PREVENTION OF ANEURYSM DEVELOPMENT AND RUPTURE BY LOCAL OVEREXPRESSION OF PLASMINOGEN-ACTIVATOR INHIBITOR-1

Background-Arterial aneurysms exhibit a loss of elastin and an increas e in the plasminogen activators urokinase plasminogen activator (u-PA) and tissue plasminogen activator (t-PA). Because u-PA, t-PA, and plas min have a limited proteolytic activity against elastin, the role of p lasminogen activators in the aneurysmal disease is unclear. To investi gate this question, we overexpressed plasminogen activator inhibitor-1 (PAI-1), an inhibitor of t-PA and u-PA, in a rat model of aortic aneu rysm. Methods and Results-Guinea pig-to-rat aortic xenografts were see ded with syngeneic Fischer 344 rat smooth muscle cells retrovirally tr ansduced with the rat PAI-1 gene (LPSN group) or the vector alone (LXS N group). Some grafts were not seeded with cells (NO group). Western b lots showed increased PAI-1 in grafts from the LPSN group compared wit h LXSN and NO groups. All grafts in the NO group (n=8) and 40% in the LXSN group ruptured between days 4 and 14. At 4 weeks in the LXSN grou p, the remaining unruptured grafts (n=6) were aneurysmal (diameter inc rease greater than or equal to 100%), whereas in the LPSN group (n=6) none of the grafts had ruptured or were aneurysmal, Elastin was preser ved in the LPSN group. t-PA, the major PA expressed in the model, was decreased in the LPSN group compared with the other groups, as determi ned by zymography. Quantitative zymography showed decreased levels of two matrix metalloproteinases (MMPs), a 28-kD caseinase, and activated MMP-9 in the LPSN group. Conclusions-The blockade of plasminogen acti vators prevents formation of aneurysms and arterial rupture by inhibit ing MMP activation.