TY - JOUR
T1 - Transplant vasculopathy
T2 - Viral anti-inflammatory serpin regulation of atherogenesis
AU - Lucas, Alexandra
AU - Dai, Erbin
AU - Liu, Liying
AU - Guan, Haiyan
AU - Nash, Piers
AU - McFadden, Grant
AU - Miller, Leslie
N1 - Funding Information:
This study was funded by grants from the National Cancer Institute of Canada (to GM), the Medical Research Council, and the Heart and Stroke Foundation of Canada (to AL). The authors would like to thank Viron Therapeutics Inc. for the generous research support and Biogen Inc. for providing Serp-1 for the original pilot experiments for the rabbit and swine studies. The authors also thank C. Walton for help with the collating of this manuscript.
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
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U2 - 10.1016/S1053-2498(00)00190-X
DO - 10.1016/S1053-2498(00)00190-X
M3 - Article
C2 - 11077219
AN - SCOPUS:0033763829
SN - 1053-2498
VL - 19
SP - 1029
EP - 1038
JO - Journal of Heart and Lung Transplantation
JF - Journal of Heart and Lung Transplantation
IS - 11
ER -