DHA 12‐LOX‐derived oxylipins regulate platelet activation and thrombus formation through a PKA‐dependent signaling pathway

Abstract

Background The effects of docosahexaenoic acid (DHA) on cardiovascular disease are controversial and a mechanistic understanding of how this omega‐3 polyunsaturated fatty acid (ω‐3 PUFA) regulates platelet reactivity and the subsequent risk of a thrombotic event is warranted. In platelets, DHA is oxidized by 12‐lipoxygenase (12‐LOX) producing the oxidized lipids (oxylipins) 11‐HDHA and 14‐HDHA. We hypothesized that 12‐LOX DHA‐oxylipins may be involved in the beneficial effects observed in dietary supplemental treatment with ω‐3 PUFAs or DHA itself. Objectives To determine the effects of DHA, 11‐HDHA, and 14‐HDHA on platelet function and thrombus formation, and to elucidate the mechanism by which these ω‐3 PUFAs regulate platelet activation. Methods and results DHA, 11‐HDHA, and 14‐HDHA attenuated collagen‐induced human platelet aggregation, but only the oxylipins inhibited ⍺IIbβ3 activation and decreased ⍺‐granule secretion. Furthermore, treatment of whole blood with DHA and its oxylipins impaired platelet adhesion and accumulation to a collagen‐coated surface. Interestingly, thrombus formation was only diminished in mice treated with 11‐HDHA or 14‐HDHA, and mouse platelet activation was inhibited following acute treatment with these oxylipins or chronic treatment with DHA, suggesting that under physiologic conditions, the effects of DHA are mediated through its oxylipins. Finally, the protective mechanism of DHA oxylipins was shown to be mediated via activation of protein kinase A. Conclusions This study provides the first mechanistic evidence of how DHA and its 12‐LOX oxylipins inhibit platelet activity and thrombus formation. These findings support the beneficial effects of DHA as therapeutic intervention in atherothrombotic diseases.

12/15-Lipoxygenase Regulates IL-33-Induced Eosinophilic Airway Inflammation in Mice

“…Previous studies have shown the regulatory effects of 14(S)-HDoHE on murine platelets and human alveolar macrophages in vitro (43,44). PD1/PDX also possesses potent anti-inflammatory functions in regulating neutrophil activation in vitro (45,46) and ameliorates pulmonary inflammation and fibrosis in vivo (47,48).…”

A Pilot Metabolomic Study on Myocardial Injury Caused by Chronic Alcohol Consumption—Alcoholic Cardiomyopathy

“…Similar to arachidonic acid, DHA can also inhibit saturated fatty acid-induced TLR4 activity and reactive oxygen species, thereby inhibiting inflammation [13]. Furthermore, DPA has been widely demonstrated to contribute to inhibition of platelet activation, anti-inflammatory effects, blood lipid improvement, and cardiovascular protective effects [14][15][16][17]. Conversely, prostaglandins, metabolites of arachidonic acid, have been widely proven to have proinflammatory effects [18].…”

Encapsulation of Docosahexaenoic Acid Oil Substantially Improves the Oxylipin Profile of Rat Tissues

“…Blood concentration was enhanced in pathological conditions such as morbid obesity ( 63 ) or metabolic syndrome ( 61 ), whereas the local level of 14-HDoHE was usually reduced in inflammatory conditions such as in arthritis ( 64 ), periodontitis ( 65 ), or pulmonary inflammation ( 66 ). 14-HDoHE was shown to be involved in the resolution of inflammation, to participate in the immune response or the platelet activation in reducing thrombus formation ( 67 , 68 ). If the mechanism of action of 14-HDoHE still remains unclear, a cerebral increase in 14-HDoHE may be a good marker to prevent potent neuroinflammation.…”