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

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• 作者：Madhu V. Singh^a ; ^{madhu-singh@uiowa.edu} ; Paari D. Swaminathan^a ; Elizabeth D. Luczak^a ; W. Kutschke^a ; Robert M. Weiss^a ; Mark E. Anderson^a ; ^b ; ^{mark-e-anderson@uiowa.edu}
• 关键词：Myocardiial infarction ; Hypertrophy ; Inflammation ; Oxidant stress ; CaMKII ; Innate immunity
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2012
• 期刊代码：171_00222828
• 类别：bio
• 出版时间：May, 2012
• 卷：52
• 期：5
• 页码：1135-1144
• 文件大小：1218 K

摘要

The toll-like receptors (TLR) and myocardial infarction (MI) promote NF-魏B-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-魏B-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^{鈭?鈭?/sup> hearts that are defective in MyD88-dependent TLR signaling. In post-MI WT hearts expression of pro-inflammatory genes TNF-伪 (Tnfa), complement factor B (Cfb), myocyte death and fibrosis were significantly increased, but increases were significantly less in MyD88鈭?鈭?/sup> hearts after MI. MyD88鈭?鈭?/sup> cardiomyocytes were defective in NF-魏B activation by LPS but not by the MyD88-independent TLR agonist poly(I:C). In contrast, TNF-伪 induced Cfb gene expression was not deficient in MyD88鈭?鈭?/sup> cardiomyocytes. Several hypertrophy marker genes were upregulated in both WT and MyD88鈭?鈭?/sup> hearts after MI, but Acta1 was significantly attenuated in MyD88鈭?鈭?/sup> 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鈭?鈭?/sup> 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.}