Abstract: Objective To investigate the potential intervention properties and possible mechanism of 5-methyltetrahydrofolate(5-MTHF)on atherosclerosis in rats. Methods Rat atherosclerosis models were established with a high-fat diet combined with vitamin D2. A total of 48 male Wister rats were randomly divided into control group, model group, 5-MTHF low-dose and high-dose groups(0.5 mg/kg, 2 mg/kg), with 12 rats in each group. The rats were sacrificed 6 weeks later, and the contents of folate, homocysteine, blood lipid, oxidative stress, inflammatory factors, and endothelial factors in the serum were measured. The pathological changes in the aorta were observed with HE staining. The mRNA expressions of nuclear factor-κB p65(NF-κB p65)and lectin-like oxidized low-density lipoprotein receptor-1(LOX-1)in aorta were detected with qRT-PCR. Results Compared with the control group, the model group had decreased body weight(P<0.05), increased levels of serum total cholesterol(TC), triglyceride(TG), low-density lipoprotein(LDC-C)(P<0.001), decreased level of high-density lipoprotein(HDL-C)(P<0.001), and smooth muscle cell hyperplasia and diffuse lipid plaques in the aorta, suggesting that the atherosclerosis models were established successfully. The serum folate content in the model group was not significantly different from that in the control group(P>0.05), but the homocysteine concentration increased by 77.47%(P<0.001). Compared with the model group, the 5-MTHF low- and high-dose groups had increased serum folate level(P=0.042, P<0.001)but decreased homocysteine concentration(P=0.046, P<0.001). Low-dose 5-MTHF did not significantly improve dyslipidemia, nitric oxide synthase(NOS), superoxide dismutase(SOD), glutathione peroxidase(GSH-Px)activities, nitric oxide(NO), malondialdehyde(MDA), inflammatory tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6), endothelin-1(ET-1), soluble intercellular adhesion molecule 1(sICAM-1), and mRNA expressions of NF-κB p65 and LOX-1(P>0.05). In the 5-MTHF high-dose group, serum TC and LDC-C contents decreased(P=0.023, P=0.036), HDL-C level increased(P=0.035); NO concentration, NOS and SOD activities increased(P=0.035, P=0.022, P=0.04); MDA, TNF-α, IL-6 and ET-1 contents decreased(P=0.022, P=0.045, P=0.024, P=0.045), but the GSH-Px activity was significantly enhanced(P=0.007); the mRNA expression of LOX-1 was down-regulated(P=0.038)but the down-regulation of the mRNA expression of NF-κB p65 was not statistically significant(P>0.05). 5-MTHF had no regression effects on plaques in atherosclerotic rats, but high-dose 5-MTHF reduced smooth muscle cell proliferation and foam cell aggregation in plaques. Conclusion 5-MTHF can improve dyslipidemia, oxidative stress and inflammation, reduce foam cell aggregation and smooth muscle cell proliferation, but does not reduce atherosclerotic plaques in atherosclerotic rats, probably by reducing homocysteine level, inhibiting oxidative stress and down-regulating the mRNA expression of LOX-1.

Key words: 5-methyltetrahydrofolate, Atherosclerosis, Homocysteine, Oxidative stress, Lectin-like oxidized low-density lipoprotein receptor-1