Cyclo-oxygenase products and atherothrombosis.
The advent of selective inhibitors of the cyclo-oxygenase (COX)-2 enzyme has afforded the opportunity to reduce the incidence of gastrointestinal complications of traditional nonsteroidal anti-inflammatory drugs (NSAIDs). The widespread use of these drugs has increased interest in their role in the cardiovascular system. Although deletion of the prostacyclin receptor (the IP) accelerates atherogenesis in the mouse, retention of one copy of the IP is atheroprotective. This is consistent with the failure of biochemically defined, selective doses of a COX-2 inhibitor to accelerate atherogenesis in the mouse, despite suppressing prostacyclin biosynthesis by roughly 60%. Inhibition of both COX isozymes, by contrast, markedly retards atherogenesis. Consistent with these observations, antagonism of the thromboxane receptor (the TP) retards atherogenesis and diminishes the proliferative response to vascular injury in the mouse. Even partial suppression of prostacyclin (without coincident inhibition of platelet COX-1-dependent thromboxane formation) by COX-2 inhibitors may be undesirable in acute vascular occlusive syndromes. However, these drugs are unlikely to accelerate progression of the underlying vascular disease. By contrast, the effects of TP antagonists, aspirin, and even traditional NSAIDs on atherosclerotic plaque progression merit further evaluation in humans.
FitzGerald
G A
GA
Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia 19104, USA. garret@spirit.gcrc.upenn.edu
Austin
S
S
Egan
K
K
Cheng
Y
Y
Pratico
D
D
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism / Q000502:physiology*; D020033:Protein Isoforms; D013450:Sulfones; D013927:Thrombosis / Q000188:drug therapy* / Q000503:physiopathology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D020033:Protein Isoforms; D013450:Sulfones; C116926:rofecoxib; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases