Signal Transduction and Targeted Therapy www.nature.com/sigtrans REVIEW ARTICLE OPEN Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets Bei Wang1,2,3, Lujin Wu1,2, Jing Chen1,2, Lingli Dong3, Chen Chen 1,2, Zheng Wen1,2, Jiong Hu4, Ingrid Fleming4 and Dao Wen Wang1,2 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. Signal Transduction and Targeted Therapy (2021) ;6:94 https://doi.org/10.1038/s41392-020-00443-w 1234567890();,: INTRODUCTION contribute to prostanoid released during inflammation. Indeed, The ω-6 polyunsaturated fatty acid (PUFA), arachidonic acid aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), (AA), and its metabolites have attracted a lot of attention in including inhibitors of COX-2 are effective in the treatment of 9,10 cardiovascular and cancer biology, particularly in relation to pain and inflammation. However, the inhibition PGI2 produc- inflammatory processes and disease.1–6 The importance of AA in tion by the endothelium may contribute to the cardiovascular side biology lies in the fact that it can be metabolized by three distinct effects of COX2 inhibitors.11 It is thought that inhibition of blood enzyme systems, i.e., cyclooxygenases (COXs, also referred to as clotting by aspirin can reduce the risk of ischaemic events such as PGG/H synthases), lipoxygenases (LOXs), and cytochrome P450 heart attacks and stroke, and prostacyclin analogues are used for (CYP) enzymes (ω-hydroxylases and epoxygenases) to generate an the treatment of pulmonary hypertension.9,12,13 impressive spectrum of biologically active fatty acid mediators The LOX pathway was the second eicosanoid and inflammatory (Fig. 1). pathway to be therapeutically targeted. The enzymes generate The COXs, which generate prostanoids, i.e., prostaglandins (PGs) leukotrienes (LTs) which were first described in 1979 by Bengt I. and thromboxane A2 (TXA2), were the first enzymes reported to Samuelsson who was awarded the Nobel Prize in Physiology or metabolize AA. This requires the release of the lipid from the Medicine in 1982.14 Arachidonate 5-LOX (or ALOX5) and LT plasma membrane by phospholipases and subsequent metabo- receptor antagonists have been developed for the treatment of 15,16 lism by the COX enzymes to PGG2 and PGH2. The latter are then asthma and seasonal allergies. These two eicosanoid path- metabolized to PGs by specific PG synthases. There are two ways (COX and LOX) are becoming increasingly important distinct COX isoforms; COX-1, which is constitutively expressed in therapeutic targets as novel receptors and metabolites are most cells, is the dominant source of prostanoids that subserve identified and their roles in many diseases are better defined. housekeeping functions.7 COX-2 (also known as PTGS2), on the The third AA metabolizing pathway is the cytochrome P450 other hand, is induced by inflammatory stimuli, hormones, and (CYP) pathway that was first described in 1980. The CYP family of growth factors, is generally assumed to be the more important enzymes contains numerous subclasses,17 but for the metabolism source of prostanoid formation in inflammation and in prolif- of AA ω-hydroxylase and epoxygenase activity are the most erative diseases, such as cancer.7,8 However, the situation is not important. However, numerous CYP enzymes have mixed black and white as both enzymes contribute to the generation hyprolase and epoxygenase functions and are able to generate of autoregulatory and homeostatic prostanoids, and both can a mixed spectrum of products. The ω-hydroxylase activity of CYP 1Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 2Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China; 3Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, China and 4Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany Correspondence: Dao Wen Wang ([email protected]) These authors contributed equally: Bei Wang, Lujin Wu Received: 1 July 2020 Revised: 4 October 2020 Accepted: 15 October 2020 © The Author(s) 2021 Metabolism pathways of arachidonic acids: mechanisms and potential. Wang et al. 2 Fig. 1 Overview of the arachidonic acid (AA) metabolism pathways. Three major phospholipase enzymes (PLA2, PLC and PLD) are responsible for releasing AA from membrane-bound phospholipids by catalyzing the red arrow indicated covalent bonds, respectively. The PGHSs (COXs) metabolize AA to protanoids, prostacyclin, and thromboxane. The LOXs metabolize AA to leukotrienes and HETEs. The P450 epoxygenases metabolize AA to midchain HETEs and four EET regioisomers. All EETs are then further metabolized to less active dihydroxyeicosatrienoic acids (DHETs) by sEH enzymes converts AA to hydroxyeicosatetraenoic acids (HETEs). way CYP-derived AA metabolites can contribute to tumor growth, 20-HETEs is the best-studied metabolite in this context and has progression, and metastasis.23 been shown to possess pro-inflammatory effects in addition to In this Review, we focus on recent insights into the roles of AA contributing to vascular function.18 The epoxygenase activity of metabolism from molecular mechanisms to clinical studies, CYP enzymes, such as the CYP2J and 2C families, generates AA particularly in CVD, cancer biology and inflammatory diseases. epoxides or epoxyeicosatrienoic acids (EETs; 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET). Bioactive EETs are produced in the liver with biologically relevant amounts also being detected in the OVERVIEW OF AA METABOLISM vascularure as well as in cardiomyocytes. The EETs are mainly The COX pathway metabolized by soluble epoxide hydrolase (sEH) to the corre- As stated above, the term COX refers to enzymes also known as sponding diols or dihydroxyeicosatrienoic acids (DHET).19,20 AA prostaglandin G/H synthases (PGHS), which metabolize AA to diols were initially thought to be less active than the epoxides, but PGH2 and PHG2. These PGs are substrates for a series of it is now clear that the epoxide and diols may even exert downstream enzymes that generate specific PGs i.e. PGE2, PGI2, antagonistic actions in some conditions. As the EETs are reported PGD2, PGF2, and TXA2.24–26 The major difference between the 2 to elicit vasodilatation, this pathway and its metabolites are COX enzymes is that while COX-1 is more or less ubiquitously currently being targeted for the treatment of cardiovascular and constitutively expressed, COX-2 is an inducible enzyme,26–28 diseases (CVDs) including hypertension, heart failure (HF), and albeit with some important exceptions.29,30 There are prefer- stroke.21,22 In addition, CYP-derived EETs also regulate some ences in the coupling between COX and downstream synthases cellular processes of carcinogenesis and progression, including cell as COX-1 couples preferentially, but not exclusively, with proliferation, survival, angiogenesis, invasion, and metastasis. CYP- thromboxane synthase, PGF synthase, and the cytosolic (c) PGE derived EETs can also promote progenitor cell differentiation, synthase(PGES)isozymes.COX-2,ontheotherhands,more proliferation, and migration, in addition to influencing capillary frequently feeds PGG2/H2 to the prostaglandin I synthase (PGIS) formation inflammation and apoptosis in endothelial cells. In this and the microsomal (m) PGES isozymes, both of which are often Signal Transduction and Targeted Therapy (2021) 6:94 Metabolism pathways of arachidonic acids: mechanisms and potential. Wang et al. 3 coinduced with COX-2 by cytokines and tumor promoters.31–34 inflammation by degrading the chemotactic peptide PGP (pro- The profile of prostanoid production is determined by the line-glycine-proline).57 Thus, in inflammation the LTA4 hydrolase differential expression of these enzymes within cells present at generates a chemotactic lipid mediator,