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.

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

Fig. 2

The main biological functions of CYP-EETs on the cardiovascular system and the main corresponding cellular signaling pathways. CYP epoxygenase metabolites of AA, EETs, act as lipid mediators eliciting numerous biological responses and impacting both vascular and cardiac function, including anti-apoptosis, anti-inflammation, vasodilation, inducing angiogenesis, anti-hypertension and aginst ischemic cardiomyopathy or non-ischemic cardiomyopathy

Fig. 3

The mechanisms of actions of EETs on tumor growth. EETs accelerated proliferation, cell cycle, and protected carcinoma cells from apoptosis through multiple signal transduction pathways. Besides, EETs improved mitochondrial function and prevented carcinoma cells from oxidative stress damage. In addition, EETs also were found to regulate multiple important cells in TME, such as promoting endothelial cell angiogenesis, fibroblast activation, and anti-inflammation