The expansive role of oxylipins on platelet biology

Abstract

In mammals, three major oxygenases, cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450 (CYP450), generate an assortment of unique lipid mediators (oxylipins) from polyunsaturated fatty acids (PUFAs) which exhibit pro- or anti-thrombotic activity. Over the years, novel oxylipins generated from the interplay of theoxygenase activity in various cells, such as the specialized pro-resolving mediators (SPMs), have been identified and investigated in inflammatory disease models. Although platelets have been implicated in inflammation, the role and mechanism of these SPMs produced from immune cells on platelet function are still unclear. This review highlights the burgeoning classes of oxylipins that have been found to regulate platelet function; however, their mechanism of action still remains to be elucidated.

Keywords: Cyclooxygenase; Eicosanoids; Lipoxygenase; Oxygenases; Prostaglandins; Thrombosis.

Fig. 1

Polyunsaturated fatty acids (PUFAs) are released from the embedded phospholipid bilayer membrane, which are then converted by intracellular oxygenases (COX, LOX, or CYP450) to generate wide array of oxylipins that can diffuse across the cellular membrane to be further converted by oxygenases, act on intracellular signaling component, peroxisome proliferator-activated receptor (PPAR), or act on receptor to regulate platelet function

Fig. 2

Arachidonic acid (AA) is oxidized by 5-LOX, 12-LOX, 15-LOX, COX, and CYP450 into their respective classes of oxylipins: 1) non-leukotrienes (LTs) (5-HETE, 5-oxo-ETE) or cysteinyl-free LTs (LTA₄, LTB₄) and cysteinyl-LTs (LTC₄, LTD₄, LTE₄); 2) 12-HETE; 3) series 2 prostaglandins (PGD₂, PGE₂, PGI₂, and TXA₂); 4) epoxyeicosatrienoic acids (EETs) (5,6-EET, 8,9-EET, 11,12-EET, 14,15-EET) and hydroxylates (19-HETE, 20-HETE)

Fig. 3

PUFA oxidation by oxygenases. a Dihomo-γ-linolenic acid (DGLA) is oxidized by 12-LOX, 15-LOX, and COX into the corresponding metabolites: 12-HETrE, 15-HETrE, and series 1 prostaglandins (PGD₁, PGE₁, TXA₂). b Docosahexaenoic acid (DHA) is also metabolized by the oxygenases into the following: 11- or 14-HDHA by 12-LOX, 17-HDHA by 15-LOX, and epoxydocosapentaenoic acids (EDPs) (7,8-EDP, 10,11-EDP, 13,14-EDP, 16,17-EDP, 19,20-EDP) by CYP450 isoforms

Fig. 4

PUFA oxidation by oxygenases. a 12-LOX acts on docosapentaenoic acid (DPA) to convert to 11- or 14-HDPA. b Linoleic acid (LA) is metabolitzed by 15-LOX to generate 13-HODE. c Eicosapentaenoic acid (EPA) is oxidized by 12-LOX, COX, CYP 450 to 12-HEPE, series 3 prostaglandins (PGD₃, PGE₃, PGI₃, and TXA₃), and epoxyeicosatetraenoic acids (EEQs) (8,9-EEQ, 11,12-EEQ, 14,15-EEQ, and 17,18-EEQ)

Fig. 5

Specialized pro-resolving lipid mediators (SPMs) constitute a wide array of lipids classes derived from the interplay of oxygenase activity on AA, EPA, and DHA. Lipoxins, (LXA₄, LXB₄) and E series resolvin (RvE₁) are derived from AA and EPA, respectively. DHA can be indirectly converted by the interaction of the oxygenases into MaR1, PDX, or D series resolvin, RvD₁

Fig. 6

LOX, COX, CYP 450 derived lipid mediators, and SPMs can be divided into either pro- or anti-thrombotic classes based on their effects on platelet function