Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

Abstract

Toll-like receptors (TLRs) are a family of patternrecognition 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 agingassociated changes in structure and function of TLR2-deficient mice hearts. Whereas young TLR2-KO mice did not develop marked cardiac dysfunction, 8-and 12-months-old TLR2-KO mice exhibited spontaneous adverse cardiac remodeling and cardiac dysfunction in an age-dependent manner. The hearts of the 8-monthsold 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 atrophyrelated 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 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 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.

The long noncoding RNA XIST regulates cardiac hypertrophy by targeting miR‐101

“…TLR2 is a member of the TLR family and is expressed not only in immune cells but also in nonimmune cells, including cardiomyocytes, fibroblasts, and vascular endothelial cells (Bagchi et al, 2017;Spurthi et al, 2018). TLR2 plays a central role in the pathogenesis of diverse heart disorders and there are various reports indicating that TLR2 is involved in stress responses under pathological conditions (Bagchi et al, 2017;Trentin-Sonoda et al, 2015;Wang et al, 2017).…”

TMEM135 is a Novel Regulator of Mitochondrial Dynamics and Physiology with Implications for Human Health Conditions

“…C. elegans studies revealed that TMEM135 could also regulate Forkhead box O (FOXO), FoxO, expression [ 11 , 84 ]. Elevated nuclear expression of FoxO and its target genes can contribute to muscle wasting and cell death [ 84 ].…”

“…C. elegans studies revealed that TMEM135 could also regulate Forkhead box O (FOXO), FoxO, expression [ 11 , 84 ]. Elevated nuclear expression of FoxO and its target genes can contribute to muscle wasting and cell death [ 84 ]. FoxO transcription factors can also contribute to cardiac growth, cardiac remodeling, and cardiac phenotypes in laminopathies, diabetic cardiomyopathy, and ischemia-reperfusion injury [ 16 , 17 , 18 ].…”

Resident macrophages as potential therapeutic targets for cardiac ageing and injury

“…22,23 Recent studies have further shown that TLR2 signalling is important for preventing the heart from ageing-associated adverse remodelling and contractile dysfunction as TLR2 À/À reduces the CRMs and impairs Akt signalling in the heart. 24 However, the precise effects of various CRM subsets and their renewal on cardiac ageing need to be further investigated.…”