Metformin protects cardiomyocytes against oxygen-glucose deprivation injury by promoting autophagic flux through AMPK pathway

Wu, Shiyong; Zhang, Hairong; Chen, Ningheng; Zhang, Chuang; Guo, Xiaoxiao

doi:10.1080/1061186x.2020.1868478

Cited by 9 publications

(6 citation statements)

References 37 publications

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“…The in vivo effect of MET on MGO-induced apoptosis was determined by using an MGO-induced vascular injury model in mice, and our data also demonstrated that MET prevented apoptosis induced by MGO by inhibiting the activation of cleaved caspase-3. These findings were consistent with previous studies [ 33 , 48 ], indicating that MET effectively prevented HUVEC apoptosis, providing novel insights into the mechanisms of action of MET.…”

Section: Discussionsupporting

confidence: 93%

Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo

Wang

Yang

et al. 2022

Cell Death Dis

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Methylglyoxal (MGO) is an active metabolite of glucose and plays a prominent role in the pathogenesis of diabetic vascular complications, including endothelial cell apoptosis induced by oxidative stress. Metformin (MET), a widely prescribed antidiabetic agent, appears to reduce excessive reactive oxygen species (ROS) generation and limit cell apoptosis. However, the molecular mechanisms underlying this process are still not fully elucidated. We reported here that MET prevents MGO-induced apoptosis by suppressing oxidative stress in vitro and in vivo. Protein expression and protein phosphorylation were investigated using western blotting, ELISA, and immunohistochemical staining, respectively. Cell viability and apoptosis were assessed by the MTT assay, TUNEL staining, and Annexin V-FITC and propidium iodide double staining. ROS generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Our results revealed that MET prevented MGO-induced HUVEC apoptosis, inhibited apoptosis-associated biochemical changes such as loss of MMP, the elevation of the Bax/Bcl-2 ratio, and activation of cleaved caspase-3, and attenuated MGO-induced mitochondrial morphological alterations in a dose-dependent manner. MET pretreatment also significantly suppressed MGO-stimulated ROS production, increased signaling through the ROS-mediated PI3K/Akt and Nrf2/HO-1 pathways, and markedly elevated the levels of its downstream antioxidants. Finally, similar results were obtained in vivo, and we demonstrated that MET prevented MGO-induced oxidative damage, apoptosis, and inflammation. As expected, MET reversed MGO-induced downregulation of Nrf2 and p-Akt. In addition, a PI3K inhibitor (LY-294002) and a Nrf2 inhibitor (ML385) observably attenuated the protective effects of MET on MGO-induced apoptosis and ROS generation by inhibiting the Nrf2/HO-1 pathways, while a ROS scavenger (NAC) and a permeability transition pores inhibitor (CsA) completely reversed these effects. Collectively, these findings broaden our understanding of the mechanism by which MET regulates apoptosis induced by MGO under oxidative stress conditions, with important implications regarding the potential application of MET for the treatment of diabetic vascular complications.

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Section: Discussionsupporting

confidence: 93%

Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo

Wang

Yang

et al. 2022

Cell Death Dis

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“…Also, MET enhanced autophagy and was cardioprotective in δ‐sarcoglycan deficiency‐induced dilated cardiomyopathy (Kanamori et al, 2019). Consistently, MET was cardioprotective in a rat myocardial infarction model and in H9c2 cardiomyoblasts during oxygen–glucose deprivation injury by promoting autophagic flux through the AMPK pathway (Wu et al, 2021). Also, prolonged MET administration in mice decreased oxidative stress resulting in lower levels of chronic inflammation (Martin‐Montalvo et al, 2013); thus, adaptation of cells to prolonged MET administration is likely important for its beneficial effects on mitostasis.…”

Section: Discussionmentioning

confidence: 83%

Autophagy activation can partially rescue proteasome dysfunction‐mediated cardiac toxicity

et al. 2022

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The ubiquitin–proteasome pathway and its functional interplay with other proteostatic and/or mitostatic modules are crucial for cell viability, especially in post‐mitotic cells like cardiomyocytes, which are constantly exposed to proteotoxic, metabolic, and mechanical stress. Consistently, treatment of multiple myeloma patients with therapeutic proteasome inhibitors may induce cardiac failure; yet the effects promoted by heart‐targeted proteasome dysfunction are not completely understood. We report here that heart‐targeted proteasome knockdown in the fly experimental model results in increased proteome instability and defective mitostasis, leading to disrupted cardiac activity, systemic toxicity, and reduced longevity. These phenotypes were partially rescued by either heart targeted‐ or by dietary restriction‐mediated activation of autophagy. Supportively, activation of autophagy by Rapamycin or Metformin administration in flies treated with proteasome inhibitors reduced proteome instability, partially restored mitochondrial function, mitigated cardiotoxicity, and improved flies' longevity. These findings suggest that autophagic inducers represent a novel promising intervention against proteasome inhibitor‐induced cardiovascular complications.

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“…To establish in vitro MI model, H9c2 cells were placed in DMEM deprived of glucose (Thermo) and placed in a 37°C anaerobic atmosphere (1% O 2 and 5% CO 2 ) for 24 h ( Du et al, 2020 ; Niu et al, 2020 ; Wu et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Resveratrol Attenuate Myocardial Injury by Inhibiting Ferroptosis Via Inducing KAT5/GPX4 in Myocardial Infarction

et al. 2022

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Myocardial infarction (MI) is a coronary artery-related disease and ranks as the leading cause of sudden death globally. Resveratrol (Res) is a bioactive component and has presented antioxidant, anti-inflammatory and anti-microbial properties. However, the effect of Res on ferroptosis during MI progression remains elusive. Here, we aimed to explore the function of Res in the regulation of ferroptosis and myocardial injury in MI. We observed that the treatment of Res attenuated the MI-related myocardium injury and fibrosis in the rats. The expression of collagen 1 and α-SMA was induced in MI rats, in which the treatment of Res could decrease the expression. Treatment of Res suppressed the levels of IL-6 and IL-1β in MI rats. The GSH levels were inhibited and MDA, lipid ROS, and Fe2+ levels were induced in MI rats, in which the treatment of Res could reverse the phenotypes. Meanwhile, the expression of GPX4 and SLC7A11 was reduced in MI rats, while the treatment of Res could rescue the expression in the model. Meanwhile, Res relieved oxygen-glucose deprivation (OGD)-induced cardiomyocyte injury. Importantly, Res repressed OGD-induced cardiomyocyte ferroptosis in vitro. Mechanically, we identified that Res was able to enhance GPX4 expression by inducing KAT5 expression. We confirmed that KAT5 alleviated OGD-induced cardiomyocyte injury and ferroptosis. The depletion of KAT5 or GPX4 could reverse the effect of Res on OGD-induced cardiomyocyte injury. Thus, we concluded that Res attenuated myocardial injury by inhibiting ferroptosis via inducing KAT5/GPX4 in myocardial infarction. Our finding provides new evidence of the potential therapeutic effect of Res on MI by targeting ferroptosis.

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Metformin protects cardiomyocytes against oxygen-glucose deprivation injury by promoting autophagic flux through AMPK pathway

Cited by 9 publications

References 37 publications

Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo

Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo

Autophagy activation can partially rescue proteasome dysfunction‐mediated cardiac toxicity

Resveratrol Attenuate Myocardial Injury by Inhibiting Ferroptosis Via Inducing KAT5/GPX4 in Myocardial Infarction

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