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Atherosclerosis (AS) is one of the main causes of cardiovascular diseases (CVDs). Trimethylamine N-oxide (TMAO) exacerbates the development of AS. This study aimed to investigate the roles of TMAO in AS. In this study, mice were fed with high fat food (HF) and/or injected with TMAO. Oil red O staining was applied for histological analysis. ELISA, qRT-PCR, and Western blot were conducted to determine the TMAO, serum, mRNA, and protein levels. CCK-8, colony formation assay, and flow cytometry assays were performed to detect the functions of human aortic endothelial cells (HUVECs). The results showed that TMAO induced thick internal and external walls and intimal plaques in vivo , and HUVEC dysfunction in vitro . TMAO and lncRNA enriched abundant transcript 1 (NEAT1) were increased in AS clinical samples and TMAO-HUVECs. Downregulated NEAT1 inhibited proliferation and promoted the apoptosis of HUVECs. NEAT1 regulated the expression of signal transducer and activator of transcription 3 (STAT3) via sponging miR-370-3p. Overexpression of miR-370-3p facilitated the effects of NEAT1 on the cellular functions of HUVECs, while STAT3 exerted opposing effects. The activation of STAT3 promoted the expression of flavin-containing monooxygenase-3 (FMO3). Taken together, our results show that TMAO-NEAT1/miR-370-3p/STAT3/FMO3 forms a positive feedback loop to exacerbate the development of AS. This novel feedback loop may be a promising therapeutic target for AS.

Objective Honokiol, a natural active compound extracted from Chinese herbal medicine, can ameliorate acute lung and kidney injury of sepsis. This study was to explore the effects of honokiol on sepsis-associated cardiac dysfunction and the underlying mechanism. Methods Septic mice were induced by cecal ligation and puncture (CLP) or lipopolysaccharide (LPS), and septic HL-1 or AC16 cells were induced by LPS. Results Honokiol improved the survival and alleviated cardiac dysfunction in mice with CLP-induced sepsis. Honokiol inhibited the increased interleukin (IL) 1-β, IL-6 and tumour necrosis factor (TNF)-α in the serum and heart of CLP- and LSP-induced septic mice. Honokiol treatment reversed the increased levels of IL1-β, IL-6 and TNF-α in LPS-induced HL-1 cells. Honokiol treatment also decreased the elevated levels of IL1-β, IL-6 and TNF-α in LPS-induced AC16 cells. The increased cardiac apoptosis in CLP- and LPS-induced septic mice was alleviated by honokiol. The enhancement of oxidative stress in the heart of CLP- and LPS-induced septic mice was suppressed after honokiol administration. Conclusion These results showed that honokiol could ameliorate sepsis-associated cardiac dysfunction via attenuating inflammation, apoptosis, and oxidative stress. Honokiol is a prospective drug for sepsis-associated heart damage in the future.

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