Journal article
MyD88 mediated inflammatory signaling leads to CaMKII oxidation, cardiac hypertrophy and death after myocardial infarction
Journal of molecular and cellular cardiology, Vol.52(5), pp.1135-1144
05/2012
DOI: 10.1016/j.yjmcc.2012.01.021
PMCID: PMC3327770
PMID: 22326848
Abstract
The toll-like receptors (TLR) and myocardial infarction (MI) promote NF-κB-dependent inflammatory transcription and oxidative injury in myocardium. The multifunctional Ca2+/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.
► MyD88−/− mice have improved post-MI survival. ► MI induces TLR/MyD88 dependent inflammatory gene expression. ► MyD88−/− mice have reduced cardiac hypertrophy and fibrosis. ► MyD88−/− mice have reduced post-MI oxidation-dependent CaMKII activation.
Details
- Title: Subtitle
- MyD88 mediated inflammatory signaling leads to CaMKII oxidation, cardiac hypertrophy and death after myocardial infarction
- Creators
- Madhu V Singh - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAPaari D Swaminathan - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAElizabeth D Luczak - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAW Kutschke - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USARobert M Weiss - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAMark E Anderson - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- Journal of molecular and cellular cardiology, Vol.52(5), pp.1135-1144
- DOI
- 10.1016/j.yjmcc.2012.01.021
- PMID
- 22326848
- PMCID
- PMC3327770
- NLM abbreviation
- J Mol Cell Cardiol
- ISSN
- 0022-2828
- eISSN
- 1095-8584
- Publisher
- Elsevier Ltd
- Language
- English
- Date published
- 05/2012
- Academic Unit
- Cardiovascular Medicine; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984094396802771
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