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Circulation. 2006;114:873-875
doi: 10.1161/CIRCULATIONAHA.106.647925
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(Circulation. 2006;114:873-875.)
© 2006 American Heart Association, Inc.

Editorial

Myocardial 15-Epi-lipoxin A4 Generation Provides a New Mechanism for the Immunomodulatory Effects of Statins and Thiazolidinediones

Bruce D. Levy, MD

From the Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, Brigham and Women’s Hospital, Boston, Mass.

Correspondence to Bruce D. Levy, MD, Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail blevy{at}partners.org


Key Words: Editorials • drugs • fatty acids • hydroxymethylglutaryl-CoA reductase inhibitors • inflammation • lipids • myocardium

"In matters of observation, chance favors only the prepared mind."

This famous maxim of Louis Pasteur, spoken in 1854 during his inaugural lecture as Professor and Dean at the University of Lille, can be applied today to the fortuitous observation that hydroxymethylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors, in addition to their designed lipid-lowering effects, display a fascinating array of antiinflammatory properties. Post hoc analyses of the West of Scotland Coronary Prevention Study (WOSCOPS) population, and more recently the Cholesterol and Recurrent Events (CARE), Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL), Long-term Intervention With Pravastatin in Ischemic Disease (LIPID), and Heart Protection Study (HPS) trials, have all found benefits conferred by statins that are independent of low-density lipoprotein cholesterol–lowering alone.1 Only through careful analyses of early clinical trials of statins administered for lowering cholesterol and cardiovascular events did scientists uncover additional benefit for these agents in cardiac protection beyond their ability to reduce cholesterol synthesis. Inflammation and immune responses are now appreciated to play pivotal roles in the pathobiology of atherosclerosis,2 and recent clinical and basic investigations have uncovered important immunomodulatory roles for statins.3 Of interest, the peroxisome proliferator-activated receptor family of transcription factors is activated by and cooperates with statins in their antiinflammatory actions. In this issue of Circulation, Birnbaum and colleagues4 present evidence for increased myocardial production of 15-epi-lipoxin (LX)A4 by atorvastatin and the peroxisome proliferator-activated receptor-{gamma} ligand pioglitazone. The generation of 15-epi-LXA4 would provide a novel mechanism for immune regulation by statins because this arachidonic acid–derived chalone displays potent antiinflammatory and proresolving properties,5 including many that have also been observed with statins (Table).


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  		Shared Antiinflammatory Actions of Statins and 15-Epi-lipoxin A4

Article p 929

Cell activation initiates the rapid generation of eicosanoids via release of arachidonic acid from cell membranes for subsequent conversion to cyclooxygenase (COX)-derived products, such as prostaglandins, or lipoxygenase (LO)-derived products, such as leukotrienes (LTs). This family of lipid mediators includes potent regulators of cardiovascular function. For example, increased cardiovascular risk has recently been attributed to COX inhibition (reviewed in Antman et al6), and the LT biosynthetic enzymes 5-LO and LTA4 hydrolase are highly expressed in human atherosclerotic lesions and linked to plaque instability.7 Similar to LTs, LXs and 15-epi-LXs are LO-derived eicosanoids, yet their biological actions differ dramatically from LTs.5 The major pathways for transcellular LX biosynthesis involve 5- and 15-LO in tissues and 5- and 12-LO in the vasculature.5 A distinct pathway for 15-epi-LX biosynthesis has been elucidated that involves COX-2 in endothelia or epithelia and 5-LO in leukocytes.5 Aspirin-acetylated COX-2 or cytochrome p450 enzymes catalyze the formation of 15R-HETE for subsequent conversion to 15-epi-LXs by leukocyte 5-LO.5 Formation of these distinct classes of eicosanoids is tightly regulated, with early COX-2 and 5-LO activity critical to both LX and 15-epi-LX production at later time points to effect resolution of acute inflammation.8,9 LXs and aspirin-triggered LXs are generated in cardiovascular tissues and display potent antiinflammatory properties. Angioplasty initiates LX formation that is further induced by concomitant aspirin therapy.10 Rabbits that are transgenic for 15-LO expression generate increased amounts of LXs and display protection from atherosclerosis.11,12 In addition, LXs and 15-epi-LXs promote endothelium-dependent vasorelaxation13,14 and inhibit peripheral and myocardial ischemia/reperfusion injury.15,16 Aspirin reduces cardiovascular events in men, and in a randomized clinical trial of aspirin ingestion by 128 healthy subjects, plasma aspirin-triggered 15-epi-LXA4 levels were increased by 81 mg of aspirin daily and inversely correlated with thromboxane.17 Stable analogues of 15-epi-LXA4 have been prepared that display potent in vivo antiinflammatory and proresolving actions.5 Thus, in addition to inhibiting prostaglandins, aspirin also triggers the formation of protective lipid mediators.

Birnbaum and colleagues4 now show evidence for 15-epi-LXA4 and, to a lesser extent, LXA4 generation from rat myocardium. In the absence of aspirin, atorvastatin and pioglitazone triggered 15-epi-LXA4 generation that was inhibited by selective pharmacological targeting of either COX-2 or 5-LO. Both atorvastatin and pioglitazone induced COX-2 expression and together had an additive impact on 15-epi-LXA4 generation. Although these findings of immunoreactive 15-epi-LXA4 formation were not validated by either physical means of detection or identification of the biosynthetic precursor 15R-HETE, they appear to indicate that aspirin is not a prerequisite for COX-2–derived 15-epi-LXA4 formation. The authors speculate on potential mechanisms, including posttranslational modification of COX-2 by S-nitrosylation, a process they have recently identified as integral to atorvastatin-mediated cardioprotection from infarction.18 Indeed, aspirin-triggered 15-epi-LXA4 induces nitric oxide production from both endothelial and inducible nitric oxide synthases for antiinflammation.19 In view of the present results, aspirin-initiated nitric oxide could provide an amplifying mechanism for continued 15-epi-LXA4 generation by S-nitrosylation of statin-induced COX-2, even if pharmacological or temporal and spatial factors limit the availability of new COX-2 to aspirin. Complete inhibition of 15-epi-LXA4 production by COX-2 inhibition diminishes the likelihood of important involvement of cytochrome p450 enzymes in statin-induced myocardial 15-epi-LXA4.

Both LXA4 and 15-epi-LXA4 interact with LXA4 receptors, termed ALX.5 This G protein–coupled receptor is widely expressed in human and rodent tissues, and the rat receptor was recently characterized.20 Of interest, antiinflammatory signaling via ALX is mechanistically linked to polyisoprenyl phosphates (Figure). Although HMG-CoA reductase inhibition by statins reduces mevalonate formation, continued flux through this pathway is critical for the generation of isoprenoids that are vital for diverse cellular functions (reviewed in Schonbeck and Libby1). Complete inhibition of isoprenoid biosynthesis by statins is toxic,21 and isoprenoid levels are preserved in even severe mevalonic aciduria (<1% mevalonate kinase activity),22 a genetic disease that is the functional equivalent of HMG-CoA reductase inhibitor therapy for polyisoprenyl phosphate biosynthesis. In addition to sterols, polyisoprenyl phosphates have many potential biosynthetic fates, including ubiquinone, protein prenylation, and dolichol.1 Synthesis of the polyisoprenyl phosphate presqualene diphosphate (PSDP) is considered essential because mice that lack squalene synthase are embryonic lethal at midgestation.23 Of note, the generalized inflammation of hyper-immunoglobulin D (IgD) syndrome and periodic fever is associated with mevalonate kinase deficiency and low isoprenoid levels,24–26 indicating that select isoprenoids have counterregulatory roles for inflammation.


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  		Formation of endogenous antiinflammatory lipid mediators by therapeutic agents. Similar to aspirin, atorvastatin and pioglitazone can trigger the formation of myocardial 15-epi-LXA4, a potent counterregulatory mediator that serves as an agonist of ALX. Activation of ALX prevents the conversion of PSDP to PSMP, and PSDP is a potent regulator of phospholipase D, phosphatidylinositol 3-kinase, and generation of reactive oxygen species.

Human polymorphonuclear leukocytes (PMNs) carry a natural deficiency in mixed function oxidase activities in the cholesterol biosynthetic pathway, yet polyisoprenyl phosphate biosynthesis remains preserved.27 PSDP is present in unactivated PMN membranes, and receptor-mediated agonists stimulate a rapid, transient, and reciprocal turnover of PSDP to its monophosphate form, presqualene monophosphate (PSMP).28 The transient changes in PSDP after LTB4 receptor activation are concurrent with the kinetics of LTB4 for PMN activation and deactivation.29 Coactivation of ALX and LTB4 receptors prevents LTB4-initiated decrements in PSDP and inhibits responses to LTB4.15,29 PSDP, but not PSMP, displays significant inhibition of phosphatidylinositol 3-kinase, phospholipase D, and O2– generation,28–30 suggesting a novel signaling role for these polyisoprenyl phosphates as endogenous regulators of cell responses. The impact of therapeutic concentrations of statins on cellular PSDP levels and remodeling events has yet to be established.

In conclusion, the findings of Birnbaum et al4 provide further evidence for important regulatory roles for eicosanoids in cardiovascular disease. Their results bring into focus the tightly orchestrated interplay between COX and LO actions in the generation of the potent antiinflammatory mediator 15-epi-LXA4 in rat myocardial tissues. Although the biosynthetic details of the conversion of arachidonate to 15-epi-LXA4 in the absence of aspirin remain to be elucidated, this biochemical pathway appears to be used by both atorvastatin and pioglitazone and involves both COX-2 and 5-LO. Already established for aspirin-triggered 15-epi-LXA4, it will be of interest to know whether these biosynthetic mechanisms for statins and thiazolidinediones are also present in human tissues. The endogenous biosynthesis of antiinflammatory and proresolving lipid mediators provides potential effector mechanisms for several of the interesting immunomodulatory actions of these agents—a remarkable, yet serendipitous observation by assiduous clinical researchers. This shared property of these very successful drugs holds promise for designing new, even more effective cardiovascular protective therapeutic strategies.


*    Acknowledgments
 
Sources of Funding

This work was supported in part by grants HL68669, DE016191, and AI068084.

Disclosures

Dr Levy has received honoraria from and has served as a consultant for Critical Therapeutics. He has received patent licensing fees from Schering AG.


*    Footnotes
 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.


*    References
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 *References
 

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