Arachidonic acid metabolism has three branches, at least as far as has been discovered to date. Two of those have been targeted clinically, and a paper in the Dec. 5, 2006, issue of the Proceedings of the National Academy of Sciences, now available online, provides evidence that the third branch also might hold therapeutic promise.
Lipoxygenases, which turn arachidonic acid into leukotrienes, are inhibited by Merck's Singulair, approved for allergies and chronic asthma. The cyclooxygenase pathway, which makes prostaglandins out of arachidonic acid, is targeted by Pfizer Inc.'s Celebrex, and once was targeted by Bextra and Vioxx before those two products had to be removed from the market for their cardiovascular risks.
While lipoxygenases and cyclooxygenases ultimately lead to vasoconstriction and inflammation, the epoxylipids or EETs that result when arachidonic acid is metabolized by epoxygenases have the opposite effects: They are anti-inflammatory and, because they promote blood vessel dilation, antihypertensive.
In the normal course of events, though, their effects are short-lived; EETs are rapidly metabolized to less active compounds. That's where the best chance for harnessing them therapeutically lies; using soluble epoxide hydrolase, or sEH, inhibitors allows EETs to hang around longer, with the net effect of lowering blood pressure and preventing inflammation.
In the PNAS paper, the authors - from the University of California at Davis, the Northern California Healthcare System in Mather, Calif., and Xiangya Second Hospital in Changsha, China - used several sEH inhibitors to treat mice with cardiac hypertrophy, or enlarged hearts. Cardiac hypertrophy can occur for a variety of reasons, and eventually leads to heart failure.
In mice, either of two sEH inhibitors given in the animals' water was able to prevent surgically induced cardiac hypertrophy. If the inhibitors were given three weeks after hypertrophy had been induced, they were able to partially reverse cardiac hypertrophy.
Though sEH inhibitors are well known for their ability to reverse hypertension, that was not why they reversed hypertrophy. Senior author Nipavan Chiamvimonvat said that the studies presented in PNAS, suggested that the anti-hypertrophic effect was not solely due to anti-hypertension.
"We are not refuting the fact that in the whole animal, the antihypertensive effects may contribute" to preventing cardiac enlargement, she told BioWorld Today. "But additionally, we have shown in vitro that [inhibiting sEH] has a direct effect in prevention of enlargement of the cells."
Further in vivo studies showed that at a molecular level, sEH inhibitors prevented the activation of the nuclear transcription factor Nf-kappa-B. Mice with cardiac hypertrophy that were treated with the compounds also were less susceptible to heart arrhythmias than their placebo-treated counterparts.
Chiamvimonvat noted that hypertrophy is thought to be an adaptive response too, and that "the root cause still needs to be addressed." But she said that once the hypertrophy has developed, it also needs to be addressed in and of itself: "Enlargement of the heart is one of the most common causes of heart failure in the United States."
The compounds Chiamvimonvat and her colleagues reported on have been licensed to Ar te Therapeutics, a Hayward, Calif.-based biotech company, which was co-founded by co-author Bruce Hammock. Ar te is developing small-molecule therapeutics for cardiovascular indications and inflammation; the company, which received Series A funding of $15 million in February 2005, is studying sEH inhibitors and hopes to enter the clinic in the first half of 2007.