Viral Anti-Inflammatory Proteins Target Diverging Immune Pathways with Converging Effects on Arterial Dilatation, Plaque and Apoptosis

Abstract

Abdominal aortic aneurysms are often fatal due to atherosclerosis, thromboembolism, rupture, and hemorrhage, however, treatment is limited to expectant monitoring and surgical intervention. Inflammation is detected in aneurysms and in plaque with associated increased apoptosis, chemokines, cytokines, hemorrhage, and thrombosis. We compared treatment with three different myxomavirus-derived anti-inflammatory proteins targeting apoptosis, thrombosis, and chemokine pathways. The effect of each protein on aortic dilatation and plaque growth was assessed after angioplasty in Apolipoprotein Enull mice. Four myxomavirus-derived proteins were studied; Serp-1 a serine protease inhibitor (serpin) targeting thrombotic and thrombolytic proteases, Serp-2 a cross-class serpin inhibiting granzyme B and caspases 1 and 8, M-T7 a broad spectrum C, CC, and CXC chemokine inhibitor, and R171E, an inactive M-T7 mutant. Cell invasion, elastin breaks, plaque progression, and aortic dilatation were significantly reduced by Serp-1, Serp-2, or M-T7 protein treatment, but not by R171E. PCR array analysis detected altered expression of a group of shared 40 apoptotic genes in monocytes after treatment with each active protein, but not R171E. Interference with inflammatory cell responses, through highly divergent inflammatory response pathways, produces similar reductions in monocyte invasion, arterial dilatation, and plaque growth potentially through modified expression of apoptotic genes.