Plasminogen Activator Inhibitor 1 Controls Abdominal Aortic Aneurism Formation via the Modulation of TGF-β/Smad2/3 Signaling in Mice

Given that plasminogen activator inhibitor 1 (PAI-1) plays an important role in human pathobiology and epigallocatechin-3-gallate (EGCG) exerts vasculoprotective actions, we investigated the role(s) of PAI-1 and the protective effect of EGCG in the mechanism of AAA formation, with a focus on inflammation, oxidative stress, proteolysis, and Apoptosis in vivo and in vitro. Nine-week-old wild-type mice (PAI-1^+/+) and PAI-1 deficiency mice (PAI-1^-/-) randomly assigned to the sham operation (0.9% saline) and AAA induction (calcium chloride) and subjected to biological and morphological analysis after four weeks. On operative day 28, the AAA lesions had decreased levels of PAI-1 mRNA and protein. As compared with AAA-PAI-1^+/+ mice, PAI-1 deficiency aggravated AAA formation accompanied by plasma TNF-α and IL-1β elevations. PAI-1^-/- resulted in harmful changes in the levels of gp91^phox, cleaved-caspase 8, TGF-β, p-Smad2/3, Collagen I/III, gp91^phox, ICAM-1, VCAM-1 mRNAs and/or protein in the AAA lesions as well as oxidative stress production and macrophage infiltration. PAI-1^-/- also increased elastin degradation and Collagen accumulation associated with the reduction of proteolytic MMP-2/-9 expressions and activities. While EGCG reversed the above changes and upregulated PAI-1 expression. In vitro, PAI-1 inhibition (silencing and pharmacological inhibitor) and overexpression, respectively, increased and lowered oxidative stress-induced VSMCs Apoptosis and investigated extracellular protein turnover-related protein changes. These results suggested that the protective role of PAI-1 and EGCG in AAA formation is based on their ability to inhibit inflammation, oxidative stress, and Apoptosis. Moreover, EGCG-mediated PAI-1 induction might provide a potential pharmacological treatment for AAA.

abdominal aortic aneurysm; apoptosis; epigallocatechin‐3‐gallate; inflammation; oxidative stress; plasminogen activator inhibitor 1.