Review article
Cardiovascular Biology of Microsomal Prostaglandin E Synthase-1

https://doi.org/10.1016/j.tcm.2011.04.002Get rights and content

Both traditional and purpose-designed nonsteroidal anti-inflammatory drugs, selective for inhibition of cyclooxygenase (COX)-2, alleviate pain and inflammation but confer a cardiovascular hazard attributable to inhibition of COX-2–derived prostacyclin (PGI2). Deletion of microsomal PGE synthase-1 (mPGES-1), the dominant enzyme that converts the COX-derived intermediate product PGH2 to PGE2, modulates inflammatory pain in rodents. In contrast with COX-2 deletion or inhibition, PGI2 formation is augmented in mPGES-1−/− mice—an effect that may confer cardiovascular benefit but may undermine the analgesic potential of inhibitors of this enzyme. This review considers the cardiovascular biology of mPGES1 and the complex challenge of developing inhibitors of this enzyme.

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) alleviate pain and reduce fever by inhibiting prostaglandin (PG) G/H synthases (commonly known as cyclooxygenases or COXs), pivotal enzymes in the biosynthetic cascade that leads to formation of prostanoids (Figure 1). Metabolism of arachidonic acid by COXs yields the intermediate PG endoperoxide product, PGH2, which is further metabolized to prostanoids by terminal synthases. The analgesic efficacy of NSAIDs is largely attributable to suppression of the formation of COX-2–derived PGE2 and PGI2, and their serious adverse gastrointestinal (GI) effects result largely from suppression of COX-1–derived PGE2 and PGI2 in gastroduodenal epithelium and COX-1–derived TxA2 formed by platelets. These observations prompted the development of purpose-designed (pd) NSAIDs selective for inhibition of COX-2, and indeed, they proved less likely to cause serious GI adverse events than the traditional (t) NSAIDs such as ibuprofen and naproxen, which inhibited both COX-1 and COX-2. Several tNSAIDs, such as diclofenac and meloxicam, also inhibit preferentially COX-2 at their therapeutic doses. Despite their diminished propensity to cause GI complications, COX-2 inhibitors were shown to increase the risk of myocardial infarction (MI), stroke, systemic and pulmonary hypertension, congestive heart failure, and sudden cardiac death (Garcia Rodriguez et al., 2008, Grosser et al., 2006, Grosser et al., 2010). This increased cardiovascular hazard is attributable to suppression of COX-2–derived prostaglandins, particularly PGI2 (Grosser et al., 2006, Grosser et al., 2010). Expression of the cardiovascular hazard in an individual patient is likely modulated by drug selectivity, potency, and exposure, underlying baseline cardiovascular risk and concomitant therapies, such as low-dose aspirin(Garcia Rodriguez et al., 2008, Grosser et al., 2006, Grosser et al., 2010).

The withdrawal from the market and failure of regulatory approval of several pd NSAIDs selective for inhibition of COX-2 prompted interest in microsomal (m)-PGE synthase (PGES)-1 as an alternative drug target (Jakobsson et al., 1999, Samuelsson et al., 2007, Thoren et al., 2003) This enzyme is a member of the MAPEG (membrane-associated proteins in eicosanoid and glutathione metabolism) superfamily and was experimentally identified by Jakobsson et al. (1999) as microsome-associated and 152 amino acids in length and as exhibiting glutathione-dependent PGE synthase activity (0.25 μmol/min/mg). The human PGES-1 gene is localized to chromosome 9q34.3, contains three exons, and spans 14.8 kb (Forsberg et al. 2000). The human mPGES-1 sequence shows approximately 80% similarity to the enzyme in mouse, rat, or cow. Electron crystallography demonstrated that microsomal PGES-1 constitutes a trimer in two-dimensional crystals (Jegerschold et al., 2008, Xing et al., 2009) (Figure 2). Human mPGES-1 inhibitors may not be pharmacologically effective in animals, and such species differences in inhibitor binding efficiency may be attributable to some key residues, such as Thr-131, Leu-135, and Ala-138 in human mPGES-1 (Pawelzik et al. 2010). These residues are situated in transmembrane helix 4, lining the entrance to the cleft between two subunits in the protein trimer, and they regulate inhibitor access to the enzyme (Pawelzik et al. 2010).

Two other PGE synthases have also been identified—mPGES-2 (Murakami and Kudo 2006) and cytosolic (c) PGES (Pini et al., 2005, Tanioka et al., 2000). However, mPGES-1 is the dominant source of PGE2 biosynthesis in mice and humans (Cheng et al. 2006), as assessed by excretion of its major urinary metabolite. Although cPGES is co-expressed with COX-1, mPGES-1 is often functionally co-regulated with COX-2, such as in the vasculature during zebrafish development (Pini et al. 2005) and in models of inflammation (Claveau et al. 2003). mPGS-1 also predominantly co-localizes with COX-1 in renal distal convoluted tubule and in medullary collecting ducts (Schneider et al. 2004).

Initially, mPGES-1 deletion in mice was found to modulate experimentally evoked pain and inflammation to a degree indistinguishable from treatment with tNSAIDs nonselective for inhibition of COXs (Kamei et al., 2004, Trebino et al., 2003).Although many small molecule inhibitors of mPGES-1 fail to block the rodent enzyme, one inhibitor has been used in mice in which the human enzyme has been overexpressed and shown to inhibit inflammatory pain (Xu et al. 2008). mPGES-1 deletion was shown to upregulate the anti-inflammatory nuclear receptor, PPARγ (Kapoor et al. 2006), which may also contribute to the efficacy of this strategy. Although these results suggested that mPGES-1 might indeed be a promising alternative drug target to COX-2, enzyme deletion has been less impressive in some rodent models of analgesia (Scholich and Geisslinger 2006). This might reflect (1) the contribution of continuing synthesis of PGE2 by other synthases in mPGES-1−/− mice or (2) the importance of PGI2 as a mediator of pain(Chen et al. 2008). Indeed, rediversion of accumulated PGH2 substrate to PGI2 synthase can augment PGI2 biosynthesis in mPGES-1−/− mice (Cheng et al. 2006).

Other areas of potential therapeutic application of mPGES-1 inhibitors have been explored. mPGES-1 was identified as the central switch during immune-induced pyresis and as a target for the treatment of fever (Engblom et al. 2003, Xu et al. 2008). Enzyme deletion delays and ameliorates the expression of experimental autoimmune encephalomyelitis, which is thought to be a model of multiple sclerosis (Kihara et al. 2009). By contrast, a note of caution was sounded by a provocative study in which mPGES-1–derived PGE2, acting via EP2 and EP4 receptors, mediated resolution of lipopolysaccharide (LPS)-induced spinal neuroinflammation after initial LPS priming (Brenneis et al. 2011).

mPGES-1 may have therapeutic potential in the chemoprevention of certain cancers (Radmark and Samuelsson 2010), including intestinal tumors (Nakanishi et al. 2008) and prostate and lung cancers (Hanaka et al. 2009). Several small molecule inhibitors have been developed, and initial experience of human tolerability of some compounds has been acquired. However, it remains a challenge to select an initial target for proof of clinical efficacy. Will these drugs be less likely to confer a cardiovascular hazard than NSAIDs selective for inhibition of COX-2? If so, will they be less efficacious than such drugs as analgesics? Might an alternative clinical target offer a more promising route to initial drug approval?

Section snippets

Thrombosis and Blood Pressure

It has long been known that NSAID consumption is associated with hypertension and that the magnitude of this response is quite variable (Chan et al. 2009). It is thus unsurprising that disruption of COX-2–dependent formation of PGI2 and/or PGE2 will elevate blood pressure in mice, and that this effect is highly conditioned by genetic background (Yang et al. 2005). Similarly, genetic deletion or pharmacological inhibition of COX-2 or disruption of the PGI2 receptor predisposes to accelerated

Summary

The mPGES-1 enzyme represents an intriguing target for drug development. Given the limitations of available data on analgesic efficacy in animals, we will not know how the analgesic efficacy of its inhibition compares with NSAIDs until such studies are performed in humans. Will augmented PGI2 formation dilute the analgesic potency of mPGES-1 inhibitors and, if so, will this only apply to certain types of pain? Limited evidence, at the preclinical level, suggests an improved adverse effect

Conflict of Interest Disclosure

Dr. FitzGerald has consulted in the past year for Astra Zeneca, Daiichi Sankyo, Logical Therapeutics, Lilly, and Nicox on NSAIDs and related compounds.

Acknowledgments

This work was supported by the American Heart Association (grant 0735397N to Dr. Wang) and the National Institutes of Health (grant HL083799 to Dr. FitzGerald). Dr. FitzGerald is the McNeil Professor of Translational Medicine and Therapeutics.

References (65)

  • N. Sakalihasan et al.

    Activated forms of MMP2 and MMP9 in abdominal aortic aneurysms

    J Vasc Surg

    (1996)
  • N. Sakalihasan et al.

    Abdominal aortic aneurysm

    Lancet

    (2005)
  • A. Schneider et al.

    Membrane-associated PGE synthase-1 (mPGES-1) is coexpressed with both COX-1 and COX-2 in the kidney

    Kidney Int

    (2004)
  • K. Scholich et al.

    Is mPGES-1 a promising target for pain therapy?

    Trends Pharmacol Sci

    (2006)
  • T. Tanioka et al.

    Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis

    J Biol Chem

    (2000)
  • S. Thoren et al.

    Human microsomal prostaglandin E synthase-1: Purification, functional characterization, and projection structure determination

    J Biol Chem

    (2003)
  • D. Wu et al.

    Comparison of microsomal prostaglandin E synthase-1 deletion and COX-2 inhibition in acute cardiac ischemia in mice

    Prostaglandins Other Lipid Mediat

    (2009)
  • D. Wu et al.

    The effects of microsomal prostaglandin E synthase-1 deletion in acute cardiac ischemia in mice

    Prostaglandins Leukot Essent Fatty Acids

    (2009)
  • R.S. Bresalier et al.

    Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial

    N Engl J Med

    (2005)
  • C.C. Chan et al.

    Do COX-2 inhibitors raise blood pressure more than nonselective NSAIDs and placebo?An updated meta-analysis

    J Hypertens

    (2009)
  • M. Chen et al.

    Predominance of cyclooxygenase 1 over cyclooxygenase 2 in the generation of proinflammatory prostaglandins in autoantibody-driven K/BxN serum-transfer arthritis

    Arthritis Rheum

    (2008)
  • Y. Cheng et al.

    Role of prostacyclin in the cardiovascular response to thromboxane A2

    Science

    (2002)
  • Y. Cheng et al.

    Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function

    J Clin Invest

    (2006)
  • D. Claveau et al.

    Microsomal prostaglandin E synthase-1 is a major terminal synthase that is selectively up-regulated during cyclooxygenase-2-dependent prostaglandin E2 production in the rat adjuvant-induced arthritis model

    J Immunol

    (2003)
  • N. Degousee et al.

    Microsomal prostaglandin E2 synthase-1 deletion leads to adverse left ventricular remodeling after myocardial infarction

    Circulation

    (2008)
  • N.P. Dowd et al.

    Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo

    J Clin Invest

    (2001)
  • K.M. Egan et al.

    COX-2-derived prostacyclin confers atheroprotection on female mice

    Science

    (2004)
  • K.M. Egan et al.

    Cyclooxygenases, thromboxane, and atherosclerosis: Plaque destabilization by cyclooxygenase-2 inhibition combined with thromboxane receptor antagonism

    Circulation

    (2005)
  • D. Engblom et al.

    Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis

    Net Neurosci

    (2003)
  • J.E. Fabre et al.

    Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation

    J Clin Invest

    (2001)
  • H. Francois et al.

    Role of microsomal prostaglandin E synthase 1 in the kidney

    J Am Soc Nephrol

    (2007)
  • J. Golledge et al.

    Abdominal aortic aneurysm: Pathogenesis and implications for management

    Arterioscler Thromb Vasc Biol

    (2006)
  • Cited by (32)

    • Pathophysiological role of prostaglandin E synthases in liver diseases

      2021, Prostaglandins and Other Lipid Mediators
      Citation Excerpt :

      Although COX-2 was once regarded as a useful target for treated related liver diseases, its targeting has been reported to cause many side effects, particularly in the renal and cardiovascular systems [9]. A recent study indicated that mPGES-1 is a relatively better target than COX-2 for treating related liver diseases [10–12]. mPGES-1 is often considered as an important target enzyme involved in the biosynthesis of PGE2, which is an important inflammatory factor [13].

    • Natural products as inhibitors of prostaglandin E<inf>2</inf> and pro-inflammatory 5-lipoxygenase-derived lipid mediator biosynthesis

      2018, Biotechnology Advances
      Citation Excerpt :

      Constitutive expression of mPGES-1 is found in distinct organs including lung, kidney, the reproductive system, and gastric mucosa, though deletion of mPGES-1 seems not detrimental unless pathological or stress conditions are imposed (Bahia et al., 2014; Koeberle and Werz, 2015; Samuelsson et al., 2007). Homeostatic functions of mPGES-1 have been proposed in stressed kidneys, e.g., upon injury, high-salt diet, water loading or water deprivation (Jia et al., 2015; Yang and Chen, 2016), and contradictory results were obtained for the regulation of blood pressure and cardiac function (Chen et al., 2013; Ozen et al., 2017; Wang and FitzGerald, 2010). Other cardiovascular events, such as thrombosis, vascular inflammation and cardiac pathologies were either not affected or even reduced by deletion of mPGES-1 (Chen et al., 2013; Raouf et al., 2016a; Wang and FitzGerald, 2010).

    • The Vascular Endothelium

      2018, Endothelium and Cardiovascular Diseases: Vascular Biology and Clinical Syndromes
    • The key residue within the second extracellular loop of human EP3 involved in selectively turning down PGE<inf>2</inf>- and retaining PGE<inf>1</inf>-mediated signaling in live cells

      2017, Archives of Biochemistry and Biophysics
      Citation Excerpt :

      Three PGES, noninducible types of cytosolic PGES (cPGES) [5,6] and microsomal PGES-2 (mPGES-2) [6,7], and an inducible type of microsomal PGES-1 (mPGES-1) [5,6,8,9] have been cloned and characterized previously. PGE2 synthesized by the inducible mPGES-1 is one of the major mediators for inflammatory diseases, such as arthritis [10,11], vascular inflammation [12,13], angiogenesis and some types of cancers [14–18]. However, PGE1 synthesized by the same enzymes has less inflammatory effects, mediating smooth muscle relaxation as well as promoting blood flow [19].

    View all citing articles on Scopus

    Miao Wang's current address is Pfizer Global Research & Development, Cardiovascular, Metabolic & Endocrine Diseases - Research Unit, Eastern Point Road, Groton, CT 06340, USA.

    View full text