title: Prostacyclin, Atherothrombosis and Diabetes Mellitus: Physiologic and Clinical Considerations.
abstract: Prostacyclin (PGI2) and other metabolites of arachidonic acid are increasingly recognized for their role in the pathophysiology of human disease. A growing body of evidence from randomized controlled trials, studies of human prostacyclin receptor (hIP) variants, and IP-receptor knockout studies in mice has shown that PGI2 may have a protective effect on atherothrombotic risk. Increased risk of atherosclerosis and thrombotic sequelae may be attributed, in part, to downregulation of the prostacyclin pathway. Clinical studies with nonsteroidal antiinflammatory drugs (NSAIDs) that were selective for the cyclooxygenase-2 (COX-2) isoenzyme, although protective of mucosa in the gastrointestinal tract, first alluded to a potential role of PGI2 in atherothrombotic risk. Outcomes from early clinical trials showed a 2- to 3-fold increase in risk of incurring a thrombotic event (e.g., myocardial infarction or stroke). Further analyses suggested that atherothrombotic risk is a continuous variable with relative NSAID COX-2 selectivity, and that the COX-2 metabolic product, PGI2, appears to play a key role. Effects of reduced PGI2 levels may be felt in particular by patients with diabetes mellitus, a patient population at the high end of the cardiovascular risk spectrum. Therapies that spare PGI2 may provide the greatest level of protection. The mechanism of protection by PGI2 is under intense investigation.
authors.forename: J
authors.initials: J
authors.lastname: Stitham
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, 300 George Street, Room 759H, New Haven, CT 06511, USA. john.hwa@yale.edu.
authors.forename: J
authors.initials: J
authors.lastname: Hwa
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology*; D003920:Diabetes Mellitus / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism*; D006262:Health; D006801:Humans; D013927:Thrombosis / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology*
chemical_list: D011464:Epoprostenol