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Abstract

Cyclooxygenase (COX), also known as prostaglandin endoperoxide synthase, is the key enzyme required for the conversion of arachidonic acid to prostaglandins. Two COX isoforms have been identified, COX-1 and COX-2. Generally, the COX-1 enzyme is produced constitutively (e.g. in gastric mucosa), whereas COX-2 is highly inducible (e.g. at sites of inflammation and cancer). Traditional non-steroidal anti-inflammatory drugs (NSAIDs) inhibit both enzymes, and a new class of COX-2 selective inhibitors (COXIBs) preferentially inhibit the COX-2 enzyme. This review summarizes our current understanding of the role of COX-1 and COX-2, with emphasis on their role on cardiovascular biology.

Keywords

cyclooxygenase non-steroidal anti-inflammatory drugs cardiovascular biology angiogenesis

Background

Cyclooxygenase catalyses the conversion of arachidonic acid to prostaglandin G2 (PGG2), PGG2 then undergoes a peroxidate reaction to PGH2. The two known COX isoforms are referred to as COX-1 and COX-2 for the order in which they were discovered. Aspirin, which works by inhibiting COX activity, has been available to the public for over 100 years; in fact, extracts from willow bark and myrtle, containing salicylates or their precursors, were prescribed by physicians for pain and fever centuries ago. However, only since 1971 has our understanding of the role of the COX enzyme in biology and disease become more clear (see review by Turini and DuBois, 2002).

Despite the wide use of non-steroidal anti-inflammatory drugs (NSAIDs) over the past century, their mechanism of action was not fully appreciated until Vane (2001) published his seminal observations indicating that the ability of NSAIDs to suppress inflammation is probably due to their ability to inhibit the COX enzyme. This effectively limits the production of pro-inflammatory prostaglandins (PGs) at a site of injury. Following this discovery, scientists and clinicians have used NSAIDs to dissect the critical role of both the COX enzymes and the eicosanoids derived from this pathway in normal physiology and disease states. Of importance, inhibition of the COX enzyme occurs at a drug concentration in the nanomolar to micromolar range. When NSAIDs and COX-2 selective inhibitors (COXIBs) are given at much higher doses, achieving concentrations of >100 μM, their effects are probably due to modulation of COX-independent signaling pathways.

Pharmacology

Cyclooxygenase catalyses the conversion of arachidonic acid into prostaglandin H2. This is then converted, by specific synthases, into one of several prostaglandins depending on the cell involved. Two isoforms of cyclooxygenase have been described. Cyclooxygenase-1 (COX-1) is a constitutive enzyme present in fairly constant amounts in most cells (although it can be upregulated under certain conditions (Murphy and Fitzgerald, 2001; von Rahden, 2005). Its “housekeeping” functions include mediating production of gastric mucous and platelet aggregation (Dermond, 2001). In terms of their molecular biology, COX-1 and COX-2 are of similar molecular weight (approximately 70 and 72 kDa respectively), having 65% amino acid sequence homology and near-identical catalytic sites. The most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution of isoleucine at position 523 in COX-1 with valine in COX-2. The relatively smaller Val523 residue in COX-2 allows access to a hydrophobic side-pocket in the enzyme (which Ile523 sterically hinders). Drug molecules, such as DuP-697 and the coxibs derived from it, bind to this alternative site and are considered to be selective inhibitors of COX-2. Not normally present in cells (Sheehan et al. 1999), COX-2 is rapidly induced by intercellular messengers including growth factors, inflammatory mediators and tumour promoters (Cha et al. 2006; Meisenberg and Simmons, 1998).

COX Inhibitors

The main COX inhibitors are the non-steroidal anti-inflammatory drugs (NSAIDs). The classical COX inhibitors are not selective (i.e. they inhibit all types of COX), and the main adverse effects of their use are peptic ulceration and dyspepsia. It is believed that this may be due to the “dual-insult” of NSAIDs—direct irritation of the gastric mucosa (many NSAIDs are acids), and inhibition of prostaglandin synthesis by COX-1. Prostaglandins have a protective role in the gastrointestinal tract, preventing acid-insult to the mucosa.

Early NSAIDs reduced pro-inflammatory prostaglandins by inhibiting COX. Gastrointestinal side-effects from this non specific enzyme inhibition, coupled with the discovery of COX-2 and its pro-inflammatory role, prompted development of specific COX-2 inhibitors (Cha et al. 2006). Meanwhile, epidemiology linked NSAIDs to a reduced risk of developing several tumours, including colorectal (Dannenberg et al. 2005; Backlund et al. 2005) gastric (Mao et al. 2007), oesophageal (Corley et al. 2003) and pancreatic cancer (Anderson et al. 2002). As COX-2 is upregulated in many tumours, the potential of COX-2 inhibitors in the treatment of cancer is under investigation.

Newer NSAIDs

Selectivity for COX-2 is the main feature of celecoxib, rofecoxib and other members of this drug class, but these drugs carry the risk of peptic ulceration. COX-2-selectivity does not seem to impact other side-effects of NSAIDs (most notably an increased risk of renal failure), and some results have aroused the suspicion that there might be an increase in the risk for heart attack, thrombosis and stroke by a relative increase in thromboxane. Rofecoxib (brand name Vioxx) was taken off the market in 2004 because of these concerns. Some other COX-2 selective NSAIDs, such as celecoxib and etoricoxib, are still on the market.

Cyclooxygenase-2 in Angiogenesis

Several processes involved in tumourigenesis have been linked with COX-2. These include proliferation, invasion, apoptosis and host immune response. However, one exciting target that has emerged is the role of COX-2 in tumour angiogenesis. Angiogenesis is the growth of new vessels from existing vasculature (Folkman, 1990; Pandya et al. 2006). It is essential for normal growth, inflammation and wound repair, but is largely quiescent in healthy adults apart from in the female reproductive cycle. A balance of angiogenic and angiostatic growth factors tightly controls physiological angiogenesis. Tipping of this balance towards a pro-angiogenic environment is termed the “angiogenic switch” and occurs in situations such as tissue hypoxia, inflammation or neoplasia (McMahon, 2000; Byrne et al. 2005).

Once the angiogenic switch has occurred, growth factors activate endothelial cells (EC) and they proliferate. Dissociation of pericytes from the vessel and proteolytic degradation of the basement membrane and extracellular matrix enables the endothelial cells to migrate into the tumour. Here they form cords, then tubules and ultimately a vascular network (Yancopoulos et al. 2000). NSAIDs have been shown to reduce angiogenesis and production of angiogenic growth factors. Tsujii et al. 1998 showed that NS398 can block increased EC migration and tubule formation and reduce VEGF in a colon cancer model of angiogenesis. A similar effect has been shown in pancreatic and gastric cancer (Chu et al. 2003; Huang et al. 2005). Rofecoxib, SC560 and diclofenac reduced, in the short term, VEGF mRNA production by oesophageal carcinoma in vitro (von Rahden, 2005). EC migration, inhibited by NS398, was restored using a TXA2 mimetic in vitro (Daniel et al. 1999).

Studies have also shown that in endothelial cells, exogenous VEGF, acting through VEGFR2, upregulated COX-2 with a corresponding increase in PGI2, proliferation and tubule formation (Murphy and Fitzgerald, 2001; Murphy et al. 2005). This group also showed upregulation of COX-2 in response to ≈Vβ3 clustering, a major endothelial cell integrin in angiogenesis (Murphy et al. 2003). In similar studies, VEGF increased PGI2 via the VEGFR1—VEGFR2 heterodimer and upregulated COX-2 via the PLCγ - IP3/Ca2+ -Calcineurin—NFAT pathway (Hernandez et al. 2001; Neagoe et al. 2005).

NSAIDs, such as aspirin, have antiangiogenic and immunomodulatory properties. COX-2 contributes to tumor angiogenesis through various mechanisms (see review by Masferrer et al. 2000). Key mechanisms appear to involve the increased expression of the proangiogenic growth factor VEGF (Williams et al. 2000); the production of the eicosanoid products thromboxane (TX) A2 (Daniel et al. 1999) in addition to PGE2 and PGI2. These can directly stimulate endothelial cell migration and growth factor—induced angiogenesis and potentially the inhibition of endothelial cell apoptosis by induction of Bcl-2 expression or Akt activation.

Both selective and non-selective NSAIDs inhibit angiogenesis through direct effects on endothelial cells (Jones et al. 1999). This effect is mediated through inhibition of MAPK (ERK2) activity and interference with ERK nuclear trans-location but is independent of protein kinase C. It also involves prostaglandin-independent and prostaglandin-dependent components. In some circumstances, both COX-1 and COX-2 appear to be regulators of angiogenesis (Tsujii et al. 1998).

Cardiovascular Side Effects of COX Inhibitors

Traditional non-selective non-aspirin NSAIDs inhibit both isoforms, COX-1 and COX-2. Cyclooxygenase catalyzes the conversion of arachidonic acid to prostaglandins, prostacyclin, and thromboxane. The COX-1 enzyme is expressed constitutively in tissues, such as the gastrointestinal mucosa, where it induces mucoprotective prostaglandins, while the COX-2 enzyme expression is inducible, in particular by inflammation. The inhibition of the COX-1-related production of prostaglandins by non-selective non-aspirin NSAIDs increases the risk for gastrointestinal bleeding. The recognition of two isoforms of COX soon led to the hypothesis that selective COX-2 inhibitors would have the beneficial properties of non-selective non-aspirin NSAIDs without gastrointestinal toxicity (Bolten W, 1998). Large clinical trials (Bombardier et al. 2000; Silverstein et al. 2000; Schnitzer et al. 2004) validated this hypothesis and confirmed that COX-2 inhibitors are associated with less gastrointestinal toxicity than non-selective non-aspirin NSAIDs. However, these trials have also raised concerns about the cardiovascular safety of this class of drugs (Mukheerjee et al. 2001).

Given the broad role of PGs in normal human physiology, it is not surprising that systemic suppression of PG synthesis through inhibition of COX can lead to unwanted side effects. It is well-known that individuals taking NSAIDs for even short periods of time can experience severe gastrointestinal and renal side effects (Murray et al. 1993; Davies, 1995), in addition to effects on other physiological systems. As many as 25% of individuals using NSAIDs experience some side effect and up to 5% develop serious health consequences.

The different effects of PGs can be explained by their varied chemistry, the diversity of PG receptors, and modulation of PG synthesis. The structural, cellular, and molecular biology of COX (Smith et al. 2000) and of prostanoid receptors (Narumiya et al. 1999) have been reviewed. Intensive research in the past 10 years has evaluated the relative contribution of each isoform. Because NSAIDs have proven efficacy in treating arthritis and pain yet can also cause deleterious side effects, a major goal of the pharmaceutical industry was to design an anti-inflammatory drug with a wider therapeutic window that lacked the serious side effects of non-selective NSAIDs. This led to the development of COXIBs, of which celecoxib (Celebrex) and rofecoxib (Vioxx) have dominated the U.S. market.

Attention has turned to the cardiovascular safety of the older non-selective non-steroidal anti-inflammatory drugs (NSAIDs). These agents are used extensively and some are available in many countries without prescription. NSAIDs reversibly block both isoforms of cyclooxygenase, but vary in their degree of selectivity (Cryer et al. 1998). In one trial, it was suggested that the apparent excess cardiovascular risk with rofecoxib may be explained by a “cardioprotective” effect of the comparator drug, naproxen (Bombardier et al. 2000; van Hecken et al. 2000). However, the results of another trial suggested that naproxen may increase the risk of myocardial infarction, (Finckh et al. 2005).

Regulatory authorities have provided variable advice regarding the safety of NSAIDs. In the United States, the US Food and Drug Administration (USFDA, 2006) requires that both selective COX-2 inhibitors and NSAIDs carry a warning highlighting the potential for increased risk of cardiovascular events. In contrast, the European Medicines Agency has required labelling of selective COX-2 inhibitors, but made no recommendation about the cardiovascular safety of the earlier NSAIDs (EMA, 2006).

COX-2 inhibitors have been found to increase the risk of atherothrombosis even with short term use. An analysis of 138 randomised trials and almost 150,000 participants (Kearney et al. 2006) showed that selective COX-2 inhibitors are associated with a moderately increased risk of vascular events, mainly due to a two-fold increased risk of myocardial infarction. Moreover, high dose regimens of some traditional NSAIDs, such as diclofenac and ibuprofen, are associated with a similar increase in risk of vascular events.

Non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), including non-selective non-aspirin NSAIDs and COX-2 inhibitors, are widely used for various arthritides and pain syndromes. COX-2 inhibitors in particular have been an enormous financial success, with more than $5 billion in sales in the United States in 2003. That market took a huge hit with the withdrawal of rofecoxib (Vioxx, Merck and Co., Inc., Whitehouse Station, New Jersey) after the release of the worrisome data on the excessive cardiac morbidity attributed to rofecoxib in a trial attempting to prove that it could reduce the occurrence of colonic adenomas. The nearly simultaneous report by Pfizer, Inc., of the adverse cardiac effects of valdecoxib (Bextra, Pfizer, Inc., New York, New York) after cardiac surgery raised the issue of whether other drugs in the class are safe to use. Patients and clinicians are anxious to know whether cardiotoxicity is a class effect, and thereby applicable to any COX-2 inhibitor, or whether cardiotoxicity is limited to certain drugs in the class. Kimmel et al. (2005) shed some light on this question by examining whether the risk for cardiotoxicity differs among the COX-2 inhibitors celecoxib (Celebrex, Pfizer, Inc.) and rofexocib and non-selective non-aspirin NSAIDs.

The role of COX-2 inhibition in atherogenesis is complex and is not fully understood. While nonselective non-aspirin NSAIDs and aspirin inhibit the formation of platelet-derived thromboxane and endothelial prostacyclin, COX-2 inhibitors preferentially suppress the vasodilator and platelet inhibitory prostaglandins without blocking the vasoconstrictive and platelet-activating prostaglandins, which could result in a pro-thrombotic effect (Finckh et al. 2005). Accelerated atherogenesis of COX-2 inhibitors might be further modulated by renovascular hypertension, inhibition of vascular inflammation, improvement of endothelial function and changes in artherosclerotic plaque stability (Altman et al. 2002; Chenevard et al. 2003; Whelton et al. 2002). These effects may differ among structurally distinct COX-2 inhibitors with different levels of COX-1 or COX-2 selectivity (Hermann et al. 2003; Solomon et al. 2004), but evidence for a differential cardiovascular effect in this class is limited.

The most reliable evidence of cardiovascular toxicity of the COX-2 inhibitors comes from large randomized, double-blind trials. Results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) study (Bombardier et al. 2000) revealed an increased risk for myocardial infarction for patients treated with 50 mg of rofecoxib, whereas similar large trials with celecoxib (Silverstein et al. 2000) or lumiracoxib (Schnitzer et al. 2004) demonstrated no statistically significant differences in cardiovascular end points compared with non-selective non-aspirin NSAIDs. However, these trials were not primarily designed or powered to prove cardiovascular safety as a primary end point; mean follow-up time was relatively short (6 to 12 months), and the selected patient samples had a relatively low rate of cardiovascular events. Therefore, the trials of celecoxib or lumiracoxib do not exclude the possibility of increased cardiovascular toxicity with these drugs. Several large observational studies found an increased rate of coronary heart disease with high-dose rofexocib but not with celecoxib (Ray et al. 2002; Graham et al. 2004). Solomon and colleagues (Solomon et al. 2004) reported increased risk for acute myocardial infarction with any dosages of rofecoxib but not celecoxib. Mamdani and colleagues (2003) found an increased risk for congestive heart failure with rofecoxib and not with celecoxib. However, no difference in the risk for myocardial infarction (Mamdani et al. 2003, 2004), but they did not address dosage and excluded short-term users. Overall, these studies suggest that not all COX-2 inhibitors share the same cardiovascular risk as rofecoxib, but the evidence is currently too limited to exclude the possibility of a COX-2 inhibitor class effect. Furthermore, non-selective non-aspirin NSAIDs might also increase cardiovascular risk (Catell-Lawson et al. 2001). The major unanswered question is whether the unopposed COX-2 inhibition or other drug specific mechanisms cause increased cardiovascular risk.

Disclosure

The author reports no conflicts of interest.

Footnotes

Acknowledgement

The author is grateful to Tara Finn for the careful reading of this manuscript.

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Cyclooxygenase-2 in Cardiovascular Biology

Abstract

Keywords

Background

Pharmacology

COX Inhibitors

Newer NSAIDs

Cyclooxygenase-2 in Angiogenesis

Cardiovascular Side Effects of COX Inhibitors

Disclosure

Footnotes

Acknowledgement

References