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Chuanzhu Yan - One of the best experts on this subject based on the ideXlab platform.
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Idebenone protects against atherosclerosis in apolipoprotein e deficient mice via activation of the sirt3 sod2 mtros pathway
Cardiovascular Drugs and Therapy, 2020Co-Authors: Wei Jiang, Hongzhi Geng, Pengfei Lin, Fuchen Liu, Chuanzhu YanAbstract: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 16 weeks. A total of 60 mice were randomized into the following four groups: (1) HFD, (2) HFD and low-dose Idebenone (100 mg/kg/d), (3) HFD and medium-dose Idebenone (200 mg/kg/d), and (4) HFD and high-dose (400 mg/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.
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Idebenone protects against atherosclerosis in apolipoprotein E-deficient mice via activation of the Sirt3-SOD2-mtROS pathway
2020Co-Authors: Wei Jiang, Hongzhi Geng, Pengfei Lin, Chuanzhu YanAbstract:Abstract Background: 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. Idebenone functions as an electron carrier and antioxidant, and previous studies have shown that it effectively clears oxygen-free radicals. In the current study, we demonstrate that Idebenone could protect against atherosclerosis using apolipoprotein E-deficient mice. Methods: High-fat diet（HFD）and Idebenone treatment with apolipoprotein E-deficient mice . A total of 60 mices were randomized into the following four groups: (1) HFD (2) Idebenone-low dose (3) Idebenone-medium dose and (4) Idebenone-high dose for 16 weeks. The HUVECs were pretreated with endothelial cell medium in the presence or absence of 0.2 mM Idebenone working solution for 3 h followed by exposure to 10 μM cholesterol for 24 h. Proteomics analysis was performed between the HFD group (n=3) and the high-dose Idebenone group (n=3, concentration = 400 mg/kg/d).Results: Compared with the HFD group, Idebenone can suppresses the formation of atherosclerotic plaques and increases the stability of atherosclerotic plaques in apoE-/- mice; Compared with the control group, Idebenone can protects against endothelial cell damage and inhibits the production of mtROS in cholesterol mediated HUVECs; Idebenone could effectively inhibit the development and progression of atherosclerosis and the injury of endothelial cells through the SIRT3-SOD2-mtROS pathway.Conclusions: 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 SIRT3-SOD2-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.
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Idebenone protects against oxidized low density lipoprotein induced mitochondrial dysfunction in vascular endothelial cells via gsk3β β catenin signalling pathways
Biochemical and Biophysical Research Communications, 2015Co-Authors: Pengfei Lin, Junling Liu, Ming Ren, Bin Zhang, Yaoqin Gong, Chuanzhu YanAbstract:The early stages of the atherosclerotic process are initiated by accumulation of oxidized low-density lipoprotein (oxLDL) and damage to the structure or function of the endothelium. Antioxidant supplementation may be a plausible strategy to prevent atherosclerotic disease by quenching excessive reactive oxidative species. In the present study, we demonstrated that Idebenone at suitable concentrations significantly prevented oxLDL-induced endothelial dysfunction. The underlying mechanisms of Idebenone included inhibition of oxidative damage, suppression of the down-regulation of Bcl-2 and up-regulation of Bax and cleaved caspase-3 in human umbilical vein endothelial cells (HUVECs) exposed to oxLDL. Moreover, Idebenone pretreatment inhibited oxLDL-mediated HUVECs damage by attenuating lipid peroxidation and promoting SOD activity. Finally, pro-incubation with Idebenone inhibited mitochondrial dysfunction induced by oxLDL through the mitochondrial-dependent apoptotic pathway and GSK3β/β-catenin signalling pathways. In summary, Idebenone is a promising agent in the treatment or prevention of atherosclerosis via inhibiting oxidative stress and improving mitochondrial function.
Wan Namkung - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of ANO1/TMEM16A Chloride Channel by Idebenone and Its Cytotoxicity to Cancer Cell Lines
PloS one, 2015Co-Authors: Yohan Seo, Jinhong Park, Minseo Kim, Ho K. Lee, Jin Hee Kim, Jin Hyun Jeong, Wan NamkungAbstract:The expression levels of anoctamin 1 (ANO1, TMEM16A), a calcium-activated chloride channel (CaCC), are significantly increased in several tumors, and inhibition of ANO1 is known to reduce cell proliferation and migration. Here, we performed cell-based screening of a collection of natural products and drug-like compounds to identify inhibitors of ANO1. As a result of the screening, Idebenone, miconazole and plumbagin were identified as novel ANO1 inhibitors. Electrophysiological studies showed that Idebenone, a synthetic analog of coenzyme Q10, completely blocked ANO1 activity in FRT cells expressing ANO1 without any effect on intracellular calcium signaling and CFTR, a cAMP-regulated chloride channel. The CaCC activities in PC-3 and CFPAC-1 cells expressing abundant endogenous ANO1 were strongly blocked by Idebenone. Idebenone inhibited cell proliferation and induced apoptosis in PC-3 and CFPAC-1 cells, but not in A549 cells, which do not express ANO1. These data suggest that Idebenone, a novel ANO1 inhibitor, has potential for use in cancer therapy.
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inhibition of ano1 tmem16a chloride channel by Idebenone and its cytotoxicity to cancer cell lines
PLOS ONE, 2015Co-Authors: Yohan Seo, Jinhong Park, Minseo Kim, Ho K. Lee, Jin Hee Kim, Jin Hyun Jeong, Wan NamkungAbstract:The expression levels of anoctamin 1 (ANO1, TMEM16A), a calcium-activated chloride channel (CaCC), are significantly increased in several tumors, and inhibition of ANO1 is known to reduce cell proliferation and migration. Here, we performed cell-based screening of a collection of natural products and drug-like compounds to identify inhibitors of ANO1. As a result of the screening, Idebenone, miconazole and plumbagin were identified as novel ANO1 inhibitors. Electrophysiological studies showed that Idebenone, a synthetic analog of coenzyme Q10, completely blocked ANO1 activity in FRT cells expressing ANO1 without any effect on intracellular calcium signaling and CFTR, a cAMP-regulated chloride channel. The CaCC activities in PC-3 and CFPAC-1 cells expressing abundant endogenous ANO1 were strongly blocked by Idebenone. Idebenone inhibited cell proliferation and induced apoptosis in PC-3 and CFPAC-1 cells, but not in A549 cells, which do not express ANO1. These data suggest that Idebenone, a novel ANO1 inhibitor, has potential for use in cancer therapy.
Nuri Gueven - One of the best experts on this subject based on the ideXlab platform.
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Idebenone: When an antioxidant is not an antioxidant.
Redox biology, 2020Co-Authors: Nuri Gueven, Rajaraman Eri, Pranathi Ravishankar, Emma RybalkaAbstract:Abstract Idebenone is a well described drug that was initially developed against dementia. The current literature widely portrays this molecule as a potent antioxidant and CoQ10 analogue. While numerous papers seem to support this view, a closer look indicates that the pharmacokinetics of Idebenone do not support these claims. A major discrepancy between achievable tissue levels, especially in target tissues such as the brain, and doses required to show the proposed effects, significantly questions our current understanding. This review explains how this has happened and highlights the discrepancies in the current literature. More importantly, based on some recent discoveries, a new framework is presented that can explain the mode of action of this molecule and can align formerly contradictory results. Finally, this new appreciation of the molecular activities of Idebenone provides a rational approach to test Idebenone in novel indications that might have not been considered previously for this drug.
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Idebenone Protects against Spontaneous Chronic Murine Colitis by Alleviating Endoplasmic Reticulum Stress and Inflammatory Response
Biomedicines, 2020Co-Authors: Sonia Shastri, Tanvi Shinde, Agampodi Promoda Perera, Nuri Gueven, Rajaraman EriAbstract:Endoplasmic reticulum (ER) stress in intestinal secretory goblet cells has been linked to the development of ulcerative colitis (UC). Emerging evidence suggests that the short chain quinone drug Idebenone displays anti-inflammatory activity in addition to its potent antioxidant and mitochondrial electron donor properties. This study evaluated the impact of Idebenone in Winnie mice, that are characterized by spontaneous chronic intestinal inflammation and ER stress caused by a missense mutation in the mucin MUC2 gene. Idebenone (200 mg/kg) was orally administered daily to 5–6 weeks old Winnie mice over a period of 21 days. Idebenone treatment substantially improved body weight gain, disease activity index (DAI), colon length and histopathology score. Immunohistochemistry revealed increased expression of MUC2 protein in goblet cells, consistent with increased MUC2 mRNA levels. Furthermore, Idebenone significantly reduced the expression of the ER stress markers C/EBP homologous protein (CHOP), activating transcription factor 6 (ATF6) and X-box binding protein-1 (XBP-1) at both mRNA and protein levels. Idebenone also effectively reduced pro-inflammatory cytokine levels in colonic explants. Taken together, these results indicate that Idebenone could represent a potential therapeutic approach against human UC by its strong anti-inflammatory activity and its ability to reduce markers of ER stress.
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Idebenone as a novel therapeutic approach for Duchenne Muscular Dystrophy
European Neurological Review, 2015Co-Authors: Gunnar M. Buyse, Nuri Gueven, Craig M. McdonaldAbstract:Progressive loss of pulmonary function leads to early morbidity and mortality in Duchenne muscular dystrophy (DMD) due to both expiratory impairment with ineffective airway clearance, and inspiratory impairment leading to nocturnal and daytime hypoventilation and respiratory failure. Glucocorticoid steroids have become a mainstay of DMD therapy with well-documented efficacy on muscle strength and respiratory function. However, the side-effect profile restricts their long-term use, particularly in non-ambulant patients. Idebenone improves secondary mitochondrial dysfunction caused by dystrophin deficiency, intracellular calcium accumulation and increased reactive oxygen species (ROS). Idebenone-mediated improved bioenergetics leads to enhanced adenosine triphosphate (ATP) production and reduced ROS. Based on this rationale, Idebenone has been investigated clinically for efficacy on reducing respiratory function decline in exploratory phase II (DELPHI) and confirmatory phase III (DELOS) trials. Idebenone significantly reduced the loss of respiratory function in 8–18-year-old DMD patients who were not using concomitant glucocorticoids. These results indicate that Idebenone can modify the natural course of respiratory disease progression in DMD, which is relevant in clinical practice where loss of respiratory function continues to be a predominant cause of early morbidity and mortality in DMD.
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Idebenone treatment in Leber's hereditary optic neuropathy: rationale and efficacy
Expert Opinion on Orphan Drugs, 2013Co-Authors: Nuri Gueven, Dharmesh FalduAbstract:Introduction: Leber's hereditary optic neuropathy (LHON) is a rare mitochondrial retinopathy, caused by mutations in subunits of complex I of the respiratory chain. It is characterized by dysfunction and eventually loss of retinal ganglion cells which results in blindness. Clinical evidence suggests that Idebenone, a short-chain quinone, can prevent vision loss and even restore vision in affected LHON patients. Areas covered: This review covers the rationale for the use of Idebenone in LHON based on its mode(s) of action, its pharmacodynamics, pharmacokinetics and its clinical efficacy. Expert opinion: Idebenone was demonstrated as safe and efficacious in several open-label case reports, retrospective cohort studies and in a double-blind, placebo-controlled clinical study. Despite some remaining questions regarding the optimal treatment regimen, Idebenone is currently the only therapeutic option for LHON patients and, thus, will become the benchmark treatment for other therapies to follow.
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Idebenone Protects against Retinal Damage and Loss of Vision in a Mouse Model of Leber’s Hereditary Optic Neuropathy
PloS one, 2012Co-Authors: Fabrice Heitz, Michael Erb, Corinne Anklin, Dimitri Robay, Vincent Pernet, Nuri GuevenAbstract:Leber’s hereditary optic neuropathy (LHON) is an inherited disease caused by mutations in complex I of the mitochondrial respiratory chain. The disease is characterized by loss of central vision due to retinal ganglion cell (RGC) dysfunction and optic nerve atrophy. Despite progress towards a better understanding of the disease, no therapeutic treatment is currently approved for this devastating disease. Idebenone, a short-chain benzoquinone, has shown promising evidence of efficacy in protecting vision loss and in accelerating recovery of visual acuity in patients with LHON. It was therefore of interest to study suitable LHON models in vitro and in vivo to identify anatomical correlates for this protective activity. At nanomolar concentrations, Idebenone protected the rodent RGC cell line RGC-5 against complex I dysfunction in vitro. Consistent with the reported dosing and observed effects in LHON patients, we describe that in mice, Idebenone penetrated into the eye at concentrations equivalent to those which protected RGC-5 cells from complex I dysfunction in vitro. Consequently, we next investigated the protective effect of Idebenone in a mouse model of LHON, whereby mitochondrial complex I dysfunction was caused by exposure to rotenone. In this model, Idebenone protected against the loss of retinal ganglion cells, reduction in retinal thickness and gliosis. Furthermore, consistent with this protection of retinal integrity, Idebenone restored the functional loss of vision in this disease model. These results support the pharmacological activity of Idebenone and indicate that Idebenone holds potential as an effective treatment for vision loss in LHON patients.
Craig M. Mcdonald - One of the best experts on this subject based on the ideXlab platform.
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Long-term data with Idebenone on respiratory function outcomes in patients with Duchenne muscular dystrophy
Neuromuscular disorders : NMD, 2019Co-Authors: Laurent Servais, Ulrike Schara, Mika Leinonen, Chiara Sm Straathof, Andrea Klein, Shabir Hasham, Thomas Meier, Liesbeth De Waele, Heather Gordish-dressman, Craig M. McdonaldAbstract:Decline in respiratory function in patients with DMD starts during early teenage years and leads to early morbidity and mortality. Published evidence of efficacy for Idebenone on respiratory function outcomes is currently limited to 12 months of follow-up time. Here we report data collected as retrospective cohort study (SYROS) from 18 DMD patients not using glucocorticoids who were treated with Idebenone (900 mg/day) under Expanded Access Programs (EAPs). The objective was to assess the long-term respiratory function evolution for periods On-Idebenone compared to periods Off-Idebenone in the same patients. The mean Idebenone exposure in the EAPs was 4.2 (range 2.4-6.1) years. The primary endpoint was the annual change in forced vital capacity percent of predicted (FVC%p) compared between Off-Idebenone and On-Idebenone periods. The annual rate of decline in FVC%p was reduced by approximately 50% from -7.4% (95% CI: -9.1, -5.8) for the Off-Idebenone periods to -3.8% (95% CI: -4.8, -2.8) for the On-Idebenone periods (N = 11). Similarly, annual change in peak expiratory flow percent of predicted (PEF%p) was -5.9% (95% CI: -8.0, -3.9) for the Off-Idebenone periods (N = 9) and reduced to -1.9% (95% CI: -3.2, -0.7) for the On-Idebenone periods during the EAPs. The reduced rates of decline in FVC%p and PEF%p were maintained for several years with possible beneficial effects on the rate of bronchopulmonary adverse events, time to 10% decline in FVC%p and risk of hospitalization due to respiratory cause. These long-term data provide Class IV evidence to further support the disease modifying treatment effect of Idebenone previously observed in randomized, controlled trials.
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Idebenone reduces respiratory complications in patients with Duchenne muscular dystrophy.
Neuromuscular disorders : NMD, 2016Co-Authors: Craig M. Mcdonald, Guenther Bernert, Ulrike Schara, T Meier, Chiara Sm Straathof, Thomas Voit, Maria Grazia D'angelo, Jean-marie Cuisset, Richard S. Finkel, N. GoemansAbstract:In Duchenne muscular dystrophy (DMD), progressive loss of respiratory function leads to restrictive pulmonary disease and places patients at significant risk for severe respiratory complications. Of particular concern are ineffective cough, secretion retention and recurrent respiratory tract infections. In a Phase 3 randomized controlled study (DMD Long-term Idebenone Study, DELOS) in DMD patients 10-18 years of age and not taking concomitant glucocorticoid steroids, Idebenone (900 mg/day) reduced significantly the loss of respiratory function over a 1-year study period. In a post-hoc analysis of DELOS we found that more patients in the placebo group compared to the Idebenone group experienced bronchopulmonary adverse events (BAEs): placebo: 17 of 33 patients, 28 events; Idebenone: 6 of 31 patients, 7 events. The hazard ratios (HR) calculated "by patient" (HR 0.33, p = 0.0187) and for "all BAEs" (HR 0.28, p = 0.0026) indicated a clear Idebenone treatment effect. The overall duration of BAEs was 222 days (placebo) vs. 82 days (Idebenone). In addition, there was also a difference in the use of systemic antibiotics utilized for the treatment of BAEs. In the placebo group, 13 patients (39.4%) reported 17 episodes of antibiotic use compared to 7 patients (22.6%) reporting 8 episodes of antibiotic use in the Idebenone group. Furthermore, patients in the placebo group used systemic antibiotics for longer (105 days) compared to patients in the Idebenone group (65 days). This post-hoc analysis of DELOS indicates that the protective effect of Idebenone on respiratory function is associated with a reduced risk of bronchopulmonary complications and a reduced need for systemic antibiotics.
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efficacy of Idebenone on respiratory function in patients with duchenne muscular dystrophy not using glucocorticoids delos a double blind randomised placebo controlled phase 3 trial
The Lancet, 2015Co-Authors: Gunnar M. Buyse, Guenther Bernert, Ulrike Schara, Chiara Sm Straathof, Thomas Voit, Jean-marie Cuisset, Richard S. Finkel, Grazia M Dangelo, Nathalie Goemans, Craig M. McdonaldAbstract:Summary Background Cardiorespiratory failure is the leading cause of death in Duchenne muscular dystrophy. Based on preclinical and phase 2 evidence, we assessed the efficacy and safety of Idebenone in young patients with Duchenne muscular dystrophy who were not taking concomitant glucocorticoids. Methods In a multicentre phase 3 trial in Belgium, Germany, the Netherlands, Switzerland, France, Sweden, Austria, Italy, Spain, and the USA, patients (age 10–18 years old) with Duchenne muscular dystrophy were randomly assigned in a one-to-one ratio with a central interactive web response system with a permuted block design with four patients per block to receive Idebenone (300 mg three times a day) or matching placebo orally for 52 weeks. Study personnel and patients were masked to treatment assignment. The primary endpoint was change in peak expiratory flow (PEF) as percentage predicted (PEF%p) from baseline to week 52, measured with spirometry. Analysis was by intention to treat (ITT) and a modified ITT (mITT), which was prospectively defined to exclude patients with at least 20% difference in the yearly change in PEF%p, measured with hospital-based and weekly home-based spirometry. This study is registered with ClinicalTrials.gov, number NCT01027884. Findings 31 patients in the Idebenone group and 33 in the placebo group comprised the ITT population, and 30 and 27 comprised the mITT population. Idebenone significantly attenuated the fall in PEF%p from baseline to week 52 in the mITT (−3·05%p [95% CI −7·08 to 0·97], p=0·134, vs placebo −9·01%p [–13·18 to −4·84], p=0·0001; difference 5·96%p [0·16 to 11·76], p=0·044) and ITT populations (−2·57%p [–6·68 to 1·54], p=0·215, vs −8·84%p [–12·73 to −4·95], p 1 . The effect of Idebenone on respiratory function outcomes was similar between patients with previous corticosteroid use and steroid-naive patients. Treatment with Idebenone was safe and well tolerated with adverse event rates were similar in both groups. Nasopharyngitis and headache were the most common adverse events (Idebenone, eight [25%] and six [19%] of 32 patients; placebo, nine [26%] and seven [21%] of 34 patients). Transient and mild diarrhoea was more common in the Idebenone group than in the placebo group (eight [25%] vs four [12%] patients). Interpretation Idebenone reduced the loss of respiratory function and represents a new treatment option for patients with Duchenne muscular dystrophy. Funding Santhera Pharmaceuticals.
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Idebenone as a novel therapeutic approach for Duchenne Muscular Dystrophy
European Neurological Review, 2015Co-Authors: Gunnar M. Buyse, Nuri Gueven, Craig M. McdonaldAbstract:Progressive loss of pulmonary function leads to early morbidity and mortality in Duchenne muscular dystrophy (DMD) due to both expiratory impairment with ineffective airway clearance, and inspiratory impairment leading to nocturnal and daytime hypoventilation and respiratory failure. Glucocorticoid steroids have become a mainstay of DMD therapy with well-documented efficacy on muscle strength and respiratory function. However, the side-effect profile restricts their long-term use, particularly in non-ambulant patients. Idebenone improves secondary mitochondrial dysfunction caused by dystrophin deficiency, intracellular calcium accumulation and increased reactive oxygen species (ROS). Idebenone-mediated improved bioenergetics leads to enhanced adenosine triphosphate (ATP) production and reduced ROS. Based on this rationale, Idebenone has been investigated clinically for efficacy on reducing respiratory function decline in exploratory phase II (DELPHI) and confirmatory phase III (DELOS) trials. Idebenone significantly reduced the loss of respiratory function in 8–18-year-old DMD patients who were not using concomitant glucocorticoids. These results indicate that Idebenone can modify the natural course of respiratory disease progression in DMD, which is relevant in clinical practice where loss of respiratory function continues to be a predominant cause of early morbidity and mortality in DMD.
Pengfei Lin - One of the best experts on this subject based on the ideXlab platform.
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Idebenone protects against atherosclerosis in apolipoprotein e deficient mice via activation of the sirt3 sod2 mtros pathway
Cardiovascular Drugs and Therapy, 2020Co-Authors: Wei Jiang, Hongzhi Geng, Pengfei Lin, Fuchen Liu, Chuanzhu YanAbstract: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 16 weeks. A total of 60 mice were randomized into the following four groups: (1) HFD, (2) HFD and low-dose Idebenone (100 mg/kg/d), (3) HFD and medium-dose Idebenone (200 mg/kg/d), and (4) HFD and high-dose (400 mg/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.
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Idebenone protects against atherosclerosis in apolipoprotein E-deficient mice via activation of the Sirt3-SOD2-mtROS pathway
2020Co-Authors: Wei Jiang, Hongzhi Geng, Pengfei Lin, Chuanzhu YanAbstract:Abstract Background: 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. Idebenone functions as an electron carrier and antioxidant, and previous studies have shown that it effectively clears oxygen-free radicals. In the current study, we demonstrate that Idebenone could protect against atherosclerosis using apolipoprotein E-deficient mice. Methods: High-fat diet（HFD）and Idebenone treatment with apolipoprotein E-deficient mice . A total of 60 mices were randomized into the following four groups: (1) HFD (2) Idebenone-low dose (3) Idebenone-medium dose and (4) Idebenone-high dose for 16 weeks. The HUVECs were pretreated with endothelial cell medium in the presence or absence of 0.2 mM Idebenone working solution for 3 h followed by exposure to 10 μM cholesterol for 24 h. Proteomics analysis was performed between the HFD group (n=3) and the high-dose Idebenone group (n=3, concentration = 400 mg/kg/d).Results: Compared with the HFD group, Idebenone can suppresses the formation of atherosclerotic plaques and increases the stability of atherosclerotic plaques in apoE-/- mice; Compared with the control group, Idebenone can protects against endothelial cell damage and inhibits the production of mtROS in cholesterol mediated HUVECs; Idebenone could effectively inhibit the development and progression of atherosclerosis and the injury of endothelial cells through the SIRT3-SOD2-mtROS pathway.Conclusions: 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 SIRT3-SOD2-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.
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Idebenone protects against oxidized low density lipoprotein induced mitochondrial dysfunction in vascular endothelial cells via gsk3β β catenin signalling pathways
Biochemical and Biophysical Research Communications, 2015Co-Authors: Pengfei Lin, Junling Liu, Ming Ren, Bin Zhang, Yaoqin Gong, Chuanzhu YanAbstract:The early stages of the atherosclerotic process are initiated by accumulation of oxidized low-density lipoprotein (oxLDL) and damage to the structure or function of the endothelium. Antioxidant supplementation may be a plausible strategy to prevent atherosclerotic disease by quenching excessive reactive oxidative species. In the present study, we demonstrated that Idebenone at suitable concentrations significantly prevented oxLDL-induced endothelial dysfunction. The underlying mechanisms of Idebenone included inhibition of oxidative damage, suppression of the down-regulation of Bcl-2 and up-regulation of Bax and cleaved caspase-3 in human umbilical vein endothelial cells (HUVECs) exposed to oxLDL. Moreover, Idebenone pretreatment inhibited oxLDL-mediated HUVECs damage by attenuating lipid peroxidation and promoting SOD activity. Finally, pro-incubation with Idebenone inhibited mitochondrial dysfunction induced by oxLDL through the mitochondrial-dependent apoptotic pathway and GSK3β/β-catenin signalling pathways. In summary, Idebenone is a promising agent in the treatment or prevention of atherosclerosis via inhibiting oxidative stress and improving mitochondrial function.
