Abstract
Background/Aims: Gut microbiota has been reported to correlate with a higher mortality and worse prognosis of cardiovascular diseases. Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite of specific dietary nutrients, which is linked to cardiac fibrosis. Recent reports have suggested that the activation of Nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome contributed to cardiac fibrosis. However, whether TMAO mediates cardiac fibrosis via activating NLRP3 inflammasome remains unclear.Methods and Results: To determine the role of TMAO–mediated cardiac fibrosis, we established mouse models of doxorubicin (DOX)-induced cardiac fibrosis with or without TMAO in drinking water. TMAO exacerbated DOX-induced cardiac dysfunction, heart weight and cardiac fibrosis manifested by enhanced collagen accumulation, higher profibrotic levels and elevated inflammatory factors as well as NLRP3 inflammasome activation. Using primary cultured mouse cardiac fibroblast, our results indicated that TMAO promoted proliferation, migration and collagen secretion in a dose-dependent manner by TGF-β/Smad3 signaling. Furthermore, TMAO treatment induced NLRP3 inflammasome activation including oxidative stress in cultured cardiac fibroblast. Importantly, the silencing of NLRP3 presented a protection effect against cardiac fibrosis including cellular proliferation, migration and collagen deposition in vitro.Conclusion: Our data suggested that TMAO aggravated DOX-induced mouse cardiac fibrosis, at least in part, through activation of the NLRP3 inflammasome, providing a new potential target for preventing the progression of cardiac fibrosis.
Highlights
Cardiac fibrosis is characterized by excessive proliferation of cardiac fibroblasts and accumulation of extracellular matrix (ECM), which leads to cardiac diastolic dysfunction and heart failure (Creemers and Pinto, 2011; Travers et al, 2016)
The mice treated with DOX showed significantly reduced relative heart weight, including heart weight/body weight (HW/BW) and heart weight/tibia length (HW/TL), which could be further reduced by additional treatment with Trimethylamine N-oxide (TMAO) (Figures 1B,C)
Our results show that TMAO promotes cardiac fibroblast proliferation, migration and collagen secretion in a dose-dependent manner, indicating that TMAO contributes to cardiac fibrosis via regulating the function of cardiac fibroblasts
Summary
Cardiac fibrosis is characterized by excessive proliferation of cardiac fibroblasts and accumulation of extracellular matrix (ECM), which leads to cardiac diastolic dysfunction and heart failure (Creemers and Pinto, 2011; Travers et al, 2016). Cardiac fibroblasts are the predominant cell type located within interstitial tissues, contributing to the secretion of ECM proteins and TMAO-Mediated Cardiac Fibrosis influencing cardiac function in the presence of certain profibrotic stimuli (Lighthouse and Small, 2016; Xiang et al, 2017). Previous studies have suggested that elevated plasma TMAO levels are associated with poor prognosis and increased mortality risk in cardiovascular disease, including heart failure (Tang et al, 2013; Heianza et al, 2017). Several animal studies have suggested that elevated TMAO levels have a strong association with cardiac fibrosis and contribute to heart failure (Chen K. et al, 2017; Zhang et al, 2017; Li et al, 2018). The roles and mechanisms of TMAO-mediated cardiac fibrosis are not fully elucidated
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