ArticleThe Journal of biological chemistry2018
Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 34 citations in OpenAlex.
- Dietary Protein Restriction Ameliorates Cardiac Inflammaging via AMPK-ULK1-Mediated Mitochondrial Quality Control.Aging cell · 2026Article
- FOXO1-NMNAT3 axis dysregulation promotes doxorubicin cardiotoxicity: NADRedox report : communications in free radical research · 2025Article
- SIRT2 attenuates stress-induced skeletal muscle atrophy by inhibiting glucocorticoid receptor signalling.bioRxiv : the preprint server for biology · 2025Article
- Review
- Identification of AS1842856 as a novel small-molecule GSK3α/β inhibitor against Tauopathy by accelerating GSK3α/β exocytosis.Aging cell · 2025Article
- Cardioprotective mechanism of Qixuan Yijianing formula in Graves' disease mice using miRNA sequencing approach.Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan · 2024Article
- The role of cardiac resident macrophage in cardiac aging.Aging cell · 2023Review
- Article
- KLF9 deficiency protects the heart from inflammatory injury triggered by myocardial infarction.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2023Article
- FOXO1 regulates NLRP3 inflammasome proteins in LPS-induced cardiotoxicity.American journal of translational research · 2023Article
- FOXO transcription factors as therapeutic targets in human diseases.Trends in pharmacological sciences · 2022Review
- Sirtuin 6 inhibition protects against glucocorticoid-induced skeletal muscle atrophy by regulating IGF/PI3K/AKT signaling.Nature communications · 2022Article
- SIRT6 Protects Against Myocardial Ischemia-Reperfusion Injury by Attenuating Aging-Related CHMP2B Accumulation.Journal of cardiovascular translational research · 2022Article
- Effect of Long-Term Supplementation with Acetic Acid on the Skeletal Muscle of Aging Sprague Dawley Rats.International journal of molecular sciences · 2022Article
- NOX1 promotes myocardial fibrosis and cardiac dysfunctionFrontiers in pharmacology · 2022Article
- Identification and Verification of Feature Biomarkers Associated With Immune Cells in Dilated Cardiomyopathy by Bioinformatics Analysis.Frontiers in genetics · 2022Article
- Cardiomyocyte Atrophy, an Underestimated Contributor in Doxorubicin-Induced Cardiotoxicity.Frontiers in cardiovascular medicine · 2022Review
- Ventricular TLR4 Levels Abrogate TLR2-Mediated Adverse Cardiac Remodeling upon Pressure Overload in Mice.International journal of molecular sciences · 2021Article
- Article
- Organ-differential Roles of Akt/FoxOs Axis as a Key Metabolic Modulator during Aging.Aging and disease · 2021Review
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Authors and funding
18 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 FoxO 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 contractile 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.
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