Virus-Encoded Serine Proteinase Inhibitor SERP-1 Inhibits Atherosclerotic Plaque Development After Balloon Angioplasty

Abstract

Purified SERP-1, a virus-encoded secreted glycoprotein, reduces plaque growth after primary balloon-mediated injury. Plaque development is decreased by inhibition of serine proteinase activity and is associated with a focal reduction in macrophage infiltration immediately after injury. Investigation of serine proteinase inhibitors may provide new insight into the regulation of arterial responses to injury.

Serine Protease Inhibitor Serp-1 Strongly Impairs Atherosclerotic Lesion Formation and Induces a Stable Plaque Phenotype in ApoE −/− Mice

“…The murine macrophage cell line RAW 264.7 showed no increase in apoptosis of these cells on exposure to Serp-1, indicating that the decrease in macrophage content in the lesions cannot be explained by apoptosis of macrophages in the plaque, but may be caused by an impaired monocyte influx. A similar inhibitory effect of Serp-1 on monocyte infiltration was reported by Lucas et al 24 To elucidate the effect of Serp-1 on lesion progression and development, the effect of Serp-1 on advanced lesions was determined by initiating Serp-1 treatment 5 weeks after collar placement. Plaque size and morphology analysis showed an almost 30% decrease in plaque size and a significant 3-fold increase in lumen size.…”

“…Carotid atherosclerotic lesions were induced by perivascular collar placement as described by von der Thüsen et al 28 Mice were anesthetized by subcutaneous injection of ketamine (60 mg/kg; Eurovet Animal Health), fentanyl citrate and fluanisone (1.26 mg/kg and 2 mg/kg, respectively; Janssen Animal Health). Sterile osmotic pumps (Alzet, type 2004, Durect Corporation) containing 0.2 mol/L endotoxin-free Serp-1 in 0.9% saline (2.0 g/kg per day) 24 were placed subcutaneously using isoflurane anesthesia 1 week after collar placement. Two pumps were filled with 125 I-Serp-1 (Iodogen method, 0.2 pmol/L, 0.34 cpm/ng) in order to measure plasma levels.…”

“…18 -21 It has been found to inhibit a range of proinflammatory proteases that are considered to be involved in atherogenesis, including urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), plasmin, and Xa. 22,23 Infusion of Serp-1 protein has been reported to attenuate postangioplasty plaque formation 24,25 and transplant vasculopathy [25][26][27] in a variety of animal models. Its effect on atherosclerosis remains uncharted, however, as the experience gained with PAI-1 implies that data obtained from endothelial injury experiments cannot necessarily be extrapolated to a beneficial effect in de novo atherogenesis.…”

Extracellular Proteases in Atherosclerosis and Restenosis

“…Protease contribution is also supported by studies in which MMP inhibitors slow smooth muscle cell chemotaxis and invasion through reconstituted basement membranes. 62 Serine protease inhibitors such Serp-1 inhibit de novo carotid artery plaque growth in apolipoprotein E Ϫ/Ϫ mice 52 and after balloon injury, 63 mainly by a striking reduction in macrophage infiltration. Similarly, PAI-1 64 inhibits the invasion of human monocytes into interstitial tissue.…”

Gene expression profile during acute rejection in rat-to-mouse concordant cardiac xenograft by means of DNA microarray

“…Serine proteinase inhibitor (SERP-I) has been shown to interact with the thrombolytic cascade, and thereby reduce proteolysis, chemotaxis and adhesion [I I]. In a balloon-injury model of rabbit aorta, a single dose of SERP-I significantly decreased the amount of early (24-h) mononuclear cell infiltration and late intima hyperplasia 30 days post-injury [12]. These reports indicate that the SERP-1 gene expression does not have a deleterious effect on DXR but does ameliorate DXR.…”