Abstract 5555: Plasminogen Activator Inhibitor-1 in Macrophages Prevents Cardiac Remodeling and Improves Left Ventricle Function in PAI-1−/−, ApoE−/− Mice
Introduction: Plasminogen activator inhibitor (PAI-1) plays a critical role in cardiac fibrosis. We have reported that deficiency of PAI-1 in vascular wall or macrophages can initiate vascular remodeling and cardiac fibrosis in (PAI-1−/−, ApoE−/−) double knockout (DKO) mice. However it is unclear whether PAI-1 in macrophages can prevent cardiac remodeling and improves left ventricle function. We assessed the hypothesis that PAI-1 in macrophages prevents cardiac remodeling and improves left ventricle function in DKO mice.
Methods: We administered angiotensin II (Ang II) (600ng/kg/min) to DKO mice and PAI-1 heterozygous (PAI-1+/−, ApoE−/−) mice by using osmotic pump for 2 weeks. After 8 weeks, LV function of hearts of DKO mice (4 months of age) and age-matched PAI-1 heterozygous mice were measured by cardiac echo. LV function (%FS) and LV diastolic diameter (LVDd) were obtained at a time of baseline and 8 weeks after Ang II infusion. To determine the effect of macrophages in development of cardiac remodeling, we transplanted bone marrow (BM) from DKO, ApoE KO, PAI-1 KO and Wild type mice to DKO mice after lethal irradiation. Then we administered same dose Ang II for 2 weeks and after 8 weeks we measured LV function.
Results: The LV function of DKO mice with Ang II was reduced (DKO Baseline: %FS=48.9% vs. DKO + Ang II: %FS=45.0%; P=0.002). LV function of PAI-1 heterozygous mice with Ang II was significantly higher than that of DKO mice with Ang II (Hetero+ Ang II: %FS=48.1%; P=0.01). In comparison with DKO, LV function of DKO mice receiving DKO BM was reduced (DKO + DKO BM + Ang II: %FS=42.9%). But LV function of DKO mice receiving ApoEKO BM and PAI-1 KO BM were not significantly reduced (DKO + ApoEKO BM + Ang II: %FS=48.8%, DKO + PAI-1 KO BM + Ang II: %FS=53.2%). And LV function of DKO mice receiving Wild type BM was better than that of baseline DKO mice (WT BM: %FS=56.2%). LVDd of DKO mice and DKO mice receiving DKO BM with Ang II were significantly larger than other mice.
Conclusions: Ang II causes cardiac remodeling and impairs LV function in DKO mice. PAI-1 and ApoE secretion from macrophages protects cardiac remodeling and improves LV function. PAI-1 may prevent structural disorganization of capillary basement membranes and protect expansion of the heart in PAI-1−/−, ApoE−/− mice.