A Lucas1, E Dai, L Liu, H Guan, P Nash, G McFadden, L Miller. 1. Vascular Biology Group, John P. Robarts Research Institute, University of Western Ontario, London, Ontario, Canada. arl@rri.on.ca
Abstract
BACKGROUND: Surgical and ischemic injury to the artery wall initiates vascular wound-healing responses that stimulate atherosclerotic plaque growth. The plasminogen activators have cellular chemotactic, adhesion, and proteolytic activity. Serp-1 is a secreted myxoma virus glycoprotein serpin that binds and inhibits plasminogen activators. We have examined the effects of Serp-1 on plaque growth and inflammatory cell invasion in animal models after balloon injury and after aortic allograft transplant. METHODS: We used histologic analysis to assess 4 animal models of angioplasty-mediated injury and 2 models of aortic allograft transplant for intimal hyperplasia and cellular invasion. We assessed plasminogen activator (uPA and tPA) and inhibitor (PAI-1) expression in rat iliofemoral arteries after balloon injury using Western blot, enzyme activity, and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Plaque growth after balloon injury decreased after Serp-1 treatment in all balloon-injury models tested. Transplant vasculopathy also significantly decreased in 2 rat models of aortic allograft transplant. Infusion of a Serp-1 active site mutant, that lacked plasminogen activator inhibiting activity, did not inhibit plaque growth. Quantitative RT-PCR detected increased transcription of PAI-1 mRNA. Increased PAI-1 protein and enzyme-inhibitory activity was also detected in Serp-1-treated arteries by activity assay and Western blot. CONCLUSIONS: Thrombolytic serpins are central regulatory agents in vascular wound-healing responses. Investigation of the inhibitory mechanisms of viral serpins may provide new insights into atherogenesis.
BACKGROUND: Surgical and ischemic injury to the artery wall initiates vascular wound-healing responses that stimulate atherosclerotic plaque growth. The plasminogen activators have cellular chemotactic, adhesion, and proteolytic activity. Serp-1 is a secreted myxoma virus glycoprotein serpin that binds and inhibits plasminogen activators. We have examined the effects of Serp-1 on plaque growth and inflammatory cell invasion in animal models after balloon injury and after aortic allograft transplant. METHODS: We used histologic analysis to assess 4 animal models of angioplasty-mediated injury and 2 models of aortic allograft transplant for intimal hyperplasia and cellular invasion. We assessed plasminogen activator (uPA and tPA) and inhibitor (PAI-1) expression in rat iliofemoral arteries after balloon injury using Western blot, enzyme activity, and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Plaque growth after balloon injury decreased after Serp-1 treatment in all balloon-injury models tested. Transplant vasculopathy also significantly decreased in 2 rat models of aortic allograft transplant. Infusion of a Serp-1 active site mutant, that lacked plasminogen activator inhibiting activity, did not inhibit plaque growth. Quantitative RT-PCR detected increased transcription of PAI-1 mRNA. Increased PAI-1 protein and enzyme-inhibitory activity was also detected in Serp-1-treated arteries by activity assay and Western blot. CONCLUSIONS: Thrombolytic serpins are central regulatory agents in vascular wound-healing responses. Investigation of the inhibitory mechanisms of viral serpins may provide new insights into atherogenesis.
Authors: Donghang Zheng; Hao Chen; Mee Y Bartee; Jennifer Williams; Jennifer A Davids; David A Lomas; Grant McFadden; Alexandra R Lucas Journal: J Cancer Sci Ther Date: 2013-08-19
Authors: Liqiang Zhang; Jordan R Yaron; Amanda M Tafoya; Sarah E Wallace; Jacquelyn Kilbourne; Shelley Haydel; Kaushal Rege; Grant McFadden; Alexandra R Lucas Journal: J Clin Med Date: 2019-10-04 Impact factor: 4.241