Type 2 diabetes (T2DM), designated as a cardiovascular risk factor by the ADA and AHA, is a growing problem in our society. Platelet activation plays a crucial role in clot formation in the vessel wall and anti- platelet therapy benefits individuals with cardiovascular risks including T2DM. Platelet activation is increased during the progression of T2DM and is of significant concern to postmenopausal women with T2DM as they are more prone to thrombosis, MI, and stroke. To better treat cardiovascular morbidity and mortality in T2DM, novel therapeutic approaches are warranted to inhibit platelet activation. Additionally, dietary fatty acids may play a role in this regulatory process as variabiity in fatty acid intake has been shown to mediate changes in hemostatic function. Fatty acids are regulated in part by 12-lipoxygenase (12-LOX) and our recent work has suggested inhibiting 12-LOX may be one approach to limiting platelet activity. While 12-LOX has been reported to exhibit both pro and anti-thrombotic effects, we have recently shown that 12-LOX can oxidize a number of free fatty acids, including the omega-3 (omega-3) and omega-6 fatty acids, which function to negatively regulate platelet reactivity and inhibit platelet activation. Therefore we hypothesize that fatty acid regulation by 12-LOX or direct inhibition of 12-LOX may be alternative mechanisms by which platelet reactivity can be controlled. 12-LOX regulation of omega-3 and omega-6 fatty acids in T2DM may present a novel approach for attenuating platelet activation in these patients. Therefore, the mechanism of 12-LOX metabolite regulation in platelets and their potential benefit in protection against thrombosis in T2DM will be investigated. We will 1) characterize the mechanism of platelet activation by fatty acids and their 12-LOX metabolites. Differences in fatty acid content metabolite formation in T2DM relative to healthy subjects may explain why their platelets are hyperactive and prone to clotting and thrombosis. We will also 2) determine if fatty acid supplementation or in vivo inhibition of 12-LOX is protective against platelet activation. Using a 12-LOX knockout mouse model, we will identify if altering the fatty acid content in the platelet or inhibiting 12-LOX activation in wildtype mice is protective against platelet activation, thrombosis, and vessel occlusion. Finally, we will 3) determine the potential clinical benefit of fatty acid supplementation as an approach to regulate platelet activation in postmenopausal women with T2DM. In this clinical study, T2DM patients will be supplemented with either ?-3 fatty acid, ?-6 fatty acid, or a placebo, for 60 days and platelet reactivity and 12-LOX metabolite formation will be assessed in order to determine if fatty acid supplementation can act as a viable anti-platelet approach in T2DM. This study will delineate the role of fatty acids in 12-LOX-mediated eicosanoid formation and protection against platelet activation. It will also determine which dietary fatty acid supplements may directly benefit T2DM patients through inhibition of unwanted platelet activation. Finally, this study will give significant insight into alternative approaches such as 12-LOX inhibition in order to regulate platelet activity in the growing T2DM population.

Public Health Relevance

Fatty acid content in the platelet is regulated by dietary intake of fatty acids including Omega-3 and Omega-6. 12-lipoxygenase (12-LOX) oxidizes fatty acids resulting in the formation of bioactive metabolites which regulate platelet activation and clot formation. In T2DM, altering the fatty acid content or inhibiting 12-LOX function may help prevent platelet activation, clot formation, and stroke.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
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Sarkar, Rita
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Thomas Jefferson University
Internal Medicine/Medicine
Schools of Medicine
United States
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Tourdot, Benjamin E; Stoveken, Hannah; Trumbo, Derek et al. (2018) Genetic Variant in Human PAR (Protease-Activated Receptor) 4 Enhances Thrombus Formation Resulting in Resistance to Antiplatelet Therapeutics. Arterioscler Thromb Vasc Biol 38:1632-1643
Holinstat, Michael (2018) New LINE(s) of Evidence for Genetic Regulation of Platelets. Arterioscler Thromb Vasc Biol 38:690-691
Adili, Reheman; Hawley, Megan; Holinstat, Michael (2018) Regulation of platelet function and thrombosis by omega-3 and omega-6 polyunsaturated fatty acids. Prostaglandins Other Lipid Mediat 139:10-18
Tilburg, Julia; Adili, Reheman; Nair, Thankam S et al. (2018) Characterization of hemostasis in mice lacking the novel thrombosis susceptibility gene Slc44a2. Thromb Res 171:155-159
Janapati, S; Wurtzel, J; Dangelmaier, C et al. (2018) TC21/RRas2 regulates glycoprotein VI-FcR?-mediated platelet activation and thrombus stability. J Thromb Haemost :
Yeung, Jennifer; Li, Wenjie; Holinstat, Michael (2018) Platelet Signaling and Disease: Targeted Therapy for Thrombosis and Other Related Diseases. Pharmacol Rev 70:526-548
Safari, Hanieh; Adili, Reheman; Holinstat, Michael et al. (2018) Modified two-step emulsion solvent evaporation technique for fabricating biodegradable rod-shaped particles in the submicron size range. J Colloid Interface Sci 518:174-183
Adili, Reheman; Tourdot, Benjamin E; Mast, Katherine et al. (2017) First Selective 12-LOX Inhibitor, ML355, Impairs Thrombus Formation and Vessel Occlusion In Vivo With Minimal Effects on Hemostasis. Arterioscler Thromb Vasc Biol 37:1828-1839
Holinstat, Michael (2017) Normal platelet function. Cancer Metastasis Rev 36:195-198
Yeung, Jennifer; Hawley, Megan; Holinstat, Michael (2017) The expansive role of oxylipins on platelet biology. J Mol Med (Berl) 95:575-588

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