PERSPECTIVES

PHYSIOLOGY
The vascular location of an enzyme accounts
COX-2 Inhibitors for the cardiovascular hazards associated with
its inhibition.

and Cardiovascular Risk

Christopher P. Cannon1 and Paul J. Cannon2

N
onsteroidal anti-inflammatory
drugs (NSAIDs) are used by mil-
lions of people worldwide to reduce Arachidonic acid
pain and inflammation. They exert their
pharmacologic effect by inhibiting the
cyclooxygenase-1 (COX-1) and COX-2
enzymes, thereby blocking conversion of Platelets Gastric mucosa Joints Endothelial cells
arachidonic acid to prostaglandin E2 (PGE2)
and PGI2 (prostacyclin), which mediate pain COX-1

(see the figure). However, because COX COX-1 COX-1

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enzymes exist throughout the body, NSAIDs COX-2 COX-2
have many physiological effects, including
complications, such as development of gas-
tric ulcers and gastrointestinal bleeding. In
2004, the blockbuster drug rofecoxib (sold Thromboxane Prostaglandins Prostaglandins Prostacyclin
commercially as Vioxx) was withdrawn (TxA2) E2 anc I2 E2 anc I2 (PGI2)
from the U.S. market when a study linked a
Vasoconstriction Gastric protection Pain Vasodilation
selective COX-2 inhibitor with a higher rate Platelet aggregation Inflammation Platelet aggregation
of heart attack and stroke. However, studies
on COX inhibitors have shown varying risk Thrombosis
profiles, fueling a debate about their associa-
tion with cardiovascular risk. A recent study COX enzyme effects. COX-1 and COX-2 enzymes convert arachidonic acid to various prostanoids in different
by Yu et al. (1) now provides a biochemical tissues. Inhibition of COX-2 reduces pain and inflammation but also blocks the vasodilatory and antiplatelet
explanation for the increased cardiovascular effects in the vascular wall. Blocking COX-1 reduces the risk of thrombosis, but also inhibits the gastroprotec-
risk associated with COX-2 inhibitors, clos- tive effects of PGE2 and PGI2, thereby predisposing to gastric ulcers and bleeding.
ing this part of the long-standing discussion.
COX enzymes convert arachidonic acid Trials have shown equal pain efficacy and A mechanistic explanation has been
to prostaglandins in the gastric lining, where reduced gastrointestinal complications (3, 4). long sought to explain these observations.
they protect the gastric mucosa, and in vas- However, large clinical studies identified NSAIDs and COX-2 inhibitors were found
cular endothelial and smooth muscle cells an increased risk of developing cardiovascu- to decrease production of PGI2, as mea-
of blood vessels, where they lead to vasodi- lar conditions, including myocardial infarc- sured by its urinary metabolite 2,3-dinor-
lation and inhibition of platelet aggregation. tion and stroke, with the use of selective 6-keto PGF1α (PGI-M) in humans (10, 11).
In platelets, prostaglandins are further con- COX-2 inhibitors (3–7). One of these studies But the source of the PGI2 (whether vas-
verted by thromboxane synthase to throm- found that the COX-2 inhibitor rofecoxib had cular cells or other tissue in the body) was
boxane A2 (TxA2) which, when released, a higher rate of cardiovascular events than unclear. Because PGI 2 prevents platelet
stimulates platelet aggregation and vaso- the older nonselective NSAID (naproxen) aggregation and vasoconstriction, Yu et al.
constriction (2). However, because pain and (3). Subsequent studies similarly reported a postulated a balance between vasoconstric-
inflammation are mediated by COX-2, and higher risk with the COX-2–selective agent tion and vasodilation in the vascular system.
gastric protection by COX-1, COX-2–selec- celecoxib (6, 7). No large trials with a placebo On one hand, TxA2 formed in platelets can
tive inhibitors can avoid the gastrointesti- comparator were available for older nonselec- lead to vasoconstriction and platelet aggre-
nal complications of nonselective NSAIDs tive NSAIDs; however, observational stud- gation. This is offset by the production of
(which inhibit both COX-1 and COX-2), ies have found higher risks of cardiovascular PGI2, which restrains platelet activation and
while still reducing pain and inflammation. events with all such agents, with the excep- promotes vasodilation. Inhibiting PGI2 and
Several COX-2 inhibitors (e.g., celecoxib, tion of naproxen (8). One large randomized PGE2 in the blood vessel wall by COX-2–
rofecoxib, etoricoxib) were developed and trial directly comparing selective and nonse- selective agents, without the concomitant
approved for clinical use in some countries. lective NSAIDs demonstrated a similar risk inhibition of TxA2, could promote hyperten-
CREDIT: C. BICKEL/SCIENCE

profile for the COX-2–selective agent etori- sion and thrombosis, and increase cardio-
1
Thrombolysis in Myocardial Infarction Study Group, Car- coxib and the traditional NSAID diclofenac, vascular risk.
diovascular Division, Brigham and Women’s Hospital, Har- reporting nearly identical rates of thrombotic Yu et al. provide evidence supporting and
vard Medical School, 75 Francis Street, Boston, MA 02115,
USA. 2Columbia Presbyterian Medical Center, Division of
cardiovascular events (9). In addition, higher expanding upon this hypothesis. In a mouse
Cardiology, New York, NY 10032, USA. E-mail: cpcannon@ rates of hypertension and heart failure were model (1), they demonstrate that deletion
partners.org seen with all NSAIDS. of the gene encoding COX-2 in vascular

1386 15 JUNE 2012 VOL 336 SCIENCE www.sciencemag.org

Published by AAAS
 PERSPECTIVES

smooth muscle cells and vascular endothe- The implications of the work by Yu et References
lial cells lowered the urinary excretion of al. are that the increased cardiovascular risk 1. Y. Yu et al., Sci. Transl. Med. 4, 132ra54 (2012).
2. Y. Cheng et al., Science 296, 539 (2002).
the PGI2 metabolite and predisposed to the is not an individual drug side effect but is 3. C. Bombardier et al., N. Engl. J. Med. 343, 1520, 2,
development of thrombosis and hyperten- rather a direct pharmacologic consequence 1528 (2000).
sion. Furthermore, deletion of COX2 gene of inhibition of COX-2. Furthermore, these 4. R. S. Bresalier et al., N. Engl. J. Med. 352, 1092 (2005).
5. D. Mukherjee, S. E. Nissen, E. J. Topol, JAMA 286, 954
in vascular endothelial cells and vascular risks apply to all COX-2 inhibitors—both (2001).
smooth muscle cells decreased the synthesis selective and nonselective NSAIDs (3–9). 6. M. M. Bertagnolli et al., N. Engl. J. Med. 355, 873
and release of nitric oxide (NO), a powerful [Naproxen is the only NSAID that has not (2006).
7. S. D. Solomon et al., Circulation 117, 2104 (2008).
vasodilator, thereby reducing vascular relax- shown increased cardiovascular risk, likely 8. L. A. García Rodríquez, A. González-Pérez, BMC Med. 3,
ation. This was accompanied by a height- due to its sustained inhibition of COX-1, 17 (2005).
ened predisposition toward both hyperten- which provides an antiplatelet effect (12).] 9. C. P. Cannon et al., Lancet 368, 1771 (2006).
10. B. F. McAdam et al., Proc. Natl. Acad. Sci. U.S.A. 96, 272
sion and thrombosis. Thus, by genetically The findings of Yu et al. thus support the (1999).
engineering mice that lack COX-2 in the clinical advice from the American Heart 11. F. Catella-Lawson et al., J. Pharmacol. Exp. Ther. 289,
vasculature, Yu et al. show that the mecha- Association, which recommends minimiz- 735 (1999).
12. T. Grosser, S. Fries, G. A. FitzGerald, J. Clin. Invest. 116, 4
nism of increased cardiovascular risk from ing the dose and duration of NSAIDS as
(2006).
COX inhibition results from specifically much as possible, as a means of reducing the 13. E. M. Antman et al., Circulation 115, 1634 (2007).
blocking COX-2 in the blood vessels and not cardiovascular risk associated with COX-2
from other tissues in the body. inhibition (13). 10.1126/science.1224398

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ANTHROPOLOGY

Absolute Dating of Cave Art Use of uranium-thorium dating shows that cave
art in Spain is older than expected.

John Hellstrom

P
aleolithic cave art is one of the most rium-230 in a geological or biogenic mate- to operate on milligrams of such material (5,
striking visual reminders of tens of rial, through decay of uranium incorporated 6) (see the figure).
millennia of human prehistory. Found within it at its time of formation. When it was Cave art is typically found in carbonate
throughout the world, it is fundamental for first applied almost 50 years ago, this tech- terrains, where the majority of caves have
understanding the earliest human culture nique required samples of 100 g or more in developed worldwide. The stalagmites, sta-
and artistic endeavor. Yet, despite great the case of cave formations such as those now lactites, and similar formations that grow
advances in dating technologies, it remains dated by Pike et al. In 1987, Edwards et al. in such caves, collectively known as spe-
extremely difficult to determine the age of a showed that U-Th dating could be conducted leothems, all contain trace amounts of ura-
thin layer of pigment on a cave or rock shel- by mass spectrometric analysis (4). Through nium and are thus amenable to U-Th dating.
ter wall. Researchers are often limited to this and subsequent advances, the efficiency Very thin sheets or drapes of this material
reconstructing relative chronology by com- of measurement has increased by more than can sometimes be found grown over the top
paring drawing styles and, where available, four orders of magnitude, enabling hypersen- of Paleolithic cave art, and in some cases
creating sometimes tenuous links to other sitive techniques like that used by Pike et al. may also underlie or even sandwich it (7, 8).
dated human remains or arti-
facts (1, 2). Mass-spectrometric
radiocarbon dating has arguably
been the most successful tech-
nique for dating cave art, in the ~1 mm
rare cases where it is possible to
directly date charcoal or other
pigments containing carbon (2).
On page 1409 of this issue, Pike
et al. report an ambitious study 1980
of paleolithic cave art sites from
Spain in which they have applied
the previously under used ura- 1990
nium-thorium (U-Th) dating 2012
method (3).
~100 g ~5 g <0.01 g
U-Th dating measures the
ingrowth of radioactive tho- U-Th sampling of calcite overgrowths. Since U-Th dating was first introduced in the 1960s, sample size requirements have
fallen continually. Large jumps in efficiency occurred with the introduction of mass spectrometric analysis and with advances
School of Earth Sciences, The University in mass spectrometric technology and can now often lead to sample sizes of less than 10 mg, or 4 mm3. As shown by Pike
of Melbourne, VIC 3010 Australia. E-mail: et al., a 1 mm-thick speleothem film overlying a cave art panel can now be dated by removing a few square millimeters of
[email protected] overgrowth, minimizing impact on the artwork.

www.sciencemag.org SCIENCE VOL 336 15 JUNE 2012 1387

Published by AAAS
COX-2 Inhibitors and Cardiovascular Risk
Christopher P. Cannon and Paul J. Cannon

Science 336 (6087), 1386-1387.

DOI: 10.1126/science.1224398

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ARTICLE TOOLS http://science.sciencemag.org/content/336/6087/1386

REFERENCES This article cites 13 articles, 6 of which you can access for free
http://science.sciencemag.org/content/336/6087/1386#BIBL

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