Grant Abstract: Role of 12-lipoxygenase in platelet reactivity and type 2 diabetes mellitus

Grant Number: 5R01HL114405-05
PI Name: Holinstat
Project Title: Role of 12-lipoxygenase in platelet reactivity and type 2 diabetes mellitus

Abstract: 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.

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