MyD88 mediated inflammatory signaling leads to CaMKII oxidation, cardiac hypertrophy and death after myocardial infarction

J Mol Cell Cardiol. 2012 May;52(5):1135-44. doi: 10.1016/j.yjmcc.2012.01.021. Epub 2012 Feb 3.


The toll-like receptors (TLR) and myocardial infarction (MI) promote NF-κB-dependent inflammatory transcription and oxidative injury in myocardium. The multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated by oxidation and contributes to NF-κB-dependent transcription, myocardial hypertrophy and post-MI death. The myeloid differentiation protein 88 (MyD88) is an adapter protein critical for many TLR functions, but downstream targets for TLR/MyD88 signaling in MI are not well understood. We asked if CaMKII and TLR/MyD88 pathways are interconnected and if TLR/MyD88 contributes to adverse outcomes after MI. Here we show that TLR-4 activation by lipopolysaccharide (LPS) induces CaMKII oxidation (ox-CaMKII) in cardiomyocytes. MI enhances ox-CaMKII in wild type (WT) hearts but not in MyD88(-/-) hearts that are defective in MyD88-dependent TLR signaling. In post-MI WT hearts expression of pro-inflammatory genes TNF-α (Tnfa), complement factor B (Cfb), myocyte death and fibrosis were significantly increased, but increases were significantly less in MyD88(-/-) hearts after MI. MyD88(-/-) cardiomyocytes were defective in NF-κB activation by LPS but not by the MyD88-independent TLR agonist poly(I:C). In contrast, TNF-α induced Cfb gene expression was not deficient in MyD88(-/-) cardiomyocytes. Several hypertrophy marker genes were upregulated in both WT and MyD88(-/-) hearts after MI, but Acta1 was significantly attenuated in MyD88(-/-) hearts, suggesting that MyD88 selectively affects expression of hypertrophic genes. Post-MI cardiac hypertrophy, inflammation, apoptosis, ox-CaMKII expression and mortality were significantly reduced in MyD88(-/-) compared to WT littermates. These data suggest that MyD88 contributes to CaMKII oxidation and is important for adverse hypertrophic and inflammatory responses to LPS and MI.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Cardiomegaly / immunology
  • Cardiomegaly / metabolism*
  • Cardiomegaly / pathology
  • Cells, Cultured
  • Complement Factor B / genetics
  • Complement Factor B / metabolism
  • Enzyme Activation
  • Female
  • Fibrosis
  • Gene Expression Regulation
  • Inflammation / genetics
  • Inflammation / metabolism
  • Kaplan-Meier Estimate
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / deficiency
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / physiology*
  • Myocardial Infarction / immunology
  • Myocardial Infarction / metabolism*
  • Myocardial Infarction / pathology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • NF-kappa B / metabolism
  • Neutrophil Infiltration
  • Oxidation-Reduction
  • Signal Transduction*
  • Toll-Like Receptors / metabolism
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism


  • Lipopolysaccharides
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Complement Factor B