Serpins, the vasculature, and viral therapeutics

Abstract

Serine protease inhibitors, termed serpins, are key regulators of numerous biological pathways that initiate inflammation, coagulation, angiogenesis, apoptosis, extra-cellular matrix composition and complement activation responses. Viruses have encoded serpins to guard themselves from host immune attack. The myxoma virus which infects rabbits secretes a highly potent anti-inflammatory serpin, Serp-1, which targets thrombolytic and thrombotic proteases as a means to fend off coagulation and inflammatory reactions to viral infection. These reactions act as a defense, produced by the host, to counter viral infection and invasion. When infused in animals after vascular injury, Serp-1 elicits exceptional anti-inflammatory activity, whereas the mammalian serpin, plasminogen activator inhibitor-1 (PAI-1), which also targets thrombotic and thrombolytic proteases can induce a pro-thrombotic response. During arterial injury, PAI-1 is highly expressed and increased PAI-1 concentration can result in acute thrombosis after aortic transplant in mouse models. The reactive center loop amino acid sequence is a fingerprint for serpin function and this function is highly sequence specific such that modification in this sequence can markedly alter activity. For instance, the alteration of the serpin reactive site loop P1-P1I amino acid sequence nullified the anti-inflammatory activity of Serp-1 and modification of P2-P7 initiated a pro-inflammatory response with vascular remodeling with aneurysm formation. Furthermore Serp-1 has demonstrated the capacity to utilize a mammalian serine protease receptor, the urokinase-type plasminogen activator receptor (uPAR), to alter cellular signaling in part through the actin binding protein cytoskeletal system (via filamin B). In this review, the molecular mechanisms relating inflammation and coagulation pathways to atherosclerosis and how the viral serpin, Serp-1, modifies these pathways in order to exhibit this profound anti-inflammatory activity without associated adverse thrombosis are discussed. Viral and vascular serpins targeting the thrombolytic cascade represent a potential new and untapped therapeutic resource.

Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL

“…All of these proteins have serine proteinase inhibitor domains. Serine proteinase inhibitors, termed serpins, are key regulators of numerous biological pathways that initiate inflammation, coagulation, apoptosis, angiogenesis, and matrix degradation (46). Moreover, we also detected the thiol proteinase inhibitor kininogen-1 and haptoglobin-related protein.…”

A Randomized Controlled, Phase 2 Trial of the Viral Serpin Serp-1 in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention

“…Serine protease inhibitors, termed serpins, are a widely distributed superfamily of proteinase inhibitors that regulate numerous biological pathways including inflammation, coagulation, angiogenesis, complement activation, and a variety of other responses and represent 2% to 10% of circulating proteins. 1 Serp-1 is a secreted glycoprotein of the serpin superfamily that inhibits tissue and urokinase-type plasminogen activators, plasmin, and factor Xa in vitro. Serp-1 exhibits potent antiinflammatory and antiatherogenic activity in vivo.…”

The Serpintine Solution

“…Serpins are so highly effective that this molecular machinery has been adopted by viruses as well as other pathogens. In some poxvirus infections, serpins confer marked survival advantages, blocking host immune responses against viruses at extraordinarily low yactomolar concentrations [11][12][13].…”

“…Heparin is a glycosaminoglycan, a polysaccharide that increases AT activity 100 fold. This is the basis for the anticlotting action of heparin when used for heart attacks or unstable coronary syndromes, arrhythmias such as atrial fibrillation when used as a bridge to cardioversion to prevent strokes, or when used to treat deep-vein thrombosis and also pulmonary emboli [12,46]. AT has also been used with some promise, albeit variable, for patients with severe sepsis and DIC [47].…”

“…One such serpin, Serp-1, is derived from myxomavirus and when deleted from the virus genome turns a lethal viral infection in European rabbits into a benign infection [11][12][13]. This demonstrates the marked potency of the Serp-1 gene expression as a protection for the virus against the host immune response.…”