The Effects of Dimethyl Fumarate on Atherosclerosis in the Apolipoprotein E-Deficient Mouse Model with Streptozotocin-Induced Hyperglycemia Mediated By the Nuclear Factor Erythroid 2-Related Factor 2/Antioxidant Response Element (Nrf2/ARE) Signaling Pathway

Abstract

BackgroundThis 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/MethodsEight-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).ResultsCompared 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.ConclusionsIn 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.

Theaflavin alleviates oxidative injury and atherosclerosis progress via activating microRNA‐24‐mediated Nrf2/HO‐1 signal

“…Activation of Nrf2 has been found to modulate redox homeostasis, prevent, and/or treat a large number of chronic inflammatory diseases in animal models and/or humans including CVD (Pall & Levine, 2015). Study has shown that the reduction of AS of the thoracic aorta has contributed to the activation of Nrf2 (Luo, Sun, Zhao, Tao, & Yan, 2019;Mimura & Itoh, 2015). HO-1 is a downstream protein of Nrf2; the increased expression of HO-1 is regulated by the activation of Nrf2.…”

Oxidative Stress and Antioxidant Treatments in Cardiovascular Diseases

“…In vitro experiments have also indicated its protective role in cardiomyocytes after I/R injury [ 157 ]. Additionally, in the apolipoprotein E (apo-E)-deficient mouse model with streptozotocin-induced hyperglycemia, DMF reduced the development of atherosclerosis [ 158 ].…”

Edaravone Improves the Post-traumatic Brain Injury Dysfunction in Learning and Memory by Modulating Nrf2/ARE Signal Pathway

“…Activated Nrf2 is translocated into the nucleus to bind to ARE, through which it can activate the expression of downstream antioxidative genes (15). Accumulating evidence has also indicated that the activation of the Nrf2/ARE signaling pathway can increase antioxidative ability and reduce oxidative stress-induced injury to cells (11,(30)(31)(32).…”