MyD88 mediated inflammatory signaling leads to CaMKII oxidation, cardiac hypertrophy and death after myocardial infarction.
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.
Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA. madhu-singh@uiowa.edu
Madhu V
MV
Singh
Paari D
PD
Swaminathan
Elizabeth D
ED
Luczak
W
W
Kutschke
Robert M
RM
Weiss
Mark E
ME
Anderson
D000818:Animals; D017209:Apoptosis; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D006332:Cardiomegaly / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D011415:Complement Factor B / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009203:Myocardial Infarction / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration; D010084:Oxidation-Reduction; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D011415:Complement Factor B