Abstract 1715: Plasminogen Activator Inhibitor-1 Provides a Proteinaceous Barrier against Monocyte Migration and Atherosclerosis
Plasminogen activator inhibitor-1 (PAI-1) is a key regulator of the fibrinolytic system and is a predictor of the development of type 2 diabetes mellitus and ischemic cardiovascular events. While PAI-1 deficiency prevents thrombosis and arteriosclerosis, the role of PAI-1 in atherosclerosis is debatable. In fact, there is strong evidence that either PAI-1 deficiency or urokinase overexpression can augment the development of atherosclerosis. We hypothesized that PAI-1 retards the development of atherosclerosis by impairing monocyte migration into arterial wall. We tested this hypothesis in a highly-inflammatory form of experimental atherosclerosis by infusing Ang II (600 ng/kg/min) or saline into apoE−/− and apoE−/−:PAI-1−/−(DKO) mice for 2 weeks. The extent of aortic atherosclerosis and cardiac structure and function were analyzed after an additional 8-week period on regular chow. While none of the Ang II-treated apoE−/− mice (n=14) and only 7% of saline-treated DKO mice (n=13) developed evidence of ischemic injury and/or myocardial infarction (MI), 64% of Ang II-treated DKO mice (n=11, P<0.001) displayed ischemic injury and myocardial fibrosis associated with coronary ostial occlusions. In order to characterize specifically the contribution of macrophage and vascular PAI-1 in atheroprotection, apoE−/− and DKO mice were transplanted with wild-type (WT) (n=7), apoE−/− (n=9), PAI-1−/− (n=10) or DKO (n=9) bone marrow. Although no cardiac injury was detected in apoE−/− mice, ischemic injury and fibrosis were present in 78% of DKO mice that received DKO marrow (p<0.001) compared to 44%, 30% and 14% of DKO mice that received apoE−/−, PAI-1−/− and WT marrow, respectively. Cardiac structural changes correlated inversely with preservation of fractional shortening by echocardiography (p<0.05 by ANOVA). These findings indicate that PAI-1 synthesized either in macrophages or the vascular wall reduces the development of coronary atherosclerosis and cardiac injury. While PAI-1 is viewed as a marker of inflammation, it actually serves as a proteinaceous barrier that retards monocyte infiltration and atherosclerosis. The DKO mouse, lacking both PAI-1 and apoE, provides a new and titratable model of occlusive coronary atherosclerosis and MI.