LOCAL OVEREXPRESSION OF TIMP-1 PREVENTS AORTIC-ANEURYSM DEGENERATION AND RUPTURE IN A RAT MODEL

Although matrix metalloproteinases (MMPs) are expressed in abundance i n arterial aneurysms, their contribution to arterial wall degeneration , dilation, and rupture has not been determined, We investigated MMP f unction in a rat model of aneurysm associated with arterial dilation, elastin loss, medial invasion by mononuclear inflammatory cells, and M MP upregulation. Rupture was correlated with increased gelatinase B (M MP-9) and activated gelatinase A (MMP-2). Syngeneic rat smooth muscle cells retrovirally transfected with tissue inhibitor of matrix metallo proteinases (TIMP)-1 cDNA (LTSN) or with the vector alone as a control (LXSN) were seeded onto the luminal surface of the vessels. The seedi ng of LTSN cells resulted in TIMP-1 local overexpression. The seeding with LTSN cells, but not LXSN cells, decreased MMP-9, activated MMP-2 and 28-kD caseinase and elastase activity, preserved elastin in the me dia, and prevented aneurysmal degeneration and rupture. We conclude th at MMP overexpression is responsible for aneurysmal degeneration and r upture in this rat model and that local pharmacological blockade might be a reasonable strategy for controlling the formation of aneurysms i n humans.