Trimethylamine-N-oxide (TMAO) promotes balloon injury-induced neointimal hyperplasia via upregulating Beclin1 and impairing flux

作者：Hong, Qingqing; Que, Dongdong; Zhong, Chongbin; Huang, Guanlin; Zhai, Weicheng; Chen, Deshu; Yan, Jing^*; Yang, Pingzhen^*

来源：Biomedicine and Pharmacotherapy, 2022, 155: 113639.

DOI：10.1016/j.biopha.2022.113639

• TMAO
• Neointimal hyperplasia
• Reendothelialization
• Autophagic flux
• Beclin1

Background and aims: TMAO is a microbiota-dependent metabolite associated with increased risk of various cardiovascular diseases. However, the relationship between TMAO and vascular injury-related neointimal hy-perplasia is unclear. This study aimed to explore whether TMAO promotes neointimal hyperplasia after balloon injury and elucidate the underlying mechanism. Methods and Results: Through hematoxylin and eosin staining and immunohistochemistry staining, we found that supplementary TMAO promoted balloon injury-induced neointimal hyperplasia, while reducing TMAO by antibiotic administration produced the opposite result. TMAO showed limited effect on rat aortic vascular smooth muscle cells (RAOSMCs) proliferation and migration. However, TMAO notably induced dysfunction of rat aortic vascular endothelial cells (RAOECs) in vitro and attenuated reendothelialization of carotid arteries after balloon injury in vivo. Autophagic flux was measured by fluorescent mRFP-GFP-LC3, transmission electron microscopy, and western blot. TMAO impaired autophagic flux, as evidenced by the accumulation of p62 and LC3II and high autophagosome to autolysosome ratios. Furthermore, we confirmed that Beclin1 level increased in TMAO-treated RAOECs and carotid arteries. Knocking down Beclin1 alleviated TMAO-induced autophagic flux impairment and neointimal hyperplasia. Conclusions: TMAO promoted neointimal hyperplasia through Beclin1-induced autophagic flux blockage, sug-gesting that TMAO is a potential target for improvement of vascular remodeling after injury.

• 单位
  Guangzhou Medical University; Southern Medical University