12‐LOX Oxylipins Derived from Omega‐3 Supplementation with Docosahexanoic Acid Potently Regulate Human Blood Platelets

Abstract

Cardiovascular disease (CVD) is the leading cause of mortality in the United States in both men and women. Thrombotic‐associated ischemic injuries due to excessive platelet activation are largely responsible for the high level of death associated with CVD. Therapies that seek to pharmacologically inhibit platelet activation, aggregation, or clot stabilization, have the potential to reduce the high mortality rates associated with CVD but are also associated with an increased risk of bleeding. The oxygenated products of polyunsaturated fatty acids—oxylipins—have been shown to be critical regulators of platelet function. Previously, it has been shown that Docosahexanoic Acid (DHA) has antiplatelet activity; therefore, we hypothesize that DHA regulates platelet function at least in part through its 12‐lipoxygenase (12‐LOX) metabolites, 11‐ and 14‐ hydroxydocosahexaenoic acid (11‐ and 14‐HDHA). Our study sought to investigate the role that 12‐LOX derived products of DHA, 11‐ and 14‐ HDHA, have on human blood platelet aggregation and activation. Platelet aggregation, granule secretion, and integrin αIIbβ3 activation were measured following agonist stimulation in the presence of DHA, 11‐ or 14‐ HDHA. Both 11‐ and 14‐ HDHA were observed to dose‐dependently attenuate aggregation in response to sub‐maximal concentrations of either thrombin or collagen. Additionally, both 11‐ and 14‐ HDHA were observed to attenuate intracellular signaling as demonstrated by a decrease in granule secretion in platelets treated with DHA compared to vehicle control treated platelets. To further the study, the effects of DHA supplementation in vivo were investigated in wild‐type mice as well as mice lacking 12‐LOX. DHA was found to play an important role in regulation of platelet function in vivo. Future studies will help to elucidate the mechanism by which DHA and its metabolites inhibit platelet function and play a role in supplementation‐dependent regulation of blood clotting. Once completed this will be the first study to clearly define a role for DHA and its 12‐LOX metabolites in the regulation of platelet aggregation and give important insight into the benefits and risks of fish oil supplementation on the cardiovascular system.Support or Funding InformationThis work was funded in part through the National Institutes of Health grants R01 GM105671 (MH), R01 HL114405 (MH), R01 MD007880 (MH)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.