Abstract
The arachidonic acid (AA) pathway plays a key role in cardiovascular biology, carcinogenesis, and many inflammatory diseases, such as asthma, arthritis, etc. Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is in turn further metabolized by cyclooxygenases (COXs) and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes to a spectrum of bioactive mediators that includes prostanoids, leukotrienes (LTs), epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid (diHETEs), eicosatetraenoic acids (ETEs), and lipoxins (LXs). Many of the latter mediators are considered to be novel preventive and therapeutic targets for cardiovascular diseases (CVD), cancers, and inflammatory diseases. This review sets out to summarize the physiological and pathophysiological importance of the AA metabolizing pathways and outline the molecular mechanisms underlying the actions of AA related to its three main metabolic pathways in CVD and cancer progression will provide valuable insight for developing new therapeutic drugs for CVD and anti-cancer agents such as inhibitors of EETs or 2J2. Thus, we herein present a synopsis of AA metabolism in human health, cardiovascular and cancer biology, and the signaling pathways involved in these processes. To explore the role of the AA metabolism and potential therapies, we also introduce the current newly clinical studies targeting AA metabolisms in the different disease conditions.
Highlights
INTRODUCTION The ω6 polyunsaturated fatty acid (PUFA), arachidonic acid (AA), and its metabolites have attracted a lot of attention in cardiovascular and cancer biology, in relation to inflammatory processes and disease.[1–6] The importance of AA in biology lies in the fact that it can be metabolized by three distinct enzyme systems, i.e., cyclooxygenases (COXs, referred to as PGG/H synthases), lipoxygenases (LOXs), and cytochrome P450 (CYP) enzymes (ω-hydroxylases and epoxygenases) to generate an impressive spectrum of biologically active fatty acid mediators (Fig. 1).The COXs, which generate prostanoids, i.e., prostaglandins (PGs) and thromboxane A2 (TXA2), were the first enzymes reported to metabolize AA
It is thought that inhibition of blood clotting by aspirin can reduce the risk of ischaemic events such as heart attacks and stroke, and prostacyclin analogues are used for the treatment of pulmonary hypertension.[9,12,13]
The bestreduced into monohydroxy eicosatetraenoic acids (HETEs) by known role of the CYP pathway is the metabolism of lipophilic peroxidases, or converted to biologically active compounds such xenobiotics, including drugs and chemical carcinogens, as well as as LTs, lipoxins (LXs), and hepoxilins
Summary
Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is in turn further metabolized by cyclooxygenases (COXs) and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes to a spectrum of bioactive mediators that includes prostanoids, leukotrienes (LTs), epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid (diHETEs), eicosatetraenoic acids (ETEs), and lipoxins (LXs) Many of the latter mediators are considered to be novel preventive and therapeutic targets for cardiovascular diseases (CVD), cancers, and inflammatory diseases. Samuelsson who was awarded the Nobel Prize in Physiology or Medicine in 1982.14 Arachidonate 5-LOX (or ALOX5) and LT receptor antagonists have been developed for the treatment of asthma and seasonal allergies.[15,16] These two eicosanoid pathways (COX and LOX) are becoming increasingly important therapeutic targets as novel receptors and metabolites are identified and their roles in many diseases are better defined. LTB4, on the other hand, acts via LTB4R (BLT1) and LTB4R2 (BLT2) receptors.[62]
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