L61	MMP in aneurysm development.
A.Daugherty, L.Cassis
University of Kentucky, Lexington, US.

Infusion of angiotensin II (AngII) via subcutaneously implanted osmotic pumps into hypercholesterolemic mice (apoE-/- or LDL receptor -/-) results in development of abdominal aortic aneurysms (AAAs). AngII-induced AAAs develop via a complex process. The first cellular change that has been identified is the medial accumulation of macrophages, associated with breaks in the elastin fibers. This proceeds to medial dissection and formation of thrombus, that is usually constrained by the adventitia. An inflammatory process occurs in which the dilated abdominal aorta is characterized by accumulation of macrophages, and T and B lymphocytes. At later stages, a neomedia forms over the dissected region and pronounced atherosclerosis develops in the aneurysmal area. It is likely that proteolysis of the extracellular matrix is responsible for several aspects of the disease. Increased abundance of matrix metalloproteinases (MMP) -2 and -9 have been detected in AngII-induced aneurysmal tissue, although only MMP-2 have been detected in an activated form. To determine the role of MMPs in the development of AngII-induced AAAs, we have administered doxycycline, which is a broad spectrum MMP inhibitor. Doxycycline (~30 mg/kg/day in drinking water) was administered to LDL receptor deficient mice fed a diet enriched in saturated fat. Administration of doxycycline attenuated both the incidence and severity of AngII-induced AAAs. Genetically engineered mice have been used to determine the role of specific MMPs in AngII-induced AAAs. Unexpectedly, deficiency of MMP-9 failed to attenuate the development of AngII-induced AAAs. In contrast, mice with MMP-2 deficiency in bone marrow-derived stem cells had significantly reduced AAA formation. A potential regulator of MMP activity is low density lipoprotein receptor related protein (LRP). Increased expression of LRP decreases activity of MMP-2 and -9 in several cell types via endocytic removal of the protease from the extracellular space. AngII downregulates LRP expression in aorta smooth muscle cells. This occurs in a region specific manner in which the AAA prone abdominal region is downregulated, but not the thoracic region. Overall, enhanced MMP activity has a potential role on many facets of AAA development.

Copyright © 2005 S. Karger AG, Basel. Any further use of this abstract requires written permission from the publisher.