Abstract 10402: Activated Protein C Rescues Sepsis-Associated Cardiac Dysfunction and Renal Injury in Aging

Abstract

Introduction: Sepsis is a progressive life-threatening condition in which mortality has been consistently linked to increasing organ dysfunction. We have found that activated protein C (APC) has cytoprotective and anti-inflammatory properties in cardiovascular disease. Whether APC is critical for maintaining systemic homeostasis under sepsis in aging remains unknown. Hypothesis: Administration of recombinant APC ameliorates sepsis-associated renal injury and cardiac dysfunction in aging via EPCR (endothelial cell protein C receptor). Methods: Young (3-6 months) and aged (18-21 months) C57BL/6J wild type (WT), and EPCR point mutation (EPCR R84A/R84A ) knock in C57BL/6J mice were subjected to cecal ligation and puncture (CLP) surgery. APC (0.2 μg/g) was injected (i.p.) 1 hour after CLP surgery and every 24 hours to determine the therapeutic effects of APC on CLP-induced sepsis. Cardiac function was assessed daily via echocardiogram. Results: The Kaplan-Meier survival curve showed that the survival rate of young mice is 90% and of aged mice is 0% on day 7 of post-CLP. Moreover, the spleens were significantly enlarged in both young and aged CLP WT mice. Intriguingly, administration of recombinant APC can keep all young animals' survival and increased survival rate of aged animals to 65% on day 7 of post-CLP. The spleen size of young/aged CLP groups were significantly reduced by APC treatment. However, the beneficial effects of APC on the survival rate and spleen enlargement caused by CLP were abolished in EPCR R84A/R84A mice versus EPCR WT/WT littermates. The renal tubules necrosis score and cardiac dysfunctions caused by CLP were worse in aged versus young mice, but APC treatment significantly rescued CLP-caused renal pathology and cardiac dysfunctions of young/aged mice and the rescuing capacity of APC for both renal pathology and cardiac dysfunctions in aged versus young mice was stronger. In addition, APC treatment reduced circulating inflammatory monocytes and neutrophils during CLP-induced sepsis in young/aged WT but not EPCR R84A/R84A mice Conclusions: Sepsis associated mortality is increased in aging. APC treatment can ameliorate age-related sepsis renal injury and cardiac dysfunctions through receptor EPCR to reduce sepsis related mortality.