| First Author | Singh MV | Year | 2012 |
| Journal | J Mol Cell Cardiol | Volume | 52 |
| Issue | 5 | Pages | 1135-44 |
| PubMed ID | 22326848 | Mgi Jnum | J:318103 |
| Mgi Id | MGI:6858266 | Doi | 10.1016/j.yjmcc.2012.01.021 |
| Citation | Singh MV, et al. (2012) MyD88 mediated inflammatory signaling leads to CaMKII oxidation, cardiac hypertrophy and death after myocardial infarction. J Mol Cell Cardiol 52(5):1135-44 |
| abstractText | The toll-like receptors (TLR) and myocardial infarction (MI) promote NF-kappaB-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-kappaB-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-alpha (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-kappaB activation by LPS but not by the MyD88-independent TLR agonist poly(I:C). In contrast, TNF-alpha 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. |
