Viral-Derived Serp-1 as an Adjunctive Therapy for Percutaneous Coronary Intervention

Abstract

The story of Serp-1 began in 1859 when Thomas Austin imported 24 European rabbits to Australia and released them into the wild for sport. Within 30 years, the rabbits had multiplied exponentially until the population reached into the millions and they had decimated the landscape. Nearly a century later, when other methods of population control had failed, the Australians acquired the myxoma virus from South America and introduced it into the rabbit population. This species-specific virus, which is harmless to humans, infected the rabbits and decreased their numbers by ≈99.9%.1 The key to the success of the myxoma virus in eradicating the rabbit population was its ability to downregulate the rabbit host's immune and inflammatory responses to infection, in part, by synthesizing and secreting Serp-1.2, 3 Years later, it was recognized that the same properties that made Serp-1 devastating for the rabbits could also have therapeutic benefits in human inflammatory disorders. Consequently, viral-derived Serp-1 was purified for experimental testing and, ultimately, clinical use. Article see p 543 Serine protease inhibitors, also known as serpins, comprise up to 10% of plasma proteins and act as regulators of coagulation cascades, fibrinolysis, complement activation, and inflammation.4 Serp-1 is a myxoma virus–derived serpin that regulates endogenous thrombolysis by binding to and inhibiting urokinase- and tissue-type plasminogen activators and plasmin.2, 3, 5, 6 Serp-1 decreases inflammation indirectly by preventing activation of the urokinase-plasminogen activator receptor. This, in turn, inhibits inflammatory cell migration, adhesion to the endothelium, matrix metalloproteinase–mediated invasion of the vessel wall, and proliferation at sites of injury.3, 5, 6 Serp-1 also limits inflammation directly by decreasing monocyte and T-lymphocyte expression of β-integrins, which are necessary for cell-cell and cell–extracellular matrix contact, as well as increasing filamin expression to prevent cell adhesion and …