Suppression of antioxidant Nrf-2 and downstream pathway in H9c2 cells by advanced glycation end products (AGEs) via ERK phosphorylation

Ko, Shun‐Yao; Chang, Shu‐Shing; Lin, I-Hsuan; Chen, Hong‐I

doi:10.1016/j.biochi.2015.07.019

Cited by 18 publications

(11 citation statements)

References 58 publications

(49 reference statements)

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“…Akt signaling can impact on crosstalk with other signaling pathways including MAPK signaling, and NF-κB signaling pathways. Additionally, the ERK signaling pathway is reported to be involved in DCM, wherein ERK is significantly phosphorylated and inhibits Nrf2 signaling, resulting in cell hypertrophy1240. Furthermore, our previous studies have confirmed that phosphorylation of Akt regulates Nrf2 activation and HO-1 expression1641.…”

Section: Discussionmentioning

confidence: 63%

“…Additionally, high levels of AGEs appear to be tightly related to instances of DCM, which result in superfluous oxidative stress and inflammatory responses. Ko and his colleagues found that 400 μg/ml AGEs could increase ROS production through suppression of antioxidant Nrf-2 and downstream pathway in H9c2 cells12. Clinically, serum AGEs levels were increased not only in patients with osteoporosis (14.75 vs. 8.12 U/ml)13, but in DM patients with vascular complications (3.40 vs. 1.12 μg/ml)14, indicating that AGEs are associated with cardiac injury resulting from DCM.…”

mentioning

confidence: 98%

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Myricitrin Alleviates Oxidative Stress-induced Inflammation and Apoptosis and Protects Mice against Diabetic Cardiomyopathy

Zhang

Shen

Chen

et al. 2017

Sci Rep

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Diabetic cardiomyopathy (DCM) has been increasingly considered as a main cause of heart failure and death in diabetic patients. At present, no effective treatment exists to prevent its development. In the present study, we describe the potential protective effects and mechanisms of myricitrin (Myr) on the cardiac function of streptozotosin-induced diabetic mice and on advanced glycation end products (AGEs)-induced H9c2 cardiomyocytes. In vitro experiments revealed that pretreatment with Myr significantly decreased AGEs-induced inflammatory cytokine expression, limited an increase in ROS levels, and reduced cell apoptosis, fibrosis, and hypertrophy in H9c2 cells. These effects are correlated with Nrf2 activation and NF-κB inhibition. In vivo investigation demonstrated that oral administration of Myr at 300 mg/kg/day for 8 weeks remarkably decreased the expression of enzymes associated with cardiomyopathy, as well as the expression of inflammatory cytokines and apoptotic proteins. Finally, Myr improved diastolic dysfunction and attenuated histological abnormalities. Mechanistically, Myr attenuated diabetes-induced Nrf2 inhibition via the regulation of Akt and ERK phosphorylation in the diabetic heart. Collectively, these results strongly indicate that Myr exerts cardioprotective effects against DCM through the blockage of inflammation, oxidative stress, and apoptosis. This suggests that Myr might be a potential therapeutic agent for the treatment of DCM.

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Section: Discussionmentioning

confidence: 63%

mentioning

confidence: 98%

Myricitrin Alleviates Oxidative Stress-induced Inflammation and Apoptosis and Protects Mice against Diabetic Cardiomyopathy

Zhang

Shen

Chen

et al. 2017

Sci Rep

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“…Overproduction of AGEs in diabetes is a risk factor for DCM ( Yuan et al, 2014 ; Guo et al, 2015 ; Hou et al, 2016 ), which leads to severe oxidative stress and inflammatory responses. Ko et al (2015) showed that 400 μg/ml AGEs could increase ROS production through inhibition of antioxidant Nrf-2 and its downstream pathway in H9c2 cells. AGEs are reported to increase ROS production by RAGE/TLR4-NF-κB-ROS pathways ( Ohtsu et al, 2017 ) and hyperglycemia stimulates ROS generation via activation of MAPK and PKC-NAD(P)H oxidase pathway ( Batchuluun et al, 2014 ; Cheng Y.S.…”

Section: Discussionmentioning

confidence: 99%

Notoginsenoside R1 Protects Against Diabetic Cardiomyopathy Through Activating Estrogen Receptor α and Its Downstream Signaling

Zhang

et al. 2018

Front. Pharmacol.

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Diabetic cardiomyopathy (DCM) leads to heart failure and death in diabetic patients, no effective treatment is available. Notoginsenoside R1 (NGR1) is a novel saponin that is derived from Panax notoginseng and our previous studies have showed cardioprotective and neuroprotective effects of NGR1. However, its role in protecting against DCM remains unexplored. Herein, we examine potential effects of NGR1 on cardiac function of diabetic db/db mice and H9c2 cardiomyocytes treated by advanced glycation end products (AGEs). In vitro experiments revealed that pretreatment with NGR1 significantly decreased AGEs-induced mitochondria injury, limited an increase in ROS, and reduced apoptosis in H9c2 cells. NGR1 eliminated ROS by promoting estrogen receptor α expression, which subsequently activated Akt and Nrf2-mediated anti-oxidant enzymes. In vivo investigation demonstrated that NGR1 significantly reduced serum lipid levels, insulin resistance, the expression of enzymes related to cardiomyopathy, and the expression of apoptotic proteins. Finally, NGR1 improved cardiac dysfunction and attenuated histological abnormalities, as evidenced by elevating ejection fraction and fractional shortening, and reducing cardiac fibrosis. Mechanistically, NGR1 promoted ERα expression, which led to the activation of Akt-Nrf2 signaling and the inhibition of the TGFβ pathway. Collectively, these results strongly indicate that NGR1 exerts cardioprotective effects against DCM through its inhibition of oxidative stress and apoptosis, and eventually suppresses cardiac fibrosis and hypertrophy, which suggests that NGR1 is a potential therapeutic medicine for the treatment of DCM.

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“…In the development of diabetic nephropathy (DN), AGEs induces expressions of fibronectin and TGF-β1, which is attenuated by sirt1 through activating the Nrf2/ARE pathway [28]. One further trial has revealed that AGEs promotes ERK phosphorylation, resulting in a reduction in Nrf-2 and downstream pathway [29]. Thus, how to activate Nrf2-mediated signaling and antioxidant system remains meaningful for the treatment of diabetic complications.…”

Section: Discussionmentioning

confidence: 99%

Myricitrin Attenuates High Glucose-Induced Apoptosis through Activating Akt-Nrf2 Signaling in H9c2 Cardiomyocytes

et al. 2016

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Hyperglycemia, as well as diabetes mellitus, has been shown to trigger cardiac cell apoptosis. We have previously demonstrated that myricitrin prevents endothelial cell apoptosis. However, whether myricitrin can attenuate H9c2 cell apoptosis remains unknown. In this study, we established an experiment model in H9c2 cells exposed to high glucose. We tested the hypothesis that myricitrin may inhibit high glucose (HG)-induced cardiac cell apoptosis as determined by TUNEL staining. Furthermore, myricitrin promoted antioxidative enzyme production, suppressed high glucose-induced reactive oxygen species (ROS) production and decreased mitochondrial membrane potential (MMP) in H9c2 cells. This agent significantly inhibited apoptotic protein expression, activated Akt and facilitated the transcription of NF-E2-related factor 2 (Nrf2)-mediated protein (heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO-1) expression as determined by Western blotting. Significantly, an Akt inhibitor (LY294002) or HO-1 inhibitor (ZnPP) not only inhibited myricitrin-induced HO-1/NQO-1 upregulation but also alleviated its anti-apoptotic effects. In summary, these observations demonstrate that myricitrin activates Nrf2-mediated anti-oxidant signaling and attenuates H9c2 cell apoptosis induced by high glucose via activation of Akt signaling.

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Suppression of antioxidant Nrf-2 and downstream pathway in H9c2 cells by advanced glycation end products (AGEs) via ERK phosphorylation

Cited by 18 publications

References 58 publications

Myricitrin Alleviates Oxidative Stress-induced Inflammation and Apoptosis and Protects Mice against Diabetic Cardiomyopathy

Myricitrin Alleviates Oxidative Stress-induced Inflammation and Apoptosis and Protects Mice against Diabetic Cardiomyopathy

Notoginsenoside R1 Protects Against Diabetic Cardiomyopathy Through Activating Estrogen Receptor α and Its Downstream Signaling

Myricitrin Attenuates High Glucose-Induced Apoptosis through Activating Akt-Nrf2 Signaling in H9c2 Cardiomyocytes

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