Lack of the antioxidant glutathione peroxidase-1 does not increase atherosclerosis in C57BL/J6 mice fed a high-fat diet

Abstract

Oxidative stress is thought to contribute to the initiation and progression of atherosclerosis. As glutathione peroxidase-1 (Gpx1) is an antioxidant enzyme that detoxifies lipid hydroperoxides, we tested the impact of Gpx1 deficiency on atherosclerotic processes and antioxidant enzyme expression in mice fed a high-fat diet (HFD). After 12 weeks of HFD, atherosclerotic lesions at the aortic sinus were of similar size in control and Gpx1-deficient mice. However, after 20 weeks of HFD, lesion size increased further in control but not in Gpx1-deficient mice, even though plasma and aortic wall markers of oxidative damage did not differ between groups. In control mice, the expression of Gpx1 increased and that of Gpx3 decreased at the aortic sinus after 20 weeks of HFD, with no change in the expression of Gpx2, Gpx4, catalase, peroxiredoxin-6, glutaredoxin-1 and -2, or thioredoxin-1 and -2. By comparison, in Gpx1-deficient mice, the expression of antioxidant genes was unaltered except for a decrease in glutaredoxin-1 and an increase in glutaredoxin-2. These changes were associated with increased expression of the proinflammatory marker monocyte chemoattractant protein-1 in control mice but not in Gpx1-deficient mice. In summary, a specific deficiency in Gpx1 was not accompanied by an increase in markers of oxidative damage or increased atherosclerosis in a murine model of HFD-induced atherogenesis.-de Haan,

Overexpression of Peroxiredoxin 4 Attenuates Atherosclerosis in Apolipoprotein E Knockout Mice

“…In these hypercholesterolemia model mice, serum TG levels might not significantly affect the progression of atherosclerosis, as compared with other cholesterol parameters, similar to that reported by other research groups (4,13). In fact, we only measured lipoproteins present in blood samples, and it is unclear how the serum concentrations reflect the local levels in the aortic wall, where atherosclerosis was analyzed (2). Therefore, the correlation between TG and PRDX4 overexpression also remains to be elucidated.…”

“…By contrast, the expression of SOD1, SOD2, and GSR was significantly reduced in the atherosclerotic aortas of hPRDX4 Supplementary Fig. S8), suggesting complementary mechanisms are responsible for the overexpression of hPRDX4 (2).…”

“…Several studies have revealed that antioxidative markers, including other PRDXs, function as antiatherogenic factors in vivo. The size of atherosclerotic lesions in the aortic sinus decreases significantly after 20 weeks of high-fat feeding in mice lacking glutathione peroxidase-1 (GPX1) (GPX1 -/ -) as compared with control wild-type (WT) mice (2). Cu,Zn-superoxide dismutase 1 (SOD1) transgenic mice develop smaller atherosclerotic lesions than do WT mice (25).…”

Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis

“…After 2 weeks, mice were randomized and injected intraperitoneally every 3 days with sterile water, vehicle peptide (Antennapedia, dissolved in 1% DMSO in sterile water, the same molar dose as CavNOxin), or CavNOxin at 2.5 and 5.0 mg/kg (dissolved in 1% DMSO in sterile water) for 14 weeks. Previous studies by our group demonstrated that this length of time allows for the development of robust atherosclerotic plaque within the vessel walls and aortic sinus in diabetic ApoE KO mice (27). Nonfasted blood glucose readings were measured every week to confirm that mice were diabetic throughout the study.…”

“…Probes and primers were purchased from Applied Biosystems (Foster City, CA). Gene expression of eNOS, vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1, MCP-1, and nuclear factor-kB subunit p65 was analyzed by quantitative RT-PCR (qRT-PCR) as described previously (27).…”