Abstract
Atherosclerosis, a chronic disease of the arteries, results from pathological processes including the accumulation and aggregation of oxidized low-density lipoprotein (oxLDL) in the vessel walls, development of neointima, formation of a fibrous cap, and migration of immune cells to damaged vascular endothelium. Recent studies have shown that mitochondrial dysfunction is closely associated with the development and progression of atherosclerosis. Idebenone, a short-chain benzoquinone similar in structure to coenzyme Q10, can effectively clear oxygen free radicals as an electron carrier and antioxidant. In the present study, we aim to investigate weather idebenone protects against atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice. apoE-/- mice receiving a high-fat diet (HFD) were treated with idebenone for 16weeks. A total of 60 mice were randomized into the following four groups: (1) HFD, (2) HFD and low-dose idebenone (100mg/kg/d), (3) HFD and medium-dose idebenone (200mg/kg/d), and (4) HFD and high-dose (400mg/kg/d). Proteomic analysis was performed between the HFD and idebenone-high-dose group. Plaque analysis was carried out by histological and immunohistochemical staining. Western blot, TUNEL staining, and MitoSOX assays were performed in human umbilical vein endothelial cells (HUVECs) to investigate the SIRT3-SOD2-mtROS pathway. Histological and morphological analysis demonstrated that idebenone significantly reduced plaque burden and plaque size. Idebenone treatment effectively stabilized the atherosclerotic plaques. In mice treated with idebenone, 351 up-regulated and 379 down-regulated proteins were found to be significantly altered in proteomic analysis. In particular, the expression of SIRT3, SOD2, and NLRP3 was significantly regulated in the idebenone treatment groups compared with the HFD group both in vivo and in vitro. We further confirmed that idebenone protected against endothelial cell damage and inhibited the production of mitochondrial reactive oxygen species (mtROS) in cholesterol-treated HUVECs. We demonstrated that idebenone acted as a mitochondrial protective agent by inhibiting the activation of NLPR3 via the SIRT3-SOD2-mtROS pathway. Idebenone may be a promising therapy for patients with atherosclerosis by improving mitochondrial dysfunction and inhibiting oxidative stress.
Highlights
Atherosclerosis, which is a form of chronic aortic disease, results from the accumulation and aggregation of oxidized low density lipoprotein(LDL)in the vessel walls, the development of neointima, the formation of a fibrous cap, and the migration of immune cells to the damaged vascular endothelium
We showed that idebenone could act as a mitochondrial protective agent during the development and progression of atherosclerosis by inhibiting the activation of NLPR3 via the SIRT3SOD2-mitochondrial reactive oxygen species (mtROS) pathway
Idebenone may be a promising therapy for patients with atherosclerosis in the future, as it can improve mitochondrial dysfunction and inhibit oxidative stress
Summary
Atherosclerosis, which is a form of chronic aortic disease, results from the accumulation and aggregation of oxidized low density lipoprotein(LDL)in the vessel walls, the development of neointima, the formation of a fibrous cap, and the migration of immune cells to the damaged vascular endothelium. Recent studies have shown that mitochondrial function is closely associated with the development and progression of atherosclerosis. As a type of chronic inflammatory disease, atherosclerosis results from the aggregation of oxidized LDL in the vessel walls, the formation of a fibrous cap, the development of intimal hyperplasia, and the migration of immune cells to the damaged vascular endothelium [2]. Mitochondrial DNA damage can lead to mitochondrial dysfunction through various physiological mechanisms, directly contributing to the formation and progression of atherosclerosis [6]. Mitochondrial dysfunction may be an important factor that promotes the initiation and progression of atherosclerosis
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