Cyclooxygenase products and atherosclerosis

MacRae F. Linton, Sergio Fazio

    Research output: Contribution to journalReview article

    15 Scopus citations

    Abstract

    Prostaglandins (PGs) and their specific receptors play critical roles in atherothrombosis. Produced from arachidonic acid via two cyclooxygenase (COX) isoforms, PGs mediate their actions via G-protein coupled receptors. Thromboxane (TX) A2 is a vasoconstrictor and platelet agonist, prostacyclin (PGI2) is a vasodilator that inhibits platelet function, and PGE2 modulates inflammation. The cardioprotective effects of aspirin are attributed to inhibition of COX-1 mediated platelet TX production. In contrast, the selective COX-2 inhibitor, rofecoxib, was removed from the market due increased cardiovascular events. Studies of pharmacological modulation of PGs and genetic deletion of specific PG receptors in murine models have provided insights into their roles in atherosclerosis, but murine models have major limitations in addressing issues of plaque rupture and thrombosis. Nonselective COX inhibition, COX-1 inhibition, TP antagonism, and deletion of the TX receptor (TP) reduce atherosclerosis in murine models; yet, elimination of COX-1 or TP expression in bone marrow-derived cells does not reduce atherosclerosis, indicating that COX-1-mediated platelet TX production is not a major driving force in murine atherogenesis. The results of COX-2 inhibition on atherosclerosis have been mixed with studies showing increased, decreased or unchanged lesion area, suggesting that the impact of COX-2 inhibition may vary with lesion stage. However, COX-2 inhibition or COX-2 gene deletion have a profound ability to prevent angiotensin II-induced aneurysm formation in mice. A number of studies have shown that genetic deletion of the PGI2 receptor (IP) accelerates the vascular response to injury. However, the data do not support a "balance" between COX-2-derived PGI2 and COX-1-derived platelet TX as a critical determinant of atherogenesis. Genetic deletion of microsomal PGES-1, a synthase that produces PGE2, reduces atherosclerosis, an effect attributed to increased PGI2 production. PGE2 modulates inflammation and may impact atherogenesis directly via a number of mechanisms. A more detailed understanding of the roles of PGs and their receptors in atherothrombosis may point to more specific targets for the prevention of atherosclerotic cardiovascular disease.

    Original languageEnglish (US)
    Pages (from-to)25-36
    Number of pages12
    JournalDrug Discovery Today: Therapeutic Strategies
    Volume5
    Issue number1
    DOIs
    StatePublished - Mar 1 2008

    ASJC Scopus subject areas

    • Molecular Medicine
    • Pharmacology
    • Drug Discovery

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