The emerging role of oxylipins in thrombosis and diabetes

Abstract

The prevalence of cardiovascular disease (CVD), the leading cause of death in the US, is predicted to increase due to the shift in age of the general population and increase in CVD risk factors such as obesity and diabetes. New therapies are required to decrease the prevalence of CVD risk factors (obesity and diabetes) as well as reduce atherothrombosis, the major cause of CVD related mortality. Oxylipins, bioactive metabolites derived from the oxygenation of polyunsaturated fatty acids, play a role in the progression of CVD risk factors and thrombosis. Aspirin, a cyclooxygenase-1 inhibitor, decreases atherothrombotic associated mortality by 25%. These potent effects of aspirin have shown the utility of modulating oxylipin signaling pathways to decrease CVD mortality. The role of many oxylipins in the progression of CVD, however, is still uncertain or controversial. An increased understanding of the role oxylipins play in CVD risk factors and thrombosis could lead to new therapies to decrease the prevalence of CVD and its associated mortality.

Keywords: 12-lipoxygenase, lipoxygenase; cardiovascular disease; diabetes; hemostasis; oxylipins; polyunsaturated fatty acids; thrombosis.

FIGURE 1

Oxylipin biosynthesis and signaling. Oxylipins are synthesized de novo from polyunsaturated fatty acids (PUFAs) in an activation dependent manner. Upon cellular activation, cPLA₂ hydrolyzes PUFAs from the lipid membrane generating free PUFAs. Oxygenases (COX, LOX, and CYP) metabolize free PUFAs into distinct oxylipins. Oxylipins can diffuse through the plasma membrane and bind GPCRs in the local environment. Additionally, select oxylipins can activate the transcription factor PPAR.

FIGURE 2

Polyunsaturated fatty acid biosynthesis. The essential fatty acids α-linolenic acid (ALA) and linoleic acid (LA) are metabolized to produce PUFAs. The initial step is the addition of a double bond to both ALA and LA to form the respective desaturated products. These desaturated metabolites are elongated and another desaturase can add a double bond to these elongated products to produce EPA and AA, respectively. EPA through a series of enzymes is converted into DHA.

FIGURE 3

PUFA platelet membrane composition and agonist induced PUFA membrane liberation. The table displays the amount of PUFAs contained in the platelet membrane of different European populations from three studies as %weight or %mmol compare to total fatty acids. Columns 1 and 2 of the table represent data from the same study comparing the platelet composition of individuals from either inland (column 1) or coastal communities (column 2) in northern Norway. Liberation of PUFAs from the platelet membrane is achieved in an agonist dependent manner. Platelet stimulation through a myriad of agonists including thrombin, ADP, and collagen cause the translocation of cPLA_2α to the plasma membrane where it cleaves PUFAs from the plasma membrane to generate free PUFAs, which can be metabolized to oxylipins.

FIGURE 4

Hemostatically active oxylipins derived from COX and platelet 12(S)-LOX.Common oxylipin precursors (GLA, DGLA, AA, ALA, EPA, and DHA) are all substrates for platelet 12(S)-LOX while COX produces oxylipins predominately from EPA, DGLA, and AA. Both COX and platelet 12(S)-LOX generate oxylipins that have either prothrombotic (green box) or anti-thrombotic (red box) signaling properties. Oxylipins designated with yellow boxes have been reported as pro and anti-thrombotic in the literature.