VIRUS-ENCODED SERINE PROTEINASE-INHIBITOR SERP-1 INHIBITS ATHEROSCLEROTIC PLAQUE DEVELOPMENT AFTER BALLOON ANGIOPLASTY

Background Recurrent atherosclerotic plaque growth, restenosis, is a s ignificant clinical problem after interventional procedures. Initiatio n of restenosis involves activation of inflammatory and thrombotic cas cades, which are regulated by serine proteinase enzymes and inhibitors . We have investigated the use of a viral serine proteinase inhibitor, SERP-1. to reduce plaque development after primary balloon angioplast y. This is the first experimental report of the use of a viral anti-in flammatory protein for the prevention of atherosclerosis. Methods and Results Seventy-four cholesterol-fed rabbits were treated with either local or systemic infusions of SERP-1 protein (or control solutions) a fter balloon-mediated injury. Sites of SERF-1 infusion in rabbits had dramatically reduced plaque compared with control infusions at the 4-w eek follow-up. At low-dose infusions (30 to 300 pg), only the primary infusion site had a demonstrable decrease in plaque, whereas at higher -dose infusions (>3000 pg), a generalized reduction in plaque developm ent was detected. An associated decrease in mononuclear cell infiltrat ion of the arterial wail was detected after SERF-1 infusion within the first 24 hours. Infusion of an active-site mutant of SERP-1 (P-1-P-1' , ala-ala) lacking serine proteinase inhibitory activity failed to pre vent plaque growth. Conclusions Purified SERP-1, a virus-encoded secre ted glycoprotein, reduces plaque growth after primary balloon-mediated injury. Plaque development is decreased by inhibition of serine prote inase activity and is associated with a focal reduction in macrophage infiltration immediately after injury. Investigation of serine protein ase inhibitors may provide new insight into the regulation of arterial responses to injury.