Use of metabolomic profiling in the study of arachidonic acid metabolism in cardiovascular disease.

Abstract

Arachidonic acid is one of the pivotal signaling molecules associated with inflammation, pain and homeostatic function. Drugs specifically targeting these signaling pathways represent more than 25% of annual pharmaceutical sales worldwide. However, chronic administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and rofecoxib (Vioxx), a potent cyclooxygenase-2 inhibitor, have been associated with adverse cardiovascular events. Understanding the possible mechanisms underlying these adverse events is critical for evaluating the risks and benefits of this group of drugs and for development of safer drugs. Using a powerful metabolomics approach, 20-hydroxyeicosatetraenoic acid (20-HETE) was identified among many of arachidonic acid metabolic products as a likely culprit for adverse cardiovascular side effect associated with rofecoxib and NSAIDs. In addition, using a similar metabolomic approach, epoxyeicosatrienoic acids (EETs), which are lipid mediators derived from arachidonic acid through the cytochrome P450 epoxygenase pathway, have been shown to exhibit cardioprotective effects in a murine myocardial infarction (MI) model. Inhibitors of the soluble epoxide hydrolase increase titers of epoxy fatty acids and both block and reverse cardiac hypertrophy in rodent models. These highly potent, orally available compounds may be promising for treating heart failure and other cardiovascular disease. In this review, we will summarize some of the recent advances using metabolomic profiling to gain insights into the involvement of arachidonic acid pathways in cardiovascular disease.