Molecular Mechanisms of Aneurysmal Degeneration

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): Abdominal aortic aneurysms (AAAs) are a common and life-threatening condition. The goal of this project is to elucidate cellular and molecular mechanisms responsible for aortic wall degeneration using a mouse model of elastase-induced AAAs previously characterized in our laboratory. This model recapitulates many critical features of human AAAs, including transmural infiltration of the aortic wall by rnononuclear phagocytes, increased local production of proinflammatory cytokines and matrix metalloproteinases (MMPs). and progressive degradation of elastin and collagen. We have shown that targeted deletion of MMP-9 inhibits elastase-induced AAAs with suppression of elastin degradation, whereas AAAs are enhanced in the absence of the endogenous MMP inhibitor, TIMP-1. Because we found even greater enhancement of AAAs in mice lacking both MMP-9 and TIMP-1, more detailed knowledge is needed regarding the in vivo interactions between MMP-9, TIMP-1, and other elastolytic MMPs, and the specific role of MMP-9 in aortic elastin degradation. It is also important to consider if altered susceptibility to AAAs will occur in mice with resistance to collagenase-mediated degradation of interstitial collagen or in mice lacking expression of coilagenase-3 (MMP-13), one of the principal MMP-collagenases. Because we have observed suppression of elastase-induced AAAs in mice with targeted deletion of cathepsin-S (Cst-S), an elastolytic and collagenolytic cysteine protease, the mechanisms by which Cat-S promotes aneurysmal degeneration also need to be defined. These issues will be addressed by accomplishing the following three specific aims: (1) Clarify how MMP-9, TIMP-1 and other elastolytic MMPs influence the development of eiastase-induced AAAs, if MMP-9 is directly responsible for aortic wall elastin degradation in vivo, and if matrilysin (MMP-7) is required for aneurysmal degeneration; (2) Establish if MMP-mediated degradation of interstitial (type I) collagen is required in the development of experimental AAAs and if MMP-13 is essential in this process; and (3) Identify the functionally important cellular sources of Cat-S during the development of elastaseinduced AAAs and the molecular mechanisms by which targeted gene deletion of Cat-S suppresses aneurysmal degeneration. Taken together, these studies will contribute important new information on the mechanisms underlying extracellular matrix degradation in aneurysmal degeneration.