Thrombotic complications such as cardiovascular diseases and stroke are a leading cause of morbidity and mortality in our aging population. Despite the strong clinical association between aging and thrombosis, the mechanisms of thrombosis in the elderly are not well understood. In a recent study we demonstrated that aged mice display increased susceptibility to thrombosis. Our findings also revealed that aged mice develop increased intra-platelet hydrogen peroxide (H2O2) levels and platelet hyperactivity (increased integrin aIIb3 activation). Importantly, genetic approaches to eliminate H2O2 prevented platelet hyperactivity in aged mice, suggesting that H2O2 is a critical mediator. Importantly, our pilot studies in human subjects demonstrate that platelets from aged humans exhibit peroxide mediated hyperactivity The objectives of this application are to identify the upstream mechanism leading to accumulation of H2O2 in platelets and to determine whether prevention of H2O2-mediated platelet hyperactivity decreases aging-associated increased thrombotic susceptibility. Our central hypothesis is that aging results in increased arterial and venous thrombotic susceptibility via enhanced platelet activation in a pathway that includes generation of superoxide by a Nox2- containing NADPH oxidase, followed by conversion of superoxide to H2O2 by superoxide dismutase1 (SOD1), leading to H2O2-induced enhancement of platelet activation. The rationale for this hypothesis is that Nox2- containing NADPH oxidase is the major source of platelet reactive oxygen species, and our recent study demonstrated upregulation of NADPH oxidase and SOD1 in platelets from aged mice.
Aim 1 will determine the mechanistic roles of NADPH oxidase and SOD1 in platelet hyperactivation in aging.
Aim 2 will determine whether inhibition of H2O2-mediated platelet hyperactivity is sufficient to decrease thrombotic susceptibility with aging. Studies will utilize a novel mouse model in which endogenous platelets are immunodepleted prior to transfer of platelets from aged or young mice, allowing assessment of the effects of donor platelets on arterial occlusion and venous thrombosis in the absence of potential confounding effects of host platelets.
Aim 3 will evaluate hyperactivity of platelets from aged humans and its thrombotic consequences. Understanding the mechanism by which platelet activation with aging contributes to thrombotic susceptibility has the potential to reveal new therapeutic strategies to minimize vascular decline in the elderly.
Heart attack and stroke due to clot formation in blood vessels are common causes of morbidity and mortality in aging. However, the mechanisms are not well defined. In this proposal we will use genetically engineered mouse models and platelets from aged humans to define how platelets are activated and contribute to clot formation in blood vessels during aging.
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