Trimethylamine N-oxide promotes atherosclerosis via CD36-dependent MAPK/JNK pathway.

BACKGROUND

Many studies have identified trimethylamine N-oxide (TMAO) as a new risk factor of cardiovascular diseases. It has been suggested that TMAO promotes atherosclerosis development. However, the underlying mechanism is still unclear.

METHODS

Apoe-/- mice were fed a high-fat diet and given water with or without TMAO for 8-week. Histological and immunohistological analyses were used to evaluate the atherogenic effect of TMAO in vivo. We also employed peritoneal elicited macrophages and RAW264.7 to assess the role of MAPK/JNK pathway in TMAO-induced formation of foam cells.

RESULTS

TMAO significantly promoted plaque progression in apoe-/- mice fed with high-fat diet for 8 weeks. Besides, macrophage recruitment, CD36 and proinflammatory cytokine expressions were enhanced by TMAO in plaque lesions. In vitro, TMAO increased the macrophage migration and the expression of TNF-α, IL-6 and ICAM1. In addition, CD36 expression and foam cell formation induced by ox-LDL were also enhanced by TMAO, which could be attenuated by siRNA-mediated knockdown of CD36. We additionally used MAPK inhibitor (SB230580) and JNK inhibitor (SP600125) to assess the MAPK/JNK pathway in TMAO-induced CD36 expression. Western blotting showed that both SB230580 and SP600125 could reduce the expression of CD36 induced by ox-LDL and TMAO. Moreover, SB230580 and SP600125 could also reduce the formation of foam cells.

CONCLUSIONS

TMAO promotes the atherosclerosis in vivo and in vitro.CD36/MAPK/JNK pathway may play a crucial role in TMAO-induced formation of foam cells.