Abstract P209: MyD88 Mediated Inflammatory Signaling Involved in Post-MI CaMKII Activation and Cardiac Hypertrophy
Toll-like receptors (TLRs) and calmodulin kinase II (CaMKII) participate in pathological responses to myocardial infarction (MI), including activation of nuclear factor kappa B (NF-κB) transcription and complement factor B expression (Singh JCI 2009). We tested the effect of MyD88 deficiency on the adverse cardiac outcome after MI. MyD88 knock out (MyD88-/-) hearts had significantly reduced hypertrophy, hypertrophic gene expression, and inflammatory gene expression compared to WT control hearts. Cultured cardiomyocytes from expressing MyD88 and a NF-κB reporter demonstrated robust induction of NF-κB upon TLR induction by bacterial lipopolysaccharides (LPS). In contrast, cardiomyocytes from MyD88-/- mice failed to induce NF-κB upon LPS treatment. An alternative MyD88-independent pathway for NF-κB remained functional in WT and MyD88-/- cells. Both LPS treatment and MI increased a Ca2+/calmodulin independet activated form of CaMKII (CaMKIIox) in cultured cardiomyocytes and mouse hearts, respectively. MyD88-/- hearts, however, did not display increased CaMKIIox upon MI. Taken together, we interpret these results to show that: (1) MyD88 participates in MI mediated hypertrophic and inflammatory gene expression, (2) CaMKII enhances NF-kB activation in cardiomyocytes by a MyD88-dependent mechanism, and (3) CaMKIIox plays a role in MyD88 dependent signaling to induce expression of proinflammatory genes in post-MI hearts.
- © 2011 by American Heart Association, Inc.