Current Atherosclerosis Reports

, Volume 14, Issue 2, pp 135–139 | Cite as

Pleiotropic Effects of Statins: The Role of Eicosanoid Production

  • Yochai Birnbaum
  • Yumei Ye
Coronary Heart Disease (J Farmer, Section Editor)


The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have potent anti-inflammatory, vasodilatory and anti-platelet effects that are independent of the lipid-lowering effects. These non–lipid-lowering or pleiotropic effects are dependent on HMG-CoA reductase inhibition in tissues other than the liver. In animal models, high-dose statins upregulate cytosolic phospholipase A2 and cyclooxygenase-2, leading to increased production of prostacyclin and 15-deoxy-PGJ2. In addition, statins activate protein kinase A, which phosphorylates 5-lipoxygenase, resulting in decreased production of the pro-inflammatory leukotrienes and increased production of 15-epi-lipoxin A4, an eicosanoid with potent anti-inflammatory and inflammation-resolution properties. It is unclear, however, whether these effects occur in the clinical setting and whether these effects (partially) explain the anti-inflammatory effects of statins in patients.


Arachidonic acid Aspirin LDL cholesterol Cyclooxygenase-2 Eicosanoids Inflammation 5-lipooxygenase Pleiotropic effects Prostacyclin Protein kinase A (PKA) Statins 



Y. Birnbaum has received grants (payable to his institution) from Pfizer, Takeda, Merck, and AstraZeneca; has received consulting fees from Takeda; and has had travel expenses for meetings covered by Takeda and Merck. Y. Ye has received grants (payable to his institution) from Pfizer, Takeda, Merck, and AstraZeneca; has received consulting fees from Takeda; and has had travel expenses for meetings covered by Takeda and Merck.


Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Wang CY, Liu PY, Liao JK. Pleiotropic effects of statin therapy: molecular mechanisms and clinical results. Trends Mol Med. 2008;14:37–44.PubMedCrossRefGoogle Scholar
  2. 2.
    Gotto Jr AM. The cardiology patient page. Statins: powerful drugs for lowering cholesterol: advice for patients. Circulation. 2002;105:1514–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Iida K, Goland S, Akima T, et al. Effect of a single 20-mg tablet of Atorvastatin on brachial artery blood flow in normolipidemic male smokers versus nonsmokers. Am J Cardiol. 2007;100:881–4.PubMedCrossRefGoogle Scholar
  4. 4.
    Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343:425–30.PubMedCrossRefGoogle Scholar
  5. 5.
    Van Aelst L, D'Souza-Schorey C. Rho GTPases and signaling networks. Genes Dev. 1997;11:2295–322.PubMedCrossRefGoogle Scholar
  6. 6.
    Bocan TM, Mazur MJ, Mueller SB, et al. Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cholesterol-fed rabbits: a biochemical and morphological evaluation. Atherosclerosis. 1994;111:127–42.PubMedCrossRefGoogle Scholar
  7. 7.
    Atar S, Ye Y, Lin Y, et al. Atorvastatin-induced cardioprotection is mediated by increasing inducible nitric oxide synthase and consequent S-nitrosylation of cyclooxygenase-2. Am J Physiol. 2006;290:H1960–1968.Google Scholar
  8. 8.
    Birnbaum Y, Lin Y, Ye Y, et al. Aspirin before reperfusion blunts the infarct size limiting effect of atorvastatin. Am J Physiol. 2007;292:H2891–2897.Google Scholar
  9. 9.
    Birnbaum Y, Ye Y, Lin Y, et al. Aspirin augments 15-epi-lipoxin A4 production by lipopolysaccharide, but blocks the pioglitazone and atorvastatin induction of 15-epi-lipoxin A4 in the rat heart. Prostag Other Lipid Mediat. 2007;83:89–98.CrossRefGoogle Scholar
  10. 10.
    Birnbaum Y, Ye Y, Rosanio S, et al. Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia-reperfusion injury. Cardiovasc Res. 2005;65:345–55.PubMedCrossRefGoogle Scholar
  11. 11.
    Ye Y, Lin Y, Atar S, et al. Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions. Am J Physiol. 2006;291:H1158–1169.Google Scholar
  12. 12.
    Ye Y, Nishi SP, Manickavasagam S, et al. Activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) by atorvastatin is mediated by 15-deoxy-delta-12,14-PGJ2. Prostag Other Lipid Mediat. 2007;84:43–53.CrossRefGoogle Scholar
  13. 13.
    Ye Y, Lin Y, Perez-Polo JR, et al. Phosphorylation of 5-lipoxygenase at ser523 by protein kinase A determines whether pioglitazone and atorvastatin induce proinflammatory leukotriene B4 or anti-inflammatory 15-epi-lipoxin a4 production. J Immunol. 2008;181:3515–23.PubMedGoogle Scholar
  14. 14.
    Birnbaum Y, Ye Y, Lin Y, et al. Augmentation of myocardial production of 15-epi-lipoxin-a4 by pioglitazone and atorvastatin in the rat. Circulation. 2006;114:929–35.PubMedCrossRefGoogle Scholar
  15. 15.
    Planaguma A, Pfeffer MA, Rubin G, et al. Lovastatin decreases acute mucosal inflammation via 15-epi-lipoxin A4. Mucosal Immunol. 2010;3:270–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Spite M, Serhan CN. Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins. Circ Res. 2010;107:1170–84.PubMedCrossRefGoogle Scholar
  17. 17.
    Serhan CN, Chiang N. Novel endogenous small molecules as the checkpoint controllers in inflammation and resolution: entree for resoleomics. Rheum Dis Clin North Am. 2004;30:69–95.PubMedCrossRefGoogle Scholar
  18. 18.
    Kim SF, Huri DA, Snyder SH. Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science. 2005;310:1966–70.PubMedCrossRefGoogle Scholar
  19. 19.
    Zhou G, Ge S, Liu D, et al. Atorvastatin reduces plaque vulnerability in an atherosclerotic rabbit model by altering the 5-lipoxygenase pathway. Cardiology. 2010;115:221–8.PubMedCrossRefGoogle Scholar
  20. 20.
    •• Poeckel D, Funk CD. The 5-Lipoxygenase/Leukotriene Pathway in Preclinical Models of Cardiovascular Disease. Cardiovasc Res. 2010;86:243–53. This article describes the role of 5-lipoxygenase and the leukotriene pathway in various models of atherosclerosis.PubMedCrossRefGoogle Scholar
  21. 21.
    Laaksonen R, Janis MT, Oresic M. Lipidomics-based safety biomarkers for lipid-lowering treatments. Angiology. 2008;59:65S–8S.PubMedCrossRefGoogle Scholar
  22. 22.
    Laaksonen R, Katajamaa M, Paiva H, et al. A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle. PLoS One. 2006;1:e97.PubMedCrossRefGoogle Scholar
  23. 23.
    Gronroos E, Andersson T, Schippert A, et al. Leukotriene D4-induced mobilization of intracellular Ca2+ in epithelial cells is critically dependent on activation of the small GTP-binding protein Rho. Biochem J. 1996;316(Pt 1):239–45.PubMedGoogle Scholar
  24. 24.
    Zhao SP, Zhang DQ. Atorvastatin reduces interleukin-6 plasma concentration and adipocyte secretion of hypercholesterolemic rabbits. Clinica Chimica Acta. 2003;336:103–8.CrossRefGoogle Scholar
  25. 25.
    Koch W, Hoppmann P, Mueller JC, et al. No association of polymorphisms in the gene encoding 5-lipoxygenase-activating protein and myocardial infarction in a large central European population. Genet Med. 2007;9:123–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Lemaitre RN, Rice K, Marciante K, et al. Variation in eicosanoid genes, non-fatal myocardial infarction and ischemic stroke. Atherosclerosis. 2009;204:e58–63.PubMedCrossRefGoogle Scholar
  27. 27.
    Gomez-Hernandez A, Sanchez-Galan E, Ortego M, et al. Effect of intensive atorvastatin therapy on prostaglandin E2 levels and metalloproteinase-9 activity in the plasma of patients with non-ST-elevation acute coronary syndrome. Am J Cardiol. 2008;102:12–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.John S. Dunn Chair in Cardiology Research and Education, The Department of Medicine, Section of CardiologyBaylor College of MedicineHoustonUSA
  2. 2.The Department of Biochemistry and Molecular BiologyUniversity of Texas Medical BranchGalvestonUSA
  3. 3.Texas Heart InstituteSt Luke’s Episcopal HospitalHoustonUSA
  4. 4.The Department of Biochemistry and Molecular BiologyUniversity of Texas Medical BranchGalvestonUSA

Personalised recommendations