The Roles of Aerobic Exercise and Folate Supplementation in Hyperhomocysteinemia-Accelerated Atherosclerosis

Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis. Effective interventions to reduce HHcy-accelerated atherosclerosis are required.

This study aimed to investigate the effects of aerobic exercise (AE) and folate (FA) supplementation on plasma homocysteine (Hcy) level and atherosclerosis development in a mouse model.

Six-week-old female apoE-/- mice were grouped into five groups (N = 6-8): HHcy (1.8 g/L DL-homocysteine (DL-Hcy) in drinking water), HHcy + AE (1.8 g/L DL-Hcy and aerobic exercise training on a treadmill), HHcy + FA (1.8 g/L DL-Hcy and 0.006% folate in diet), HHcy + AE + FA (1.8 g/L DL-Hcy, 0.006% folate, and aerobic exercise training on a treadmill), and a control group (regular water and diet). All treatment was sustained for 8 weeks. Triglyceride, cholesterol, lipoprotein, and Hcy levels were determined enzymatically. Plaque and monocyte chemoattractant protein-1 (MCP-1) expression levels in mouse aortic roots were evaluated by immunohistochemistry.

Compared to the HHcy group (18.88 ± 6.13 μmol/L), plasma Hcy concentration was significantly reduced in the HHcy + AE (14.79 ± 3.05 μmol/L, p = 0.04), HHcy + FA (9.4 ± 3.85 μmol/L, p < 0.001), and HHcy + AE + FA (9.33 ± 2.21 μmol/L, p < 0.001) groups. Significantly decreased aortic root plaque area and plaque burden were found in the HHcy + AE and HHcy + AE + FA groups compared to those in the HHcy group (both p < 0.05). Plasma MCP-1 level and MCP-1 expression in atherosclerotic lesions were significantly decreased in the HHcy + AE and HHcy + AE + FA groups compared to the HHcy group (all p < 0.05).

AE reduced atherosclerosis development in HHcy apoE-/- mice independently of reducing Hcy levels. FA supplementation decreased plasma Hcy levels without attenuating HHcy-accelerated atherosclerosis. AE and FA supplementation have distinct mechanisms in benefiting atherosclerosis.