Transplant vasculopathy: viral anti-inflammatory serpin regulation of 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.
Lucas
A
A
Vascular Biology Group, John P. Robarts Research Institute, University of Western Ontario, London, Ontario, Canada. arl@rri.on.ca
Dai
E
E
Liu
L
L
Guan
H
H
Nash
P
P
McFadden
G
G
Miller
L
L
D000800:Angioplasty, Balloon; D000818:Animals; D001011:Aorta / Q000473:pathology / Q000637:transplantation; D001161:Arteriosclerosis / Q000473:pathology*; D002645:Chickens; D003324:Coronary Artery Disease / Q000473:pathology*; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors*; D011183:Postoperative Complications / Q000473:pathology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D015843:Serpins / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature; D017539:Tunica Intima / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D017540:Tunica Media / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects*
D015843:Serpins; D010960:Plasminogen Activators