doi: 10.1161/01.RES.0000228471.38761.93
© 2006 American Heart Association, Inc.
Editorials |
COX-2, Another Important Player in the Nitric Oxide–Endothelin Cross-Talk
Good News for COX-2 Inhibitors?
From the Medizinische Klinik und Poliklinik, Johannes Gutenberg-Universität, Mainz, Germany.
Correspondence to Thomas Münzel MD, II.Medizinische Klinik und Poliklinik, Johannes Gutenberg-Universität Mainz, Langenbeckstrasse 1, D-55131 Mainz, Germany. E-mail tmuenzel{at}uni-mainz.de
See related article, pages 1439–1445
Key Words: COX-2 • endothelin • prostanoids
Traditionally, the role of the endothelium was thought to be primarily that of a selective barrier to the diffusion of macromolecules from the vessel lumen to the interstitial space. During the past 20 years, numerous additional roles for the endothelium have been defined such as regulation of vascular tone, modulation of inflammation, promotion as well as inhibition of vascular growth, and modulation of platelet aggregation and coagulation. Endothelial dysfunction is a characteristic feature of patients with cardiovascular risk factors such as hypercholesterolemia, hypertension, diabetes mellitus, and chronic smoking. More recent studies indicate that it may predict long-term atherosclerotic disease progression as well as cardiovascular event rate.1 There is a growing body of evidence that decreased endothelial bioavailability of nitric oxide (NO·) in particular attributable to increased production of reactive oxygen species, such as superoxide (O2·–), leads to an activation of the renin–angiotensin system,2,3 increased formation of cyclooxygenase (COX)-dependent vasoconstrictors,4 but also to increased expression of the most potent endogenous vasoconstrictor endothelin-1 (ET-1).5–9
Of the 4 active endothelins (ET-1 to ET-4) ET-1 is the predominant isoform in the cardiovascular system. ET-1 exerts its major cardiovascular effects through activation of 2 distinct G protein–coupled receptors, the ETA and ETB receptors. ETA receptors are found exclusively in smooth muscle cells. Endothelin-1 promotes vasoconstriction, mitogenesis, and thrombosis predominantly via binding to the ETA receptor. ETB receptors are localized to some extent in smooth muscle cells, but also in endothelial cells. Activation of ETB receptors has been demonstrated to cause the release of NO· and prostacyclin (PGI2).10,11 In normal states with p reserved vascular (endothelial) NO· bioavailability, stimulation of ETA receptors opposes the effects caused by the stimulation of the ETB receptor on endothelial cells. Until now, it remains to be established to what extent chronic NO· deficiency may alter the expression of the ETA receptor. Importantly, increased endothelin-mediated vasoconstriction has been proposed to play an important pathophysiological role in diseases like arterial and pulmonary hypertension and atherosclerosis.
Another important vasoconstrictor system that is regulated by NO represents the prostaglandin H synthase (PGHS) or COX pathway. Two isoforms exist: COX-1 and COX-2. COX-2 is considered the inducible isoform. Its expression is increased by a number of cardiovascular risk factors such as cholesterol, lipoproteins, and cytokines. Under normal conditions, the production of vasodilatory prostaglandins, such as PGI2, dominates whereas in the setting of decreased NO bioavailability, eg, attributable to increased oxidative stress (in particular ONOO–), the prostacyclin synthase becomes inactivated and vasoconstrictor prostaglandins prevail.12 Recently studies with cultured smooth muscle cells revealed an ETA dependent upregulation of COX-2.13 Furthermore, Desjardins and coworkers found COX-derived products to be involved in increased contractions to ET-1 in a swine model of coronary endothelial dysfunction and left ventricular hypertrophy.14
In this issue of Circulation Research, Zhou et al15 examined to what extent chronic NO deficiency may alter ETA mediated vasoconstriction and the involvement of vasoconstricting prostanoids. The presented results provide evidence that the selective ETA receptor agonist ET-1 (1–31) mediated vasoconstriction was strikingly enhanced in endothelial nitric oxide synthase (eNOS)-deficient mice as compared with vessels from wild-type animals, whereas constrictions in response to phenylephrine and the thromboxane analog U-46619 were not different (Figure).
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A simple explanation for this phenomenon would have been an upregulation of the ETA receptor expression. Surprisingly, immunofluorescent techniques and Western blot analysis revealed the opposite. Although the precise mechanism of ETA receptor–mediated downregulation remains to be established, there is evidence in the literature demonstrating that, eg, an upregulation of vascular endothelin-1 formed in an autocrine fashion may downregulate its own receptors.9
Increased constriction in response to ETA-receptor stimulation was markedly inhibited by the nonselective COX inhibitor indomethacin and by the TXA2/PGH2-receptor antagonist SQ-29548 pointing to a significant role of COX-derived prostanoids. Enhanced contraction to the ETA agonist was also substantially inhibited by celecoxib, a selective COX-2 inhibitor. Further evidence for a role of COX-2 was provided by Western blot analysis demonstrating that COX-2 expression was found to be increased in the media of eNOS knockout as compared with wild-type mice. Vascular contraction of eNOS knockout animals in response to the COX substrate arachidonic acid was clearly enhanced whereas the constrictor response to the TXA2 analog U-46619 were not altered at all, indicating that increased production of mediators rather than changes in the sensitivity of the TXA2/PGH2 receptor account for this phenomenon. Collectively, these findings suggest that increased expression of COX-2 and subsequently increased formation of vasoconstricting prostanoids mediate increased contraction in response to ETA receptor stimulation by ET-1 in eNOS knockout mice.
These findings are in keeping with previous observations that the nonselective COX inhibitor indomethacin reduced blood pressure in hypertension after prolonged NO synthase inhibition, indicating a predominant role of COX-dependent vasoconstrictors.4 Also in patients with arterial hypertension there seems to be an involvement of cyclooxygenase in ET-1 (but not phenylephrine)-induced decreases in forearm blood flow, as they are blunted in response to treatment with indomethacin.16 However, compensatory effects of the COX-dependent pathway in response to loss of NO-bioactivity are not limited to vasoconstriction, but can affect vasodilation in certain vascular beds, too.17
The major strength of the study of Zhou and colleagues15 lies in drawing attention to a pathway of pathophysiologic relevance that has not thoroughly enough been addressed mostly because of the frequent use of the nonselective COX-inhibitor indomethacin, eg, in vascular reactivity studies to exclude effects of vasoactive prostanoids. The majority of these studies examining endothelial dysfunction focused exclusively on the NO signaling pathway neglecting the possible impact of prostanoids in mediating vascular pathology, especially in conditions of decreased NO bioavailability as pointed out by the authors.15 Certainly, the concept of the study excluding NO via genetic knockout, inhibition of NO· synthase, and/or denudation of the endothelial layer strengthens the hypothesis but may limit the extrapolation of the findings toward more pathophysiologic conditions.
Because almost every cardiovascular risk factor goes along with decreased vascular NO bioavailability, these experimental observations may have important clinical implications. Substances that modulate endothelin-1 expression and/or endothelin-induced vasoconstriction such as NO donors, ET-1 antagonists, statins, and ACE-inhibitors, and now in addition inhibitors of COX-2, may have synergistic effects in pathological settings including heart failure, and arterial and pulmonary hypertension.
The principle question is whether these conditions require therapy with COX-2 inhibitors. We know that patients with coronary artery disease being treated with compounds such as rofecoxib are at risk for developing ischemic events.18 With respect to experimental pulmonary hypertension, where endothelin-1 as well as NO deficiency plays an important pathophysiological role, COX-2 inhibition has been shown to exacerbate rather than to reduce right ventricular end-systolic pressure.19 Thus, although COX-2 is upregulated in the setting of NO deficiency, results from experimental and clinical studies raise doubt that the long-term use of COX-2 inhibitors may favorably influence prognosis of patients with vascular disease.
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Acknowledgments |
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Acknowledcgments
T.M. is supported by the Deutsche Forschungsgemeinschaft, SFB 553-C14
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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