MOLECULAR MECHANISMS OF ANEURYSMAL DEGENERATION

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DESCRIPTION: (Adapted from investigator's abstract) Abdominal aortic aneurysms (AAA) are an increasingly important vascular disorder caused by structural degeneration of the elastic media. The factors regulating degradation and repair of elastic fibers during various phases of this disease process are unknown. Chronic inflammation and increased production of elastolytic matrix metalloproteinases (MMP's) are characteristic of established AAA, and in particular, the expression of 92-kD gelatinase by aneurysm-infiltrating macrophages. Reflecting the human disease, 92-kD gelatinase is increased in an experimental rat model of AAA which, as well, reproduces tissue remodeling events seen in human AAA. The purpose of this proposal is to elucidate the cellular and molecular mechanisms underlying the development, progressive expansion, and rupture of AAA by testing the hypothesis that elastase-induced AAA in the rat are caused by increased expression of elastolytic MMPs and that MMP-mediated elastin degradation exceeds connective tissue repair. We will focus on the expression of 92-kD gelatinase by mononuclear phagocytes during each phase of experimental aneurysmal degeneration, how this MMP is regulated in vivo, and the consequences of blocking its action pharmacologically. We will also examine the role played by elastin fiber repair towards counteracting the effects of proteolytic elastin degradation. Finally, we will determine the relationship between hypertension and increased expansion of AAA vis a vis the expression of elastolytic MMPs and proteins involved in connective tissue repair. Ascertaining the molecular mechanisms responsible for aneurysmal degeneration will facilitate the development of novel therapeutic strategies for this common disease process.