In this proposal, we postulate that expression and shedding of the heparan sulfate proteoglycan syndecan-1 may provide an important mechanism that inhibits abdominal aortic aneurysm (AAA) formation by limiting proteolytic or inflammatory activity and by promoting local reparative responses. In particular, we speculate that macrophage syndecan-1 shed in response to pro-inflammatory stimuli, such as elevated local mechanical stress or oxidized lipids, will preferentially bind and effectively sequester chemokines and proteases relevant to AAA formation. Specifically, we intend to: (1) determine the capacity of arterial wall mechanics and oxidized lipids, both as isolated and interactive factors, to modulate syndecan-1 expression during the course of AAA formation. The expression of syndecan-1 will be characterized in both angiotensin-associated and elastase-induced murine models of AAA formation. Moreover, the capacity of mechanical stress and oxidized lipids to modulate macrophage syndecan-1 expression will be defined in vitro. (2) Characterize the signal transduction pathways activated by mechanical stress and/or oxidized lipids that converge in regulating macrophage syndecan-1 expression and shedding. The extent to which redox-sensitive and insensitive MAP kinase signaling pathways converge in regulating macrophage syndecan-1 expression and shedding will be determined. In addition, the role of metalloproteinases as primary mediators of accelerated syndecan-1 shedding in macrophages will be determined. (3) Elucidate the role of syndecan-1 in modulating aneurysm formation and rupture via a regulatory effect on inflammatory and proteolytic responses. To further elucidate the role of macrophage syndecan-1 in AAA formation and rupture, the incidence of these events will be studied using relevant transgenic mice and bone marrow transplantation protocols. In vitro studies will be performed to define the ability of syndecan-1 to bind and inhibit selected chemokines, proteases, or protease inhibitors. (4) Determine the effectiveness of multivalent heparanoid glycodendrimers, as a syndecan-mimetic, in limiting aortic aneurysm formation and growth. The efficacy of heparanoid glycodendrimers to limit the frequency, size, and growth rate of aortic aneurysms will be determined. These data will be correlated with the ability of these compounds to inhibit chemokine and/or protease activity in vitro and in vivo.
The cause of an aortic aneurysm remains poorly understood and successful pharmacotherapy is lacking despite the role of aneurysms as a major source of morbidity and death. The investigations described in this proposal are directed at defining the role of the heparan sulfate proteoglycan, syndecan-1, in regulating aneurysm formation and growth. The molecular mechanisms that regulate this phenomenon will be identified and a potential therapeutic strategy evaluated.
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