Homocysteine promotes cardiac fibrosis by regulating the Akt/ FoxO3 pathway

Background: Evaluated plasma homocysteine (Hcy) is an independent risk factor for cardiac fibrosis which is a common feature of cardiovascular disease, although the mechanisms are still unclear. This study aims to explore the mechanism of Hcy-induced cardiac fibrosis. Methods: The mRNA and protein levels of Forkhead box O3 (FoxO3) and differentiation markers were detected in primary cardiac fibroblasts (CFs) after 300 mu M Hcy treatment. Scratch and transwell migration assay were used to determine the effect of Hcy on proliferation and migration in CFs. The protein levels involved in the fibrotic processes in mice fed with high methionine diet (HMD) for 4 or 8 weeks were investigated by western blot. CFs were infected with FoxO3 recombinant adenovirus to explore the potential role of FoxO3 in Hcy-induced cardiac dysfunction. Results: Hcy treatment significantly promoted the differentiation, proliferation and migration of CFs, while FoxO3 activity were decreased in CFs. In HMD hearts, the protein levels of TIMP1, Fibronectin and alpha-SMA were increased after 4 or 8 weeks, but the FoxO3 activity was decreased. Moreover, the HMD hearts had a higher level of Bcl2 but lower of Bax and LC3II protein. In addition, FoxO3 overexpression attenuates Hcy-induced dysfunction in CFs. Conclusions: Hcy promotes myofibroblast activation and resistance to autophagy and apoptosis in CFs, and eventually results in cardiac fibrosis by regulating the Akt/FoxO3 pathway. Thus, FoxO3 is a promising therapeutic target to prevent cardiac remodeling.

Automated summary

The study reveals that the mechanism of Hcy-induced cardiac fibrosis involves differentiation, proliferation, and migration of CFs, leading to fibrosis through regulation of the Akt/FoxO3 pathway. Overexpression of FoxO3 can alleviate Hcy-induced dysfunction in CFs.