Abstract

BACKGROUND: This study aimed to investigate the effects of dimethyl fumarate (DMF) on thoracic aortic atherosclerosis in the apolipoprotein E (apo-E)-deficient mouse model with streptozotocin (STZ)-induced hyperglycemia, and the signaling pathways involved.

MATERIAL AND METHODS: Eight-week-old ApoE–/– male mice (n=30) were randomly divided into three groups: the Control group (ApoE–/–) (n=10); the diabetic model (STZ) group (n=10); and the DMF-treated (25 mg/kg) diabetic model (DMF+STZ) group (n=10). The area of the thoracic aortic atherosclerosis was determined by histology. Reactive oxygen species (ROS) levels in mouse serum and homogenates of the thoracic aorta were determined by colorimetry. Levels of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase subunit gp91phox were detected by immunological hybridization, and levels of heme oxygenase-1 (HO-1) were measured by enzyme-linked immunosorbent assay (ELISA).

RESULTS: Compared with the Control group, in the STZ group, the area of aortic atherosclerosis was significantly increased, the levels of serum and aortic ROS, HO-1, nuclear factor-κB (NF-κB), intercellular adhesion molecule 1 (ICAM-1), and gp91phox were increased, and nuclear factor erythroid 2-related factor 2 (Nrf2), endothelial nitric oxide synthase (eNOS), and phosphorylated eNOS (p-eNOS) were significantly reduced. Compared with the STZ group, in the DMF+STZ group, the area of aortic atherosclerosis was significantly reduced, the levels of serum and aortic ROS, HO-1, NF-κB, ICAM-1, and gp91phox were significantly reduced, and Nrf2, eNOS, and p-eNOS were significantly increased.

CONCLUSIONS: In the apo-E-deficient mouse model with STZ-induced hyperglycemia, DMF reduced the development of atherosclerosis of the thoracic aorta through the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway.

Keywords: atherosclerosis, Diabetes Mellitus, NF-E2 Transcription Factor, Antioxidant Response Elements, Aorta, Apolipoproteins E, Diabetes Mellitus, Experimental, Dimethyl Fumarate, Heme Oxygenase-1, Hyperglycemia, Mice, Knockout, NADPH Oxidases, NF-E2-Related Factor 2, Nitric Oxide Synthase Type III, Peptide Fragments, Streptozocin