Trimethylamine N-Oxide Exacerbates Cardiac Fibrosis via Activating the NLRP3 Inflammasome

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.

Metagenomic data-mining reveals enrichment of trimethylamine-N-oxide synthesis in gut microbiome in atrial fibrillation patients

“…The upregulated levels of inflammatory cytokines in the ganglionated plexi as a result of the activation of p65 NF-κB signaling might facilitate these effects [ 19 ]. Furthermore, TMAO exacerbated doxorubicin-induced myocardial fibrosis, at least partially via the activation of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome [ 21 ]. These epidemiological studies, as well as animal experiments, have demonstrated the crucial role of TMAO in promoting AF development.…”

“…Several researches have reported the linkage between TMAO and the progression of AF diseases [ 18 – 20 ]. TMAO increases the instability of atrial electrophysiology, induces acute electrical remodeling, and aggravates cardiac fibrosis, thereby facilitating the progression of AF [ 19 , 21 ]. However, relevant bacterial species and metabolic pathways underlying TMAO production in the gut of AF patients and whether TMAO serves as a pathological link between disordered GM and AF are yet to be elucidated.…”

The gut microbiota and its interactions with cardiovascular disease

“…TMAO prolongs the effect of angiotensin, eventually leading to adverse cardiac remodelling (Ufnal, et al , ). Another mechanistic link is that TMAO promotes myocardial fibrosis via activation of NLRP3 inflammasome‐associated TGF‐β/Smad3 signalling; in addition, the finding that NLRP3 silencing can abolish the increases in the levels of IL‐1β, TGF‐β and other profibrotic markers induced by TMAO in cardiac fibroblasts (Li, et al , ) suggests that TMAO could be a new potential target for retarding the development of myocardial remodelling and the progression of myocardial functional impairment (Table ).…”

Mitochondrial Dysfunction and Inflammaging in Heart Failure: Novel Roles of CYP-Derived Epoxylipids

“…Elevated levels of pro-inflammatory cytokines secondary to NLRP-3 inflammasome activation, such as IL-1β, are often detected in elderly individuals correlating with age-related CVD [ 38 , 73 ]. Indeed, the formation of NLRP-3 inflammasome promotes collagen production and IL-1β activation leading to adverse cardiac remodeling and caspase-1 mediated cell death [ 74 , 75 ]. Mature IL-1β promotes the LV expression of pro-fibrotic tumor growth factor β (TGF-β), excessive extracellular matrix (ECM) accumulation and collagen I deposition [ 76 , 77 ].…”