Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets

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.

Human Saliva as a Diagnostic Specimen for Early Detection of Inflammatory Biomarkers by Real-Time RT-PCR

“…1. Mechanism of inflammatory cascade: In the presence of a perceived threat or infection, the cell membrane disrupts and the enzyme phospholipase A2 acts on the phospholipid layer, hydrolysing the esterified arachidonic acid [51]. This polyunsaturated fatty acid metabolizes via enzymes such as cyclooxygenase (COX-1 and COX-2) and lipoxygenase to produce eicosanoids such as prostaglandins, leukotrienes, thromboxanes, and lipoxins.…”

Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

“…Arachidonic acid is a conditionally essential polyunsaturated fatty acid that, in endothelial cells, plays a crucial role in regulating NO release and angiogenesis [ 43 , 96 , 97 ]. Arachidonic acid is cleaved by glycerophospholipids on the plasma membrane or the nuclear envelope by phospholipase A2 (PLA2), PLC, and phospholipase D (PLD) ( Figure 1 ) [ 98 ] and may be metabolized into an impressive array of bioactive eicosanoids, e.g., prostanoids, thromboxane, leukotrienes, and epoxyeicosatrienoic acids (EETs) ( Figure 1 ), by three distinct families of enzymes, respectively: COXs, LOXs, and CYP ω-hydroxylases and epoxygenases [ 98 , 99 ]. ROS may be generated as byproducts of arachidonic acid oxidation by several COX (e.g., COX-1), LOX (e.g., 5-LOX) and CYP (e.g., CYP2C8 and 9) enzymes [ 98 , 99 , 100 , 101 ].…”

“…Arachidonic acid is cleaved by glycerophospholipids on the plasma membrane or the nuclear envelope by phospholipase A2 (PLA2), PLC, and phospholipase D (PLD) ( Figure 1 ) [ 98 ] and may be metabolized into an impressive array of bioactive eicosanoids, e.g., prostanoids, thromboxane, leukotrienes, and epoxyeicosatrienoic acids (EETs) ( Figure 1 ), by three distinct families of enzymes, respectively: COXs, LOXs, and CYP ω-hydroxylases and epoxygenases [ 98 , 99 ]. ROS may be generated as byproducts of arachidonic acid oxidation by several COX (e.g., COX-1), LOX (e.g., 5-LOX) and CYP (e.g., CYP2C8 and 9) enzymes [ 98 , 99 , 100 , 101 ]. Intriguingly, LOXs- and COXs-derived arachidonic acid metabolites may stimulate multiple NOX isoforms, including NOX1 and NOX4, to induce ROS signaling in response to chemical stimulation [ 98 , 99 ].…”

“…ROS may be generated as byproducts of arachidonic acid oxidation by several COX (e.g., COX-1), LOX (e.g., 5-LOX) and CYP (e.g., CYP2C8 and 9) enzymes [ 98 , 99 , 100 , 101 ]. Intriguingly, LOXs- and COXs-derived arachidonic acid metabolites may stimulate multiple NOX isoforms, including NOX1 and NOX4, to induce ROS signaling in response to chemical stimulation [ 98 , 99 ].…”

Phospholipase A2 Drives Tumorigenesis and Cancer Aggressiveness through Its Interaction with Annexin A1

“…Moreover, AA can be oxidized by the enzyme 5lipoxygenase (LOX) to produce leukotrienes, an additional class of inflammatory mediators. In addition, when AA is metabolized by cytochrome P450, epoxides are produced and act in lowering blood pressure (Figure 1) [77].…”