doi: 10.1161/01.CIR.0000033635.42612.88
(Circulation. 2002;106:2041.)
© 2002 American Heart Association, Inc.
Editorial |
Statins as Potent Antiinflammatory Drugs
From the Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, La.
Correspondence to David J. Lefer, PhD, Department of Molecular and Cellular Physiology, 1501 Kings Highway, Shreveport, LA 71130. E-mail dlefer{at}lsuhsc.edu
Key Words: Editorials • statins • nitric oxide synthase • leukocytes
Statin drugs have previously been shown to very significantly reduce cardiovascular disease events in a number of large clinical trials.1 As a result, statins are now considered to represent one of the most powerful classes of agents for the treatment of cardiovascular diseases.2 Statins are rapidly becoming frontline therapy for diabetes mellitus, hypertension, and other known cardiovascular disease risk factors. Originally, reductions in cardiovascular disease events and mortality and overall improved outcomes were attributed to dramatic reductions in circulating serum lipid levels that were mediated by inhibition of liver 3-hydroxy 3-methyl glutaryl coenzyme A (HMG-CoA) reductase.1 However, more recent experimental and clinical investigations have revealed that statins can exert a number of cholesterol-independent, cardioprotective actions. In this regard, statins are potent modulators of endothelial cell nitric oxide synthase (eNOS) function and have been shown to upregulate eNOS enzyme levels and nitric oxide (NO) synthesis.3–5
See p 2104
Pruefer and colleagues6 now demonstrate in this issue of Circulation powerful antiinflammatory properties of simvastatin in the setting of Staphylococcus aureus 
-toxin infection. Endotoxemia represents a potent stimulus for vascular inflammation that is characterized by enhanced leukocyte recruitment to the microvascular endothelium. The report by Pruefer et al6 elegantly demonstrates that pretreatment with clinically relevant doses of simvastatin attenuates endotoxin-induced leukocyte rolling and transmigration in the rat mesentery. Simvastatin was administered 18 hours before administration of endotoxin. Simvastatin therapy also resulted in a 50% upregulation of eNOS expression in the endothelium and a 50% decrease in endothelial cell P-selectin expression. Circulating cholesterol levels were not reported in this study, but it is unlikely that acute statin therapy would alter lipid levels in rodents. The data presented in this paper are very convincing and provide yet another example of the potent antiinflammatory actions of acute statin therapy. The results of the study by Pruefer et al6 may have important clinical implications for the treatment of inflammatory disease states with statin therapy.
Previous experimental and clinical studies have also demonstrated that statins can downregulate both acute and chronic inflammatory processes. Early evidence for the direct vascular effects of statins was provided by clinical studies demonstrating improvements in coronary endothelial function in patients as early as 1 month after the initiation of statin therapy.7,8 It soon became evident that statins had potent actions on the vascular endothelium that might be mediated by eNOS. Landmark studies by Laufs et al3–5 reported that statins upregulate eNOS function under baseline conditions and after hypoxic conditions. Laufs and colleagues3 reported that simvastatin and lovastatin increased endothelial cell eNOS mRNA half-life from 13 to 38 hours. Furthermore, Laufs and colleagues3–5 discovered that statins augmented endothelial NOS function via inhibition of biosynthesis of L-mevalonate and the isoprenoid geranylgeranylpyrophosphate (GGPP). GGPP is involved in the posttranslational modification of a variety of proteins, including eNOS, and Ras-like proteins, such as Rho. Inhibition of Rho results in a 3-fold increase in eNOS and nitrite generation, since Rho is an endogenous inhibitor of endothelial NO generation. More recently, Kureishi et al9 have provided a very elegant demonstration that simvastatin activates the protein kinase Akt resulting in enhanced eNOS phosphorylation and NO generation via eNOS. The results of Kureishi and colleagues9 demonstrate that statins can produce a very rapid improvement in endothelial function that is independent of changes in eNOS mRNA levels. Kureishi et al9 also reported for the first time that simvastatin treatment can attenuate endothelial cell apoptosis and augment angiogenesis in the ischemic rabbit hind limb model system. Since eNOS-derived NO represents a highly potent antiinflammatory signaling pathway, the investigation of statins a antiinflammatory agents is very logical.
After the landmark discovery that statins upregulate eNOS function, a number of studies have reported very powerful antiinflammatory actions of statins that are largely eNOS-dependent. Lefer et al10 were among the first to report antiinflammatory actions of statins in an in vitro model of acute myocardial ischemia-reperfusion. Subsequently, Pruefer et al11 utilized intravital microscopy to demonstrate that statin therapy very significantly inhibits leukocyte–endothelial cell interactions independently of any lipid lowering actions in normocholesterolemic rats. More recently, rosuvastatin has been shown to exhibit similar antiinflammatory properties in the microvasculature.12 Since these initial studies of statin therapy in acute myocardial infarction in vitro, there have been a number of in vivo reports demonstrating highly potent antiinflammatory and cardioprotective actions of statins in the setting of acute myocardial infarction in normocholesterolemic,13 hypercholesterolemic,13 and diabetic14 animal models. The cardioprotective actions of statin therapy are not transient in nature and have been shown to be present at 6 months of reperfusion after statin therapy before the onset of acute myocardial infarction.15 Statin therapy has been shown to inhibit leukocyte accumulation in the ischemic-reperfused myocardium and to be highly dependent on eNOS, since eNOS deficient mice are completely resistant to statin-mediated cardioprotection.
Clinical evidence supporting the potent antiinflammatory and cardioprotective actions is beginning to emerge. It is now well appreciated that atherogenesis is primarily an inflammatory process mediated in large part by the recruitment of blood monocytes to the vessel wall.16 Statin therapy has been shown to attenuate vascular inflammation in patients, as evidenced by significant reductions in inflammatory markers such as high sensitivity C-reactive protein (hsCRP)17 and soluble CD40 ligand.18 Furthermore, it has been reported very recently that statin therapy in patients is associated with a significant reduction in mortality very early after percutaneous coronary interventions.19 It is possible that these acute effects of statin therapy may be related to attenuation of inflammatory processes. In addition, results from the Platelet Receptor Inhibition in ischemic Syndrome Management (PRISM) study20 clearly demonstrated that withdrawal of statin therapy very significantly increases event rates in patients with acute coronary syndromes. Interestingly, the increased event rate occurred during the first week after the onset of symptoms and was independent of cholesterol levels.
In summary, statins are now becoming recognized as powerful antiinflammatory agents that exert beneficial effects beyond low-density lipoprotein cholesterol reduction. Upregulation of endothelial function (ie, eNOS enzyme activity) is thought to be a primary mechanism responsible for these antiinflammatory properties. Pruefer et al6 now provide additional evidence that statin therapy attenuates inflammation and further extend out understanding of this very exciting class of cardiovascular agents.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Dr Lefer is a speaker for Merck and Company and has received research grants from Merck and Company and AstraZeneca.
References
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2. Lefer AM, Scalia R, Lefer DJ. Vascular effects of HMG-CoA reductase inhibitors (statins) unrelated to cholesterol lowering: new concepts for cardiovascular disease. Cardiovasc Res. 2001; 49: 281–287.
3. Laufs U, La Fata V, Plutzky J, et al. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998; 97: 1129–1135.
4. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA activity stability by Rho GTPase. J Biol Chem. 1998; 273: 24266–24271.
5. Laufs U, La Fata V, Liao JK. Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J Biol Chem. 1997; 272: 31725–31729.
6. Pruefer D, Makowski J, Schnell M, et al. Simvastatin inhibits inflammatory properties of staphylococcus aureus -toxin. Circulation. 2002; 106: 2104–2110.
7. Treasure CB, Klein JL, Weintraub WS, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med. 1995; 332: 481–487.
8. O’Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation. 1997; 95: 1126–1131.
9. 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 Med. 2000; 6: 1004–1010.[CrossRef][Medline] [Order article via Infotrieve]
10. Lefer AM, Campbell B, Shin YK, et al. Simvastatin preserves the ischemic-reperfused myocardium in normocholesterolemic rat hearts. Circulation. 1999; 100: 178–184.
11. Pruefer D, Scalia R, Lefer AM. Simvastatin inhibits leukocyte-endothelial cell interactions and protects against inflammatory processes in normocholesterolemic rats. Arterioscler Thromb Vasc Biol. 1999; 19: 2894–2900.
12. Stalker TJ, Lefer AM, Scalia R. A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on microvascular endothelium, the role of mevalonic acid. Br J Pharmacol. 2001; 133: 406–412.[CrossRef][Medline] [Order article via Infotrieve]
13. Scalia R, Gooszen ME, Jones SP, et al. Simvastatin exerts both anti-inflammatory and cardioprotective effects in apolipoprotein E-deficient mice. Circulation. 2001; 103: 2598–2603.
14. Lefer DJ, Scalia R, Jones SP, et al. HMG-CoA reductase inhibition protects the diabetic myocardium from ischemia-reperfusion injury.FASEB J. April 27, 2001. 10.1096-/fj00–0819fje. Available at http://www.fasebj.org. Accessed September 18, 2002.
15. Jones SP, Trocha SD, Lefer DJ. Pretreatment with simvastatin attenuates myocardial dysfunction after ischemia and chronic reperfusion. Arterioscler Thromb Vasc Biol. 2001; 21: 2059–2064.
16. Ridker PM, Rifai N, Pfeffer M, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation. 1999; 100: 230–235.
17. Cipollone F, Mezzetti A, Porreca E, et al. Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy. Circulation. 2002; 106: 399–402.
18. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
19. Chan AW, Bhatt DL, Chew DP, et al. Early and sustained survival benefit associated with statin therapy at the time of percutaneous coronary intervention. Circulation. 2002; 105: 691–696.
20. Heeschen C, Hamm CW, Laufs U, et al. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation. 2002; 105: 1446–1452.
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