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Review
. 2023 Jun:246:108420.
doi: 10.1016/j.pharmthera.2023.108420. Epub 2023 Apr 24.

Bioactive lipid regulation of platelet function, hemostasis, and thrombosis

Livia Stanger  1 , Michael Holinstat  2
Affiliations
Review

Bioactive lipid regulation of platelet function, hemostasis, and thrombosis

Livia Stanger et al. Pharmacol Ther. 2023 Jun.

Abstract

Platelets are small, anucleate cells in the blood that play a crucial role in the hemostatic response but are also implicated in the pathophysiology of cardiovascular disease. It is widely appreciated that polyunsaturated fatty acids (PUFAs) play an integral role in the function and regulation of platelets. PUFAs are substrates for oxygenase enzymes cyclooxygenase-1 (COX-1), 5-lipoxygenase (5-LOX), 12-lipoxygenase (12-LOX) and 15-lipoxygenase (15-LOX). These enzymes generate oxidized lipids (oxylipins) that exhibit either pro- or anti-thrombotic effects. Although the effects of certain oxylipins, such as thromboxanes and prostaglandins, have been studied for decades, only one oxylipin has been therapeutically targeted to treat cardiovascular disease. In addition to the well-known oxylipins, newer oxylipins that demonstrate activity in the platelet have been discovered, further highlighting the expansive list of bioactive lipids that can be used to develop novel therapeutics. This review outlines the known oxylipins, their activity in the platelet, and current therapeutics that target oxylipin signaling.

Keywords: Hemostasis; Oxygenase; Platelet; Prostaglandins; Signal transduction; Thrombosis.

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Conflict of interest statement

Declaration of Competing Interest Dr. Holinstat is a consultant and equity holder for Veralox Therapeutics and Cereno Scientific. All other authors declare no competing interests for this work.

Figures

Fig. 1.
Fig. 1.
Substrates and oxylipin products of cyclooxygenase-1 (COX-1). TxA2: thromboxane A2; PGD2: prostaglandin D2; PGE2: prostaglandin E2; PGF2: prostaglandin F2; PGI2: prostacyclin; TxA1: thromboxane A1; PGD1: prostaglandin D1; PGE1: prostaglandin E1; TxA3: thromboxane A3; PGD3: prostaglandin D3; PGE3: prostaglandin E3; PGI3: prostaglandin I3. Created using Biorender.com.
Fig. 2.
Fig. 2.
Substrates and oxylipin products of 12-lipoxygenase (12-LOX): 11(S)-HDHA: 11(S)-hydroxydocosahexaenoic acid; 14(S)-HDHA: 14(S)-hydroxydocosahexaenoic acid; 12(S)-HETE: 12(S)-hydroxyeicosatetranoic acid; 12(S)-HETrE: 12(S)-hydroxy-8,10,14-eicosatrienoic acid; 12(S)-HEPE: 12(S)-hydroxyeicosapentaenoic acid; 11(S)-HDPA: 11(S)-hydroxy-docosapentaenoic acid; 14(S)-HDPA: 14(S)-hydroxy-docosapentaenoic acid. Note: 12-LOX metabolizes PUFAs to produce hydroperoxide fatty acids which are rapidly reduced to alcohols by glutathione peroxidase. Since the alcohol is the primary product detected from tissue samples, we show the alcohols as the lipoxygenase products for simplicity. Created using Biorender.com.
Fig. 3.
Fig. 3.
Substrates and oxylipin products of 15-lipoxygenase (15-LOX): 17(S)-HDHA: 17(S)-hydroxydocosahexaenoic acid; 15(S)-HETE: 15(S)-hydroxyeicosatetranoic acid; 15(S)-HETrE: 15(S)-hydroxyeicosatrienoic acid; 15(S)-HEPE: 15(S)-hydroxyeicosapentaenoic acid; 13(S)-HODE: 13(S)-hydroxyoctadecadienoic acid. Note: 15-LOX metabolizes PUFAs to produce hydroperoxide fatty acids which are rapidly reduced to alcohols by glutathione peroxidase. Since the alcohol is the primary product detected from tissue samples, we show the alcohols as the lipoxygenase products for simplicity. Created using Biorender.com.
Fig. 4.
Fig. 4.
Arachidonic acid products of 5-lipoxygenase (5-LOX): 5(S)-HETE: 5(S)-hydroxyeicosatetranoic acid; LTA4: leukotriene A4; LTB4: leukotriene B4; LTC4: leukotriene C4; LTD4: leukotriene D4; LTE4: leukotriene E4; 5-oxo-ETE: 5-oxo-eicosatetranoic acid. Note: 5-LOX metabolizes PUFAs to produce hydroperoxide fatty acids which are rapidly reduced to alcohols by glutathione peroxidase. Since the alcohol is the primary product detected from tissue samples, we show the alcohols as the lipoxygenase products for simplicity. Created using Biorender.com.
Fig. 5.
Fig. 5.
Oxylipin receptors on the platelet and effects on platelet activation. DP: prostaglandin DP receptor; TPα: thromboxane receptor; IP: prostacyclin receptor; PPARα: peroxisome proliferator-activated receptor alpha; PPARβ: peroxisome proliferator-activated receptor beta; PPARγ: peroxisome proliferator-activated receptor gamma; CysLT2R: cysteinyl leukotriene receptor 2; ChemR23: chemerin receptor 23; EP1: prostaglandin E2 receptor 1; EP2: prostaglandin E2 receptor 2; EP3: prostaglandin E2 receptor 3; EP4: prostaglandin E2 receptor 4; PAR4: protease-activated receptor 4; GPR31: G-protein-coupled receptor 31; PGD2: prostaglandin D2; PGD3: prostaglandin D3; TxA2: thromboxane A2; PGF2: prostaglandin F2; PGI2: prostacyclin; 12(S)-HETrE: 12(S)-hydroxy-8,10,14-eicosatrienoic acid; PGE2: prostaglandin E2; TxA1: thromboxane A1; PGI3: prostaglandin I3; 11(S)-HDPA: 11(S)-hydroxy-docosapentaenoic acid; 14(S)-HDPA: 14(S)-hydroxy-docosapentaenoic acid; 15(S)-HETE: 15(S)-hydroxyeicosatetranoic acid; 15(S)-HETrE: 15(S)-hydroxyeicosatrienoic acid; LTC4: leukotriene C4; Resolvin E1: 5S,12R,18R-trihydroxyeicosapentaenoic acid; PGE1: prostaglandin E1; PGE3: prostaglandin E3; TxA3 thromboxane A3; 12(S)-HETE: 12(S)-hydroxyeicosatetranoic acid. Created using Biorender.com.
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