Abstract 1194: Plasminogen Activator Inhibitor-1 Provides an Anti-Inflammatory Barrier to Ang II-Induced Aortic Atherosclerosis in Mice
Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of plasminogen activators, and strongly influences vascular integrity, matrix biology, and cellular migration. While increased plasma PAI-1 likely contributes to the development of ischemic cardiovascular events, its role in the pathogenesis of atherosclerosis is uncertain. Depending on the model used, PAI-1 deficiency has been reported to protect against or even promote the development of atherosclerosis. We hypothesized that PAI-1 serves as a proteinaceous barrier against the accumulation of inflammatory cells in the arterial wall and thereby protects against the development of atherosclerosis. We investigated the effects of PAI-1 on angiotensin II (Ang II)-induced aortic atherosclerosis (AA) in apoE−/− mice using both genetic and bone marrow (BM) transplantation approaches. The extent of AA was analyzed after a 2 week infusion period (Ang II 600 ng/kg/min or saline) followed by an 8-week period on regular chow (n=8–12/group). AA lesion was minimal (0.2% of surface area) in saline-treated apoE−/− mice. Lesion area increased 10-fold in Ang II-treated apoE−/− mice (p<0.03), by 11-fold in saline-treated DKO mice (p<0.01) and by nearly 40-fold (p<0.001) in Ang II-treated DKO mice. The specific contribution of macrophage or arterial PAI-1 on lesion development was investigated by transplanting apoE−/−and DKO mice with BM from wild-type (WT), apoE−/−, PAI-1−/− or DKO mice. In apoE−/− mice, WT and PAI-1−/− BM normalized the atherogenic effect of Ang II, while DKO BM was associated with a 15-fold increase in the extent of AA (p<0.02). In DKO mice, transplantation with marrow from either apoE−/− (n=9) and PAI-1−/− mice provided partial protection, while WT marrow provided total protection against Ang II-induced atherosclerosis (p<0.001). These results indicate that complete PAI-1 deficiency is equal to Ang II in promoting the development of atherosclerosis. However, PAI-1 from macrophages or in the vascular wall can provide protection in this Ang II-dependent model of accelerated atherosclerosis. Although excess PAI-1 likely contributes to the development of atherothrombotic events, some PAI-1 appears to be valuable in limiting the development of atherosclerotic lesions.