Prostacyclin, atherothrombosis, and cardiovascular disease.
Prostacyclin (PGI(2)) is a major product of COX-2 catalyzed metabolism of arachidonic acid in the endothelium. Recent studies have demonstrated that PGI(2) protects against atherothrombosis. The prostacyclin receptor knockout mice exhibit increased atherosclerosis, enhanced thrombosis, and enhanced proliferative response to carotid vascular injury with increased intima to media ratios [1-3]. Moreover, the recent withdrawal of rofecoxib (Vioxx) due to increased cardiovascular events further supports the critical role of prostacyclin in inhibiting atherothrombosis in humans. Such studies have paralleled intense chemical biology studies to develop more stable prostacyclin analogues. Indeed a number of these analogues are currently being successfully used for the treatment of pulmonary hypertension. In this review we will summarize the current literature on some principles of prostacyclin analogue development, our current understanding of the receptor, and recent developments which implicate prostacyclin in atherothrombotic protection. More than 68 million Americans suffer from cardiovascular disease, which causes more deaths, disability and economic loss than any other group of diseases. Further clinical investigations of orally stable prostacyclin analogues for treatment of cardiovascular diseases other than pulmonary hypertension may now be warranted.
Arehart
E
E
Department of Pharmacology & Toxicology, Dartmouth Medical School, Hanover, NH 03755, USA.
Gleim
S
S
Kasza
Z
Z
Fetalvero
K M
KM
Martin
K A
KA
Hwa
J
J
D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy*; D051546:Cyclooxygenase 2 / Q000187:drug effects; D015195:Drug Design; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D051379:Mice; D008822:Mice, Transgenic; D011465:Prostaglandins, Synthetic / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D044006:Receptors, Epoprostenol / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D013927:Thrombosis / Q000188:drug therapy*
D011465:Prostaglandins, Synthetic; D044006:Receptors, Epoprostenol; D011464:Epoprostenol; D051546:Cyclooxygenase 2