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Prostacyclin discovery represented the culmination of the late Sir
John Vane scientific accomplishments. It generated a tremendous amount of
work in disciplines such as physiology, pharmacology, pathology, biochemistry,
greatly advancing the field of vascular biology. It is now clear that
prostacyclin generation by the endothelium is what protects against
cardiovascular diseases and what modulates physiological angiogenesis
[1,2].
Contrary to initial assumptions about cox-1 involvement, it is now
clear that the coupling cox-2 /PGI2 synthase occurring in endothelial cell
caveolae is the major event leading to a sustained production of
prostacyclin released both in the circulation and into the sub-endothelium[3,4].
PGI2 synthase, a constitutively expressed enzyme in human endothelial
cells, belongs to the cytochrome P450 family and it has two binding sites
for caveolin 1 clearly separated from the PGH2 catalytic site. Thus, the
enzyme produces PGI2 as soon as cox-2 is induced and inserted into
caveolae, provided that arachidonate is made available by cytosolic
phospholipase A2. PGI2 synthase gene is characterized by a promoter having
a variable number of sp1 binding sites and its expression varies among
individuals. According to Suita study, Japanese having several binding
sites are less prone to hypertension with respect to individuals having
few binding sites [2].
Clinical trials carried out in order to ascertain the absence of side
effects of anti-inflammatory drugs during long term treapments, initially
revealed that cox-2 specifics inhibitors at therapeutical doses were well
tolerated. More recently Graham and colleagues pointed out the risk of
acute myocardial infarction and sudden cardiac death in patients treated
with cox-2 selective and non-selective non-steroidal anti-inflammatory
compounds. Similar considerations have been aroused by FitzGerald in a
recent editorial [1,5].
Clinical studies carried out by Merck on patients suffering from intestinal
polyps and using rofecoxib (Vioxx) revealed the cardiotoxicity of this
drug, forcing Merck to withdraw Vioxx from the market.
Celebrex has been considered much less prone to affect the cardiovascular
system [1,6,7].
Prompted by these observations we speculated that cardiotoxicity of Vioxx
could be explained by assuming that not only an inhibition of cox-2 but
also an inhibition of PGI2 synthase was involved [8].
As a matter of fact a compensatory increase of cox-1 level following cox-2
inhibition has been recently reported [9]
If it is the case that under conditions in which PGI2 synthase is fully
active, enough PGI2 to protect the cardiovascular system could be
produced. We have verified that human endothelial cells exposed to Vioxx
at therapeutic doses, dramatically reduce PGI2 synthase activity while
little effect is observed when Celebrex as well as classical anti-inflammatory drugs are tested.
We strongly recommend that in future novel specific cox-2 inhibitors
should be tested in vitro and in vivo as PG2 synthase possible inhibitors.
1. GA FitzGerald, Coxibs and cardiovascular disease, N. Engl. J. Med.
351 (2004), pp. 1709-1711.
2. V Tomasi, E Spisni, C Griffoni, T Guarnieri, Caveolae, Caveolar
enzymes and angiogenesis, Current Topics in Biochemical Research 3 (2000),
pp. 81-90.
3. JY Liou, WG Deng, DW Gilroy, SK Shyue, KK Wu, Co-localization and
interaction cyclooxygenase-2 with caveolin-1 in human fibroblasts, J.
Biol. Chem. 276 (2001), pp. 34975-34982.
4. E Spisni, C Griffoni, S Santi, M Riccio, R Marulli, G Bartolini, M
Toni, V Ullrich, V Tomasi, Colocalization prostacyclin (PGI2) synthase-
caveolin-1 in endothelial cells and new roles for PGI2 in angiogenesis,
Exp. Cell Res. 266 (2001), pp. 31-43.
5. DJ Graham, D Campen and R Hui et al., Risk of acute myocardial
infarction and sudden cardiac death in patients treated with cyclo-
oxygenase 2 selective and non-selective non-steroidal anti-inflammatory
drugs: nested case-control study, Lancet 365 (2005), pp. 475-481.
6. The Lancet Editorial, Vioxx: an unequal partnership between safety
and efficacy, The Lancet 364 (2004), pp. 1287-1288.
7. M Wadman, Vioxx may go back on sale after scraping past FDA panel,
Nature 433 (2005).
8. E Spisni, G Bartolini, M Orlandi, B Belletti, S Santi, V Tomasi,
Prostacyclin (PGI2) synthase is a constitutively expressed enzyme in human
endothelial cells, Exp. Cell Res. 219 (1995), pp. 507-513.
9. H Wang, W Ma, L Tejada, H Zhang, JD Morrow, SK Das, SK Dey, Rescue
of female infertility from the loss of cyclooxygenase-2 by compensatory up
-regulation of cyclooxygenase-1 is a function of genetic makeup, J. Biol.
Chem. 279 (2004), pp. 10649-10658.
Competing interests:
None declared
Competing interests:
No competing interests
17 May 2005
Vittorio Tomasi
Professor of physiology
Vittorio Tomasi, Cristiana Griffoni and Enzo Spisni
Department of Biology, University of Bologna, 40126 Bologna, Italy
Why cardiovascular actions of Vioxx are more serious than Celebrex and other conventional anti-inflammatory drug effects
Prostacyclin discovery represented the culmination of the late Sir
John Vane scientific accomplishments. It generated a tremendous amount of
work in disciplines such as physiology, pharmacology, pathology, biochemistry,
greatly advancing the field of vascular biology. It is now clear that
prostacyclin generation by the endothelium is what protects against
cardiovascular diseases and what modulates physiological angiogenesis
[1,2].
Contrary to initial assumptions about cox-1 involvement, it is now
clear that the coupling cox-2 /PGI2 synthase occurring in endothelial cell
caveolae is the major event leading to a sustained production of
prostacyclin released both in the circulation and into the sub-endothelium[3,4].
PGI2 synthase, a constitutively expressed enzyme in human endothelial
cells, belongs to the cytochrome P450 family and it has two binding sites
for caveolin 1 clearly separated from the PGH2 catalytic site. Thus, the
enzyme produces PGI2 as soon as cox-2 is induced and inserted into
caveolae, provided that arachidonate is made available by cytosolic
phospholipase A2. PGI2 synthase gene is characterized by a promoter having
a variable number of sp1 binding sites and its expression varies among
individuals. According to Suita study, Japanese having several binding
sites are less prone to hypertension with respect to individuals having
few binding sites [2].
Clinical trials carried out in order to ascertain the absence of side
effects of anti-inflammatory drugs during long term treapments, initially
revealed that cox-2 specifics inhibitors at therapeutical doses were well
tolerated. More recently Graham and colleagues pointed out the risk of
acute myocardial infarction and sudden cardiac death in patients treated
with cox-2 selective and non-selective non-steroidal anti-inflammatory
compounds. Similar considerations have been aroused by FitzGerald in a
recent editorial [1,5].
Clinical studies carried out by Merck on patients suffering from intestinal
polyps and using rofecoxib (Vioxx) revealed the cardiotoxicity of this
drug, forcing Merck to withdraw Vioxx from the market.
Celebrex has been considered much less prone to affect the cardiovascular
system [1,6,7].
Prompted by these observations we speculated that cardiotoxicity of Vioxx
could be explained by assuming that not only an inhibition of cox-2 but
also an inhibition of PGI2 synthase was involved [8].
As a matter of fact a compensatory increase of cox-1 level following cox-2
inhibition has been recently reported [9]
If it is the case that under conditions in which PGI2 synthase is fully
active, enough PGI2 to protect the cardiovascular system could be
produced. We have verified that human endothelial cells exposed to Vioxx
at therapeutic doses, dramatically reduce PGI2 synthase activity while
little effect is observed when Celebrex as well as classical anti-inflammatory drugs are tested.
We strongly recommend that in future novel specific cox-2 inhibitors
should be tested in vitro and in vivo as PG2 synthase possible inhibitors.
____________________________________________________________________
References
1. GA FitzGerald, Coxibs and cardiovascular disease, N. Engl. J. Med.
351 (2004), pp. 1709-1711.
2. V Tomasi, E Spisni, C Griffoni, T Guarnieri, Caveolae, Caveolar
enzymes and angiogenesis, Current Topics in Biochemical Research 3 (2000),
pp. 81-90.
3. JY Liou, WG Deng, DW Gilroy, SK Shyue, KK Wu, Co-localization and
interaction cyclooxygenase-2 with caveolin-1 in human fibroblasts, J.
Biol. Chem. 276 (2001), pp. 34975-34982.
4. E Spisni, C Griffoni, S Santi, M Riccio, R Marulli, G Bartolini, M
Toni, V Ullrich, V Tomasi, Colocalization prostacyclin (PGI2) synthase-
caveolin-1 in endothelial cells and new roles for PGI2 in angiogenesis,
Exp. Cell Res. 266 (2001), pp. 31-43.
5. DJ Graham, D Campen and R Hui et al., Risk of acute myocardial
infarction and sudden cardiac death in patients treated with cyclo-
oxygenase 2 selective and non-selective non-steroidal anti-inflammatory
drugs: nested case-control study, Lancet 365 (2005), pp. 475-481.
6. The Lancet Editorial, Vioxx: an unequal partnership between safety
and efficacy, The Lancet 364 (2004), pp. 1287-1288.
7. M Wadman, Vioxx may go back on sale after scraping past FDA panel,
Nature 433 (2005).
8. E Spisni, G Bartolini, M Orlandi, B Belletti, S Santi, V Tomasi,
Prostacyclin (PGI2) synthase is a constitutively expressed enzyme in human
endothelial cells, Exp. Cell Res. 219 (1995), pp. 507-513.
9. H Wang, W Ma, L Tejada, H Zhang, JD Morrow, SK Das, SK Dey, Rescue
of female infertility from the loss of cyclooxygenase-2 by compensatory up
-regulation of cyclooxygenase-1 is a function of genetic makeup, J. Biol.
Chem. 279 (2004), pp. 10649-10658.
Competing interests:
None declared
Competing interests: No competing interests