 15:S549 (Abstract)
67. Van Staa TP, Wegman S, de Vries F, Leufkens B, Cooper C 2001 Use of statins and risk of fractures. JAMA 285:1850–1855[Abstract/Free Full Text]
68. Bauer DC, Mundy GR, Jamal SA, Black DM, Cauley JA, Harris F, Doung T, Cummings SR 1999 Statin use, bone mass and fracture: an analysis of two prospective studies. J Bone Miner Res 14:S179
69. Chan KA, Andrade SE, Boles M, Buist DS, Chase GA, Donahue JG, Goodman MJ, Gurwitz JH, LaCroix AZ, Platt R 2000 Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of fracture among older women. Lancet 355:2185–2188[CrossRef][Medline]
70. Wang PS, Solomon DH, Mogun H, Avorn J 2000 HMG-CoA reductase inhibitors and the risk of hip fractures in elderly patients. JAMA 283:3211–3216[Abstract/Free Full Text]
71. LaCroix AZ, Cauley JA, Jackson R, McGowan J, Pettinger M, Hsia J, Chen Z, Lewis C, Bauer DC, Daugherty S, McNeely SG, Passaro M 2000 Does statin use reduce risk of fracture in postmenopausal women? J Bone Miner Res 15:S155
72. Reid IR, Hague W, Emberson J, Baker J, Tonkin A, Hunt D, MacMahon S, Sharpe N 2001 Effect of pravastatin on frequency of fracture in the LIPID study: secondary analysis of a randomised controlled trial. Long-term Intervention with Pravastatin in Ischemic Disease. Lancet 357:509–512[CrossRef][Medline]

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