Circulating Age-related Lipid Mediators in Thrombosis

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DESCRIPTION (provided by applicant): Aging is associated with an increased risk of venous thrombosis, but we do not understand the factors that connect aging to an increasing propensity for pathologic thrombotic events. The oxidative theory of aging has stout support in describing age-related decreases in organ function; it is less apparent that this pro-oxidative state underlies venous thrombotic events associated with aging. Recent appreciation for a role of platelets in these thrombi, a recent understanding of a novel mode of platelet activation, and the presence of agonists in the circulation of aged animals may provide a molecular understanding of age-related changes that promote venous thrombosis. Platelets have stored RNA that encodes tissue factor, and other relevant proteins, and appropriate stimuli causes activation-dependent splicing and translation that reprograms the phenotype of the platelet. One result of this is strong tissue factor expression on platelets, along with phosphatidylserine expression and microparticle shedding. Mitochondrial dysfuction accounts for the latter processes. Aging is associated with a pro-oxidative state, and the primary target of oxidizing radicals are the polyunsaturated fatty acids esterifed in membrane phospholipids. Some phospholipid oxidation products structurally resemble PAF and potently activate all cells of the innate immune system. Others are transported into cells and depolarize mitochondria, initiate caspase dependent apoptosis, and allow phosphatidylserine to be displayed on the cell surface. These agonists are potent, and their formation is unregulated. Resveratrol is an anti-oxidant that additionally protects mitochondria and reduces signaling of atypical platelet receptors. We find oxidized phospholipids in the circulation of aged animals that are PAF receptor agonists and ones that potently depolarize mitochondria. The levels of these rival that of chronic inflammation. We propose to describe these agents, and manipulate their levels in 4 aims: Define age- and gender-related accumulation of circulating thrombotic/depolarizing mediators; Molecularly define the effect of oxidized phospholipids on platelets; Define pro-thrombotic signal transduction events downstream of receptors that reprogram the platelet phenotype; Determine whether resveratrol intervention suppresses age-related venous thrombosis.