Statins: effects beyond cholesterol lowering

Ziad A. Massy1, and Carlos Guijarro2

1 Division of Nephrology, CH Beauvais and INSERM U 507, Necker Hospital, Paris, France and 2 Fundación Hospital Alcorcón, Madrid, Spain

Keywords: 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors; cholesterol; statins

Introduction

Recent large-scale placebo-controlled clinical trials have established beyond doubt the benefits of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-Co A) reductase inhibitors (statins) in the primary and secondary prevention of coronary heart disease [1]. The role of hypercholesterolaemia in the pathogenesis of atherosclerosis is also well established and statins are the most powerful available agents to safely reduce blood cholesterol levels. However, the greater than expected success of statin therapy has raised the possibility that certain beneficial effects go beyond their ability to reduce circulating cholesterol levels [2]. For example, the clinical benefits of statin therapy appear disproportionate to the improvement in atherosclerotic lesions demonstrated in angiographic studies [3]. Therefore, statins may reduce cardiovascular events by mechanisms different from regression of coronary atherosclerosis. Second, the rate of clinical events in some trials in from treated groups was lower than expected from estimations based on Framingham equations using in-trial cholesterol levels, whereas estimations were highly accurate for patients assigned to placebo [4]. Finally, case-control studies recently generated interesting data suggesting that statins may provide additional benefits in some (apparently) unrelated conditions such as the prevention of bone mass loss [5], the development of new onset diabetes mellitus [6], and dementia [7].

Statins exert their action by inhibiting the rate-limiting step in cholesterol synthesis, namely the conversion of HMG-CoA into mevalonate (Figure 1Go). However, statins additionally inhibit the synthesis of a variety of compounds, including the so-called isoprenoids derived from the mevalonate pathway, which are involved in a number of important biological processes in all types of cells [8]. Changes in the levels of these compounds could be responsible for the effects of statins beyond their lipid-lowering effects. In the present review, we will briefly summarize recent data suggesting a potential role for statins in modulating several pathophysiological processes other than those involved in lipid metabolism.



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Fig. 1. Potential effects of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-Co A) reductase inhibitors on activation of immune-competent cells. The pleiotropic effects of HMG-Co A reductase inhibitors on low-density lipoprotein (LDL) cholesterol levels, the pharmacology of lipoprotein-bound drugs such as cyclosporine, and isoprenylation of GTP-binding proteins (e.g. Ras) may result in the modulation of signal transduction from receptors, gene expression (cytokines, growth factors, and major histocompatibility complex class II (MHC-II)), and cell cycle progress.

 

Statins and the control of cell number

Cell proliferation and death (including programmed cell death) play an essential role in the repertoire of responses to injury in a variety of pathophysiological conditions including atherosclerosis [9] and many renal diseases. Statins have been shown to inhibit both smooth muscle and mesangial cell proliferation in vitro, independent of cholesterol availability [10,11]. This effect can be reversed, at least partially, by the addition to the culture medium of mevalonate or isoprenoid derivatives such as farnesyl and geranylgeranyl. In addition, treatment with statins attenuated neointimal thickening and mesangial cell proliferation in animal models of atherosclerosis and nephritis independent of lipid levels, suggesting that the above in vitro findings maybe relevant in vivo [12,13].

Recent studies have demonstrated that statins may promote apoptosis in vascular smooth muscle cells as well as in renal tubular epithelial cells [14,15]. Statins may also sensitize smooth muscle cells to cytokine or Fas-induced apoptosis [16]. Although relatively scant, recent reports have shown that statin-induced increases in apoptosis may be responsible for their beneficial effect of attenuating neointimal thickening in a model of atherosclerosis [17]. Interestingly, this model of statin therapy did not induce apoptosis in normal vessels, suggesting a selective apoptosis induction in injured vessels. It is conceivable that both the inhibition of cell proliferation and the stimulation of apoptosis may contribute to organ protection by preventing an inadequate accumulation of cells. On the other hand, apoptosis of vascular smooth muscle cells may contribute to fibrous cap weakening, and thereby promote plaque rupture and vessel thrombosis [18]. It must be emphasized that it is unknown at present whether statins significantly affect cell proliferation and/or apoptosis in the micro-environment of human atherosclerotic plaques.

Statins and thrombosis

In recent years, it has become evident that most ischaemic events do not take place in areas with the highest degree of stenosis. Therefore, attention has shifted to conditions that may contribute to the local formation of an occlusive thrombus, and particularly to plaque stability [18]. Given the modest anatomic effects of statins, many investigators have focused on the potential effects of statins on plaque inflammation, stability, and thrombosis. As hypercholesterolaemia is associated with a prothrombotic state, it is not surprising that effective anti-lipaemic agents such as statins may attenuate this thrombogenic potential [19,20]. But again, some clinical and experimental data suggest that statins may exert anti-thrombotic effects independent of cholesterol reduction by affecting the vessel wall as well as platelet function [21]. For instance, statins have been shown to inhibit tissue factor expression by macrophages through isoprenoid depletion and to prevent the activation of nuclear factor kappa B (NF-{kappa}B) [22]. In addition, statins also prevent the down-regulation of nitric oxide synthase induced by oxidized lipoproteins, representing a novel mechanism for the attenuation of platelet aggregation [23].

The anti-thrombotic effects of statins also include their ability to promote fibrinolysis. In this regard, lovastatin has been shown to promote tissue plasminogen activator synthesis (tPA), and to reduce plasminogen activator inhibitor 1 (PAI-1) [24], resulting in increased fibrinolytic activity. These effects were independent of cholesterol levels and were related to the inhibition of the isoprenylation of Rho proteins.

Statins and inflammation

The important role of inflammation in the genesis of atherosclerotic lesions has been fully recognized during the past decade [9]. Several reports have linked inflammation markers to cardiovascular risk, particularly C-reactive protein (CRP) [25]. Recently, preliminary studies have suggested that statins may have anti-inflammatory properties. A subanalysis of the CARE trial demonstrated that pravastatin lowers serum CRP levels and eliminates the higher risk cardiovascular events that are associated with this marker of inflammation [25]. It is noteworthy that the CRP reduction in the pravastatin group was not related to the magnitude of lipid alterations during treatment, suggesting a direct anti-inflammatory effect of statins [25]. These actions may help to stabilize the plaque and reduce the risk of acute coronary syndromes [18]. In vitro observations of the anti-inflammatory action of statins on vascular and non-vascular cells also suggest some direct beneficial effects beyond lipid reduction. In several experimental models, statins inhibited NF-{kappa}B activation, which is a pivotal transcription factor regulating the expression of a variety of inflammatory genes [26]. The inhibition of NF-{kappa}B activation could explain the reduced synthesis of inflammatory cytokines, such as interleukin-6, under these in vitro conditions [27]. It is noteworthy that the synthesis of CRP in liver is stimulated by interleukin-6, and preliminary data indicate that pravastatin treatment interferes with lipopolysaccharide-stimulated interleukin-6 accumulation in peripheral blood cells of healthy elderly subjects [28].

Statins and endothelial function

In atheroslerosis patients, endothelial dysfunction is present even in early stages of the disease. As a class of drugs, statins have the ability to improve impairments in endothelial dysfunction, primarily by increasing nitric oxide biosynthesis and bioavailability [29,30]. These benefits are seen early (4–6 weeks) in the course of treatment [29,30], supporting the idea that early initiation of statin therapy may be beneficial in patients with acute coronary syndromes. The improvement in endothelial function with statins may be primarily related to lipid lowering, since other hypolipaemic strategies also improve endothelial function in humans [31]. However, in several experimental models, statins have been shown to upregulate the expression of endothelial nitric oxide synthase, to decrease superoxide production by endothelial cell, and to promote angiogenesis directly, and this occurs independent of their cholesterol-lowering effects [32,33].

Statins and immunomodulation

Two recent studies demonstrated that statin administration after cardiac transplantation produced beneficial effects, not only on lipid abnormalities, but also on the incidence of acute rejection and coronary vasculopathy [34,35]. Among the many possible explanations (Figure 1Go), these effects may be due to the inhibiting actions of statins on the recruitment and activation of immune-competent cells. In vitro studies demonstrated that statins exert inhibitory effects on several functions in immune-competent cells, including inhibition of expression of major histocompatibility complex class II [36,37]. However, animal and human data demonstrated that statin therapy by itself does not appear to affect immune function [38,39]; in fact, the coadministration of cyclosporin A is necessary to observe immunomodulatory effects [34,38]. Apparently, the two compounds act synergistically to modulate immune responses [40].

Conclusion

Considerable experimental data suggest that statins modulate a variety of pathophysiological processes that extend beyond their effects on lipid metabolism. In experimental models, it has been possible to manipulate lipid levels so that anti-lipaemic effects of statins were entirely dissociated from other actions. However, the demonstration of these lipid-independent actions in humans has been more difficult. At present, we cannot ascertain the relative contributions of lipid-dependent and lipid-independent mechanisms in the proven clinical benefits of statins. However, the available data suggest a role for non-lipid-dependent effects in man. Although the doses of statins used in experimental models generally have been far higher than those used in the clinical setting, it is possible that concentrations of statins needed to affect activated cells are lower than those needed to affect normal cells [17]. Finally, it is also possible that therapeutic doses of statins may potentiate the effects of other drugs impacting on cell function, including such as those used in immunosuppression [34,38].

Notes

Correspondence and offprint requests to: Ziad A. Massy, INSERM U507, Necker Hospital, 161 rue de Sèvres, F-75730 Paris Cedex 15, France. Back

References

  1. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. J Am Med Assoc1999; 282: 2340–2346[Abstract/Free Full Text]
  2. Massy ZA, Keane WF, Kasiske BL. Inhibition of the mevalonate pathway: benefits beyond cholesterol reduction. Lancet1996; 347: 102–103[ISI][Medline]
  3. Levine GN, Keaney JF, Vita JA. Medical progress: cholesterol reduction in cardiovascular disease–clinical benefits and potential mechanisms. N Engl J Med1995; 332: 512–521[Free Full Text]
  4. West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation1998; 97: 1440–1445[Abstract/Free Full Text]
  5. Cummings SR, Bauer DC. Do statins prevent both cardiovascular disease and fracture. J Am Med Assoc2000; 283: 3255–3257[Free Full Text]
  6. Freeman D, Norrie J, Sattar N et al. Pravastatin and the development of diabetes mellitus: Evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation2001; 103: 357–362[Abstract/Free Full Text]
  7. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet2000; 356: 1627–1631[ISI][Medline]
  8. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature1990; 343: 425–430[ISI][Medline]
  9. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med1999; 340: 115–126[Free Full Text]
  10. Corsini A, Mazzotti M, Raiteri M et al. Relationship between mevalonate pathway and arterial myocyte proliferation – in vitro studies with inhibitors of HMG-CoA reductase. Atherosclerosis1993; 101: 117–125[ISI][Medline]
  11. Massy ZA, Guijarro C, O'Donnell MP, Kasiske BL, Keane WF. Regulation of mesangial cell proliferation by the mevalonate pathway. Contrib Nephrol1997; 120: 191–196[ISI][Medline]
  12. Soma MR, Donetti E, Parolini C et al. HMG CoA reductase inhibitors – in vivo effects on carotid intimal thickening in normocholesterolemic rabbits. Arterioscler Thromb1993; 13: 571–578[Abstract]
  13. Nabeshima K, Inui K, Uda S et al. HMG-CoA reductase inhibitor suppression of glomerular cell proliferation in rats with anti-Thy-1.1 nephritis. Contrib Nephrol1997; 120: 153–159[ISI][Medline]
  14. Guijarro C, Blanco-Colio LM, Ortego M et al. 3-Hydroxy-3-methylglutaryl coenzyme A reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. Circ Res1998; 83: 490–500[Abstract/Free Full Text]
  15. Iimura O, Vrtovsnik F, Terzi F, Friedlander G. HMG-CoA reductase inhibitors induce apoptosis in mouse proximal tubular cells in primary culture. Kidney Int1997; 52: 962–972[ISI][Medline]
  16. Knapp AC, Huang J, Starling G, Kiener PA. Inhibitors of HMG-CoA reductase sensitize human smooth muscle cells to fas-ligand and cytokine-induced cell death. Atherosclerosis2000; 152: 217–227[ISI][Medline]
  17. Baetta R, Donetti E, Comparato C et al. Proapoptotic effect of atorvastatin on stimulated rabbit smooth muscle cells. Pharmacol Res1997; 36: 115–121[ISI][Medline]
  18. Fuster V, Fayad ZA, Badimon JJ. Acute coronary syndromes: biology. Lancet1999; 353 [Suppl 2]: SII5–SII9[ISI][Medline]
  19. Notarbartolo A, Davi G, Averna M et al. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia. Arterioscler Thromb Vasc Biol1995; 15: 247–251[Abstract/Free Full Text]
  20. Lacoste L, Lam JY, Hung J et al. Hyperlipidemia and coronary disease. Correction of the increased thrombogenic potential with cholesterol reduction. Circulation1995; 92: 3172–3177[Abstract/Free Full Text]
  21. Dangas G, Smith DA, Unger AH et al. Pravastatin: an antithrombotic effect independent of the cholesterol-lowering effect. Thromb Haemost2000; 83: 688–692[ISI][Medline]
  22. Colli S, Lalli M, Eligini S et al. Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol1997; 17: 265–272[Abstract/Free Full Text]
  23. Laufs U, Gertz K, Huang P et al. Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation and protects from cerebral ischemia in normocholesterolemic mice. Stroke2000; 31: 2442–2449[Abstract/Free Full Text]
  24. Essig M, Vrtovsnik F, Nguyen G, Sraer JD, Friedlander G. Lovastatin modulates in vivo and in vitro the plasminogen activator/plasmin system of rat proximal tubular cells: role of geranylgeranylation and Rho proteins. J Am Soc Nephrol1998; 9: 1377–1388[Abstract]
  25. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation1999; 100: 230–235[Abstract/Free Full Text]
  26. Guijarro C, Egido J. Transcription factor {kappa}B (NF{kappa}B) and renal disease. Kidney Int2001; 59: 415–424[ISI][Medline]
  27. Massy ZA, Kim Y, Guijarro C, Kasiske BL, Keane WF, O'Donnell MP. Low-density lipoprotein-induced expression of interleukin-6, a marker of human mesangial cell inflammation: effects of oxidation and modulation by lovastatin. Biochem Biophys Res Commun2000; 267: 536–540[ISI][Medline]
  28. Rosenson RS, Tangney CC, Casey LC. Inhibition of proinflammatory cytokine production by pravastatin. Lancet1999; 353: 983–984[ISI][Medline]
  29. O'Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation1997; 95: 1126–1131[Abstract/Free Full Text]
  30. Dupuis J, Tardif JC, Cernacek P, Theroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (reduction of cholesterol in ischemia and function of the endothelium) trial. Circulation1999; 99: 3227–3233[Abstract/Free Full Text]
  31. Leung WH, Lau CP, Wong CK. Beneficial effect of cholesterol-lowering therapy on coronary endothelium-dependent relaxation in hypercholesterolaemic patients. Lancet1993; 341: 1496–1500[ISI][Medline]
  32. Davis ME, Harrison DG. Cracking down on caveolin: role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in modulating edothelial cell nitric oxide production. Circulation2001; 103: 2–4[Free Full Text]
  33. Kureishi Y, Luo Z, Shiojima I et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med2000; 6: 1004–1010[ISI][Medline]
  34. Kobashigawa JA, Katznelson S, Laks H et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med1995; 333: 621–627[Abstract/Free Full Text]
  35. Wenke K, Meiser B, Thiery J et al. Simvastatin reduces graft vessel disease and mortality after heart transplantation. A four-year randomized trial. Circulation1997; 96: 1398–1402[Abstract/Free Full Text]
  36. Katznelson S. Effect of HMG-CoA reductase inhibitors on chronic allograft rejection. Kidney Int1999; 71 [Suppl]: S117–121
  37. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med2000; 6: 1399–1402[ISI][Medline]
  38. Kakkis JL, Ke B, Dawson S et al. Pravastain increases survival and inhibits natural killer cell enhancement factor in liver transplanted rats. J Surg Res1997; 69: 393–398[ISI][Medline]
  39. Muldoon MF, Flory JD, Marsland A, Manuck SB, Whiteside TL, Rabin B. Effects of lovastatin on the immune system. Am J Cardiol1997; 80: 1391–1394[ISI][Medline]
  40. Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K. Effects of different inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. Immunnopharmacology1996; 34: 51–61