TLR4 mutation and HSP60-induced cell death in adult mouse cardiac myocytes
| Autor: | J. P. Heiserman, B. S. Kim, Anne A Knowlton, N. Siebenborn, L. Chen, Se-Chan Kim, A. L. Tran |
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| Rok vydání: | 2015 |
| Předmět: |
Biochemistry & Molecular Biology
medicine.medical_specialty Programmed cell death Necrosis Cells Apoptosis chemical and pharmacologic phenomena Biology Cardiovascular Biochemistry Mitochondrial Proteins Mice Nox2 Internal medicine medicine 2.1 Biological and endogenous factors TLR2 Animals Point Mutation Myocyte Myocytes Cardiac TLR4 Aetiology Receptor Cells Cultured Myocytes Original Paper Mice Inbred C3H Cultured Cardiac myocyte Chaperonin 60 Cell Biology Inbred C3H Molecular biology Cell Hypoxia Toll-Like Receptor 4 Heart Disease Endocrinology Hypoxia/reoxygenation lipids (amino acids peptides and proteins) Biochemistry and Cell Biology medicine.symptom Cardiac HSP60 |
| Zdroj: | Cell stress & chaperones, vol 20, iss 3 |
| ISSN: | 1466-1268 1355-8145 |
| DOI: | 10.1007/s12192-015-0577-0 |
| Popis: | Extracellular (ex) HSP60 is increasingly recognized as an agent of cell injury. Previously, we reported that low endotoxin exHSP60 causes cardiac myocyte apoptosis. Our findings supported a role for Toll-like receptor (TLR) 4 in HSP60 mediated apoptosis. To further investigate the involvement of TLR4 in cardiac injury, we studied adult cardiac myocytes from C3H/HeJ (HeJ) mice, which have a mutant, nonfunctional TLR4, and compared the results with parallel studies using wild-type (WT) mice. Nuclear factor κB (NFκB) activation is an early step downstream of TLR4. NFκB was activated 1h after treatment with HSP60 in WT, but not HeJ mouse myocytes. ExHSP60 caused apoptosis in cardiac myocytes from WT mice, but not in myocytes from the HeJ mutants. To further elucidate the importance of exHSP60 in cardiac myocyte injury, both WT and HeJ mutant isolated mouse adult cardiac myocytes were exposed to hypoxia/reoxygenation. Anti-HSP60 antibody treatment reduced apoptosis in the WT group, but had no effect on the HeJ mutant myocytes. Unexpectedly, necrosis was also decreased in the HeJ mutants. Necrosis after hypoxia/reoxygenation in WT cardiac myocytes was mediated in part by TLR2 and TLR4 through rapid activation of PKCα, followed by increased expression of Nox2, and this was ameliorated by blocking antibodies to TLR2/4. These studies provide further evidence that TLR4 mediates exHSP60-associated apoptosis and that exHSP60 has an important role in cardiac myocyte injury, both apoptotic and necrotic. |
| Databáze: | OpenAIRE |
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