Abstract 12536: A Novel Toll-Like Receptor 9 Signaling in Cardiomyocytes
Background- An emerging concept in the field of innate immunity is the “danger model”, in which antigen-presenting cells are activated by molecules, including DNA, released from injured self cells. Recent research has demonstrated the importance of Toll-like receptors (TLRs) in non-infectious insults i.e. ischemia in various tissues. Although it is not surprising that TLRs are widely distributed in immune cells, their expression has also been found in non-immune cells including cardiomyocytes. However, the roles and signaling pathways of TLRs in cardiomyocytes remain largely unknown.
Methods and Results- Stimulation of TLR9 signaling by administration of CpG oligodeoxynucleotide (a synthetic TLR9 ligand) induced negative inotropic effects in ex-vivo Langendorff-perfused wild-type mice hearts within 30 minutes. HPLC analysis of collected hearts at the end of perfusion showed marked decreases in creatine phosphate and ATP (both of which are key energy sources for cardiomyocytes), an increase in the AMP/ ATP ratio, and marked activation of AMP-activated protein kinase (AMPK). These effects were totally diminished in TLR9 knockout mice. Treatment with CpG oligodeoxynucleotide induced activation of AMPK in rat primary neonatal cardiomyocytes but not in primary cardiac fibroblasts, strongly supporting the TLR9-induced AMPK activation occurred specifically in cardiomyocytes. Of note, TLR9 stimulation protected cultured neonatal cardiomyocytes against hypoxic insult in an AMPK-dependent manner, without activating NFκB or MAPK, while this canonical TLR signaling was activated in macrophages without AMPK activation. In addition, TLR9-mediated AMPK activation in cardiomyocytes was not affected by dsRNA-mediated knockdown of MyD88 that is the key player in canonical TLR signaling. These results collectively indicate that TLR9-mediated signaling in cardiomyocytes is distinct from the canonical TLRs signaling that has been well characterized in immune cells.
Conclusion- These data suggest that the same ligand-receptor system involving TLR9 concomitantly activates the self-protection mechanism in cardiomyocytes by modulating energy metabolism, while on the other hand inducing an inflammatory response by immune cells.
- © 2011 by American Heart Association, Inc.