Abstract P127: A Viral Anti-apoptotic Serpin, Serp-2, Inhibits Plaque Growth in a Mouse Aortic Transplant Model: Inhibition of Transplant Vasculopathy is Granzyme B Dependent
Introduction: Transplant vasculopathy with chronic rejection is a leading cause of transplant loss after the first year post transplant. Innate immune response activation with endothelial dysfunction and Macrophage and T cell invasion drive arterial plaque growth and vessel occlusion. Apoptotic death in endothelial cells induces a pro-thrombotic, and pro-inflammatory state and apoptosis in monocytes and smooth muscle cells increases cytokine release and, potentially, plaque rupture. Poxviruses encode cross-class inhibitory serpins that target granzyme B (serine protease) and caspases 1 and 8 (cysteine proteases) in the apoptotic and inflammasome pathwasy. Serp-2 and CrmA (cytokine response modifier) are viral cross-class inhibitors. CrmA is a more potent inhibitor, binding caspase 1 (interleukin converting enzyme-1β, ICE), caspase 8, and granzyme B (GRNZB), with greater inhibition of inflammation in chicken chorioallantoic membranes, whereas Serp-2 binds ICE and Granzyme B with lower affinity in vitro, but has greater effects on viral virulence in infected rabbits. Prior work has demonstrated reduced vascular inflammation in rat aortic allograft and balloon angioplasty as well as ApoEnull mouse aortic angioplasty and carotid cuff compression models with Serp-2, but not CrmA, treatment. With this study we examine the effects of Serp-2 on aortic transplant vasculopathy development in mice deficient for granzyme B (GRNZB−/−), apolipoprotein E (ApoE−/−), or plasminogen activator inhibitor-1 (PAI-1−/−).
Methods: Donor aorta from
ApoE−/−/GRNZB−/− double knock out,
C57Bl/6 wild type (WT) mice was transplanted into recipient WT Balb/C mice.
Plaque growth was assessed at 28 days follow up after aorta transplant.
Results: 1) Saline treated PAI-1−/− aortic transplant had increased (P=.047) while GRNZB−/− and ApoE−/−/GRNZB−/− transplant had decreased plaque as compared with WT C57BL/6. CrmA increased plaque growth in all models. 3) Serp-2 reduced plaque in PAI-1−/− when compared to CrmA (P=. 038), but not in GRNZB−/−, or ApoE−/−/GRNZB−/− DKO transplants.
Conclusion: Serp-2 but not CrmA treatment significantly reduces plaque growth in a mouse aortic transplant model. Serp-2 inhibition is granzyme B dependent.