N‑acetylcysteine inhibits atherosclerosis by correcting glutathione‑dependent methylglyoxal elimination and dicarbonyl/oxidative stress in the aorta of diabetic mice

• Published in: Molecular medicine reports Vol. 23; no. 3
• Main Authors: Fang, Xin, Liu, Lihua, Zhou, Shaoqiong, Zhu, Mengen, Wang, Bin
• Format: Journal Article
• Language: English
• Published: Greece Spandidos Publications 01.03.2021; Spandidos Publications UK Ltd; D.A. Spandidos
• Subjects: Acetylcysteine; Acetylcysteine - pharmacology; Acids; AKT protein; Animal models; Animals; Antioxidants; Aorta; Aorta - metabolism; Aorta - pathology; Apolipoprotein E; Apolipoproteins; Arteriosclerosis; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Cardiovascular disease; Cardiovascular diseases; Care and treatment; Cholesterol; Complications and side effects; Coronary vessels; Development and progression; Diabetes; Diabetes Complications - drug therapy; Diabetes Complications - genetics; Diabetes Complications - metabolism; Diabetes mellitus; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Drinking water; Endothelial cells; Glucose; Glutathione - metabolism; Glutathione peroxidase; Health aspects; Hyperglycemia; Laboratory animals; Lipids; Male; Malondialdehyde; Metabolism; Mice; Mice, Knockout, ApoE; Nitric oxide; Nitric-oxide synthase; Oxidative stress; Oxidative Stress - drug effects; Proteins; Pyruvaldehyde; Pyruvaldehyde - metabolism; Reactive oxygen species; Rodents; Solvents; Streptozocin; Superoxide dismutase; Umbilical vein; China
• DOI: 10.3892/mmr.2021.11840
• ISSN: 1791-2997

In diabetic animal models, high plasma/tissue levels of methylglyoxal (MG) are implicated in atherosclerosis. N‑acetylcysteine (NAC) is a cysteine prodrug that replenishes intracellular glutathione (GSH) levels, which can increase the elimination of MG in diabetes mellitus (DM). The present study investigated the anti‑atherosclerotic role of NAC in DM and aimed to determine whether the mechanism involved GSH‑dependent MG elimination in the aorta. Apolipoprotein‑E knockdown ( ) mice injected with streptozotocin for 5 days exhibited enhanced atherosclerotic plaque size in the aortic root; notably, a high‑lipid diet aggravated this alteration. NAC treatment in the drinking water for 12 weeks decreased the size of the atherosclerotic lesion, which was associated with a reduction in MG‑dicarbonyl stress and oxidative stress, as indicated by decreased serum malondialdehyde levels, and increased superoxide dismutase‑1 and glutathione peroxidase‑1 levels in the diabetic aorta. Endothelial damage was also corrected by NAC, as indicated by an increase in the expression levels of phosphorylated (p‑)Akt and p‑endothelial nitric oxide synthase (eNOS) in the aorta, as well as nitric oxide (NO) in the serum. In addition, MG‑treated human umbilical vein endothelial cells (HUVECs) exhibited increased reactive oxygen species and decreased antioxidant enzyme expression levels. NAC treatment corrected the alteration in HUVECs induced by MG, whereas the protective role of NAC was blocked via inhibition of GSH. These findings indicated that the diabetic aorta was more susceptible to atherosclerotic lesions compared with non‑diabetic mice. Furthermore, NAC may offer protection against atherosclerotic development in DM by altering aortic and systemic responses via correcting GSH‑dependent MG elimination, leading to decreased oxidative stress and restoration of the p‑Akt/p‑eNOS pathway in the aorta.