Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice
| Autor: | Aishwarya Raghuraman, S. V. N. Rao, Sangeeta Maity, Shamik Majumdar, Perumal Arumugam Desingu, Aditi Jain, Mohsen Sarikhani, S.A. Kumar, Kondapalli Mrudula Spurthi, Danish Khan, Sneha Mishra, Nagalingam R. Sundaresan, Rosa J. Samuel, Shikha Yadav, Ishwar Singh, Ankit Kumar Tamta, Dipankar Nandi, S. G. Ramachandra |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Aging Heart Diseases FOXO1 030204 cardiovascular system & hematology Biochemistry 03 medical and health sciences Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine Internal medicine medicine Animals Myocytes Cardiac Receptor Molecular Biology PI3K/AKT/mTOR pathway Cells Cultured Microbiology & Cell Biology Mice Knockout Cardiotoxicity Toll-like receptor Akt/PKB signaling pathway business.industry Forkhead Box Protein O1 Macrophages Molecular Bases of Disease Cell Biology medicine.disease Toll-Like Receptor 2 Mice Inbred C57BL 030104 developmental biology Endocrinology Gene Expression Regulation Heart failure Signal transduction business Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 293(34) |
| ISSN: | 1083-351X |
| Popis: | Toll-like receptors (TLRs) are a family of pattern-recognition receptors involved in innate immunity. Previous studies have shown that TLR2 inhibition protects the heart from acute stress, including myocardial infarction and doxorubicin-induced cardiotoxicity in animal models. However, the role of TLR2 in the development of aging-associated heart failure is not known. In this work, we studied aging-associated changes in structure and function of TLR2-deficient mice hearts. Whereas young TLR2-KO mice did not develop marked cardiac dysfunction, 8- and 12-month-old TLR2-KO mice exhibited spontaneous adverse cardiac remodeling and cardiac dysfunction in an age-dependent manner. The hearts of the 8-month-old TLR2-KO mice had increased fibrosis, cell death, and reactivation of fetal genes. Moreover, TLR2-KO hearts displayed reduced infiltration by macrophages, increased numbers of myofibroblasts and atrophic cardiomyocytes, and higher levels of the atrophy-related ubiquitin ligases MuRF-1 and atrogin-1. Mechanistically, TLR2 deficiency impaired the PI3K/Akt signaling pathway, leading to hyperactivation of the transcription factor Forkhead box protein O1 (FoxO1) and, in turn, to elevated expression of FoxO1 target genes involved in the regulation of muscle wasting and cell death. AS1842856-mediated chemical inhibition of FoxO1 reduced the expression of the atrophy-related ubiquitin ligases and significantly reversed the adverse cardiac remodeling while improving the contrastile functions in the TLR2-KO mice. Interestingly, TLR2 levels decreased in hearts of older mice, and the activation of TLR1/2 signaling improved cardiac functions in these mice. These findings suggest that TLR2 signaling is essential for protecting the heart against aging-associated adverse remodeling and contractile dysfunction in mice. |
| Databáze: | OpenAIRE |
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