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

描述（由申请人提供）：2型糖尿病（T2DM）被美国糖尿病协会（ADA）和美国心脏协会（AHA）认定为心血管危险因素，是一个日益严重的社会问题。血小板活化在血管壁凝块形成中起着至关重要的作用，抗血小板治疗对包括T2DM在内的心血管风险患者有益。在T2DM的进展过程中，血小板活化增加，这对绝经后T2DM妇女来说是一个重要的问题，因为她们更容易发生血栓、心肌梗死和中风。为了更好地治疗2型糖尿病的心血管发病率和死亡率，需要新的治疗方法来抑制血小板活化。此外，膳食脂肪酸可能在这一调节过程中发挥作用，因为脂肪酸摄入量的变化已被证明可以介导止血功能的变化。脂肪酸在一定程度上受12-脂氧合酶（12-LOX）的调节，我们最近的工作表明抑制12-LOX可能是限制血小板活性的一种方法。虽然12-LOX已被报道显示出促血栓和抗血栓作用，但我们最近发现12-LOX可以氧化许多游离脂肪酸，包括ω -3 （ω -3）和ω -6脂肪酸，其功能是负性调节血小板反应性并抑制血小板活化。因此，我们假设通过12-LOX调节脂肪酸或直接抑制12-LOX可能是控制血小板反应性的替代机制。12-LOX调节2型糖尿病患者的omega-3和omega-6脂肪酸可能是一种降低这些患者血小板活化的新方法。因此，我们将研究12-LOX代谢物在血小板中的调节机制及其对T2DM患者血栓形成的潜在保护作用。我们将1)描述脂肪酸及其活化血小板的机制

DESCRIPTION (provided by applicant): 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.