Abstract 5683: Insights From Network Analysis: Deficiency of Glutathione Peroxidase-1 Increases In-stent Stenosis
In-stent stenosis (ISS) is the principal cause of PCI failure. We used a novel genome-wide gene expression network approach in human atherectomy samples (n=89) to identify signaling networks critical to the process of ISS. We found that a subnetwork with glutathione peroxidase-1 (GPx1) as its hub was among the most significantly differentially regulated between de novo atherosclerosis and ISS (Fig 1⇓, bar thickness denotes association strength). We investigated the importance of GPx1 in ISS using a novel model of balloon angioplasty and stenting (BAS) and a knockout mouse with constitutive deficiency of GPx1. Thoracic aortic segments underwent BAS before being grafted onto the carotid artery of isogenic recipients. Groups included donor GPx1-KO mice and their littermate controls (n=5/group). Despite equal stent expansion and injury scores, ISS was increased by 45% (P<0.001) in GPx1-KO mice 28 days following stenting, confirming the observational data from the human studies (Fig 2⇓, white arrows denote neointima). To investigate a mechanism for these findings, we quantified superoxide production (O2-). O2- production was significantly increased in GPx1-KO mice measured on both aortic sections using oxidative confocal microtopography (~2.8-fold, P<0.001) and whole aorta by lucigenin enhanced illuminescence (~2.2-fold, P<0.001). Further, studies aimed at establishing a therapeutic role for the isoflavone genistein in modulating GPx1 activity demonstrated increased enzymatic activity in coronary endothelial cells (~78%, P=0.01). Taken together, these findings establish an important role for GPx1 network signaling in vascular wall redox processes critical to ISS.