Work

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

Year: 2025

Type: article

Abstract: ABSTRACT 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

Source: The FASEB Journal

DOI: 10.1096/fj.202403133rr