Abstract 5396: The Role of the Myeloid-Related Protein 8/14 Complex in Postischemic Heart Failure
The complex formed by two members of the S100 calcium binding protein family, myeloid-related protein complex 8/14 (MRP8/14) exerts pro-inflammatory and pro-apoptotic activity against various cells. Since enhanced MRP8/14 serum levels have recently been associated with acute coronary syndromes (ACS) this study sought to identify the pathophysiological relevance of MRP8/14 in the development and progression of postischemic heart failure (HF). Here we demonstrate that MRP8/14 acts as an early mediator of inflammation and organ damage in I/R injury of the heart via the receptor for advanced glycation end products (RAGE). Wildtype (WT) and RAGE−/− mice were subjected to myocardial infarction by transient ligation of the left anterior descending (LAD) coronary artery and survival, infarction size, cardiac function and remodeling were analyzed up to 4 weeks. Both cardiac RNA and protein levels of MRP8/14 were already elevated 30 minutes after hypoxia in vitro and in ischemic heart with sustained activation up to 28 after ischemic injury. Treatment of mice with recombinant MRP8/14 resulted in increased infarction sizes (70.5±4.5% vs. 57.0±4.3%, n=10, p<0.001) determined after 7 days and reduced cardiac performance in echocardiography after 28 days following I/R injury (18.4±2.1% vs30.6%±3.6, n=10, p<0.001). Moreover treatment with MRP8/14 resulted in an accelerated transition to HF, rapid onset of remodelling and excessive mortality compared to untreated WT-mice with ischemic injury. Signaling studies in isolated ventricles point to the involvement of the MAP kinases JNK, ERK1/2 as well as the nuclear transcription factor NF-κB in ischemic heart failure. Interestingly, infarct size, markers of tissue damage and remodelling were not affected by administration of MRP8/14 in RAGE−/− mice which demonstrated significantly reduced cardiac tissue damage and improved cardiac recovery compared to WT mice. Our novel proof-of- concept study provides evidence that the sustained activation of S100A8/9 critically contributes to the development of postischemic heart failure via RAGE potentially driving the progressive course of patients with HF.