MOLECULAR MECHANISMS OF ANEURYSMAL DEGENERATION

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (Adapted from Applicant's Abstract): Abdominal aortic aneurysms (AAAs) are a common degenerative disease with life-threatening implications. The purpose of this research program is to better understand the regulation of individual gene products within the aneurysmal aorta and their parthophysiologic implications in disease progression. A novel murine model of elastase-induced aortic injury has been developed that recapitulates many critical features of human AAA, including transmural infiltration of the aortic wall by mononuclear phagocytes, increased local production of matrix metalloproteinases (MMPs), and progressive degradation of aortic wall collagen and elastin. Using this model, it has been shown that mice with targeted gene disruption of MMP-9 exhibit a significant reduction in aneurysmal degeneration. It has also been shown that the treatment with doxycycline reduces aortic wall expression of MMP-9 in patients undergoing elective AAA repair, and that doxycycline suppresses phorbol-stimulated expression of MMP-9 in cultured human THP-1 mononuclear phagocytes. These studies suggest that inflammatory cell production of MMP-9 plays a critical role in the process of aneurysmal degeneration and that treatment with doxycycline has the potential to repress mononuclear phagocyte expression of this enzyme. This project will extend these observations by identifying the critical molecular steps involved in elastase-induced aneurysmal degeneration in the mouse and by elucidating the molecular pathways by which aneurysmal degeneration might be suppressed by MMP-inhibiting tetracyclines. These goals will be accomplished through four specific aims: (1) determine if the generation of biologically-active elastin degradation peptides is responsible for leukocyte recruitment, aortic wall infiltration, and MMP expression during the initiation of elastase-induced AAA; (2) clarify the molecular mechanisms(s) by which targeted deletion of MMP-9 suppresses the development of elastase-induced AAA; (3) establish if urokinase-type plasminogen activator (u-PA) or additional MMPs are required in the development of elastase-induced AAA; and (4) define the molecular mechanism(s) by which doxycycline suppresses PMA-stimulated expression in cultured human THP-1 mononuclear phagocytes, and determine if a reduction in MMP-9 expression can explain the protective effects of doxycycline in vivo. These investigations can be expected to add considerably to our understanding of the molecular mechanisms of aneurysmal degeneration, potentially forming the basis for new treatment strategies.