Oestrogen activates COX2 pathway

Heart disease and atherosclerosis is more pronounced in men than in women, but this difference is reduced after menopause. Although some studies have shown that the female hormone oestrogen slows heart disease in mouse models, the underlying mechanism is largely unknown. In Science Express, FitzGerald and colleagues show that female mice are protected from hardening of the arteries as a result of oestrogen activation of the cyclooxygenase (COX)-2 enzyme, which causes an increase in the amount of the atheroprotective molecule prostacyclin, PGI₂.

During inflammation, phospholipase enzymes convert membrane phospholipids to arachidonic acid. Arachidonic acid is the precursor for prostaglandins, such as PGI₂, and thromboxanes, which are derived from the COX1 and COX2 pathways. The COX prostaglandin products are acted on by thromboxane synthase (in platelets) or prostacyclin synthase (in endothelium) to form thromboxanes or PGI₂, respectively. PGI₂ has an important and beneficial role in vascular function, as it inhibits platelet adhesion to the vascular endothelium and is a strong vasodilator. The COX pathway is inhibited by aspirin and non-steroidal anti-inflammatory drugs (NSAIDs). Newer anti-inflammatory drugs selectively target the inducible isoform COX2 and have fewer gastrointestinal side effects than the non-selective COX inhibitors such as aspirin and ibuprofen.

Mice deficient in the low-density lipoprotein (LDL) receptor were used to investigate the role of PGI₂; LDL-deficient male mice develop atherosclerosis more rapidly than females. Knocking out the prostacyclin receptor (IP) in these female mice took away the atheroprotective effect of oestrogen. These mice also showed increased oxidative stress. By removing the ovaries of female LDL-deficient mice, the authors were able to identify the direct effects of oestrogen. Administration of oestrogen to ovariectomized mice increased PGI₂ synthesis. Furthermore, PGI₂ synthesis was also increased after administration of oestrogen to female mice deficient in the oestrogen receptor β, but not the α-receptor, showing that PGI₂ biosynthesis occurs by activation of the α-receptor. In LDL- and IP-deficient female mice, administration of oestrogen did not confer protection from athersclerosis compared with LDL-deficient mice alone.

Because of the direct link between oestrogen and the protective COX2 pathway, this study raises a number of concerns about the use of selective COX2 inhibitors in premenopausal women. It also raises the possibility of an interaction between hormone replacement therapy and drugs that inhibit COX2, including traditional NSAIDs. In light of the recent studies linking long-term use of COX2 inhibitors with increased cardiovascular risk, this study provides some insight into how this risk might occur, and identifies potential biomarkers of this evolving risk. Although there is considerable interest in the further potential clinical use of COX2 inhibitors, interest in therapeutic target selection is shifting downstream in the prostaglandin biosynthetic/response pathway, towards specific prostaglandin synthases and receptors.