Abstract 14454: Myeloid-related Protein Complex 8/14 Aggravates Postischemic Heart Failure
Background: Myeloid-related protein complex 8/14 (MRP8/14) regulates myeloid cell function and controls inflammation through activation of the receptor of advanced glycation endproducts (RAGE) and Toll-like receptors 2/4/9. This study sought to identify the pathophysiological relevance of MRP8/14 in the development and progression of postischemic heart failure (HF).
Methods and Results: Hypoxia led to a time-dependent, sustained induction of cellular and extracellular MRP8/14 accompanied by increased NF-κB binding activity with consecutively sustained TNF-α, IL-6 and TGF-β expression in isolated cardiac fibroblasts, macrophages and cardiomyocytes. Short interference (si) RNA knock-down of MRP8/14 and RAGE in vitro inhibited the expression of these cytokines. In a murine model of post-ischemic heart failure both cardiac RNA and protein levels of MRP8/14 were already elevated 30 minutes after hypoxia and showed a sustained activation up to 28 days after ischemic injury. Treatment of mice with recombinant MRP8/14 resulted in even increased infarction sizes and reduced cardiac performance following I/R injury. 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. Chimera experiments after bone marrow transplantation confirmed the importance of RAGE expression on immune cells for the recruitment of innate immune cells accelerating the development of post-ischemic heart failure. Signaling studies in isolated ventricles demonstrated the involvement of the MAP kinases as well as the nuclear transcription factor NF-κB in ischemic heart failure. 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.
Conclusion: 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.
- © 2010 by American Heart Association, Inc.