Homocysteine promotes cardiac fibrosis by regulating the Akt/FoxO3 pathway

Area of Science:

• Cardiovascular Biology
• Cellular Mechanisms of Fibrosis
• Molecular Signaling Pathways

Background:

• Plasma homocysteine (Hcy) is a known risk factor for cardiac fibrosis, a key feature of cardiovascular disease.
• The precise mechanisms underlying Hcy-induced cardiac fibrosis remain incompletely understood.
• This study investigates the molecular pathways through which Hcy contributes to cardiac fibrosis.

Purpose of the Study:

• To elucidate the mechanism of homocysteine (Hcy)-induced cardiac fibrosis.
• To explore the role of Forkhead box O3 (FoxO3) in Hcy-mediated cardiac fibroblast activation.
• To identify potential therapeutic targets for preventing Hcy-induced cardiac remodeling.

Main Methods:

• Assessed mRNA and protein levels of Forkhead box O3 (FoxO3) and differentiation markers in primary cardiac fibroblasts (CFs) following Hcy treatment.
• Utilized scratch and transwell assays to evaluate the impact of Hcy on CF proliferation and migration.
• Investigated fibrotic protein levels and FoxO3 activity in mice fed a high methionine diet (HMD) and in CFs with FoxO3 overexpression.

Main Results:

• Hcy treatment increased CF differentiation, proliferation, and migration while decreasing FoxO3 activity.
• HMD-fed mice exhibited elevated levels of fibrotic markers (TIMP1, Fibronectin, α-SMA) and reduced FoxO3 activity.
• FoxO3 overexpression mitigated Hcy-induced cardiac fibroblast dysfunction, suggesting a protective role.

Conclusions:

• Homocysteine promotes cardiac fibrosis by enhancing myofibroblast activation and inhibiting autophagy and apoptosis via the Akt/FoxO3 pathway.
• Forkhead box O3 (FoxO3) plays a critical role in regulating Hcy-induced cardiac fibrosis.
• FoxO3 represents a potential therapeutic target for preventing cardiac remodeling and fibrosis.