Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects

Ma, Wen-Qi; Sun, Xuejiao; Zhu, Yi; Liu, Naifeng

doi:10.1016/j.freeradbiomed.2021.01.033

Cited by 97 publications

(69 citation statements)

References 59 publications

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“…It is manifested as liposome peroxidation of the polyunsaturated fatty acids highly expressed on the cell membrane under the action of divalent iron, and it thereby induces cell death (18). Studies have shown that ferroptosis may be related to the calcification of VSMCs (46). The relationship with endothelial cell calcification has not yet been studied, and our results confirm for the first time that ferroptosis is involved in the process of endothelial cell calcification.…”

Section: Relative Protein Expression Of Ferritin Relative Protein Expression Of Dmt1supporting

confidence: 64%

Effect of iron overload on endothelial cell calcification and its mechanism

Zhao¹,

Yang²,

Song³

et al. 2021

Ann Transl Med

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Background: Vascular calcification is related to many diseases. Iron has a certain relationship with endothelial cells and vascular calcification. The purpose of this study was to assess the effect of iron overload on endothelial cell calcification and related mechanisms through cell experiments.Methods: Human umbilical vein endothelial cells were treated with different concentrations of FeSO 4 (50, 100, 150, and 200 μM), and deferoxamine (DFO) and ferrostatin. Alkaline phosphatase activity, malondialdehyde (MDA) level, reactive oxygen species (ROS) level, and lipid superoxidation after FeSO 4 treatment were assessed. Alizarin red staining was used to observe calcium deposition. Quantitative polymerase chain reaction (qPCR) and western blot were adopted to examine the expression of calcification markers, iron metabolism-related factors, apoptosis pathway-related factors and ferroptosis markers. The TUNEL method was employed to detect cell apoptosis.Results: FeSO 4 of 100 μM significantly promoted the occurrence of cell ferroptosis, increased the levels of MDA and ROS, and decreased the ratio of glutathione (GSH) or glutathione disulfide (GSSG) and the expression level of glutathione peroxidase (GPX4). The addition of DFO and ferrostatin significantly modified the effects of FeSO 4 . Calcium deposition was most obvious in the cells treated with 100 μM FeSO 4 .FeSO 4 significantly upregulated Runt-related transcription factor 2 (RUNX2) and Bone morphogenetic protein 2 (BMP2), ferritin heavy chain (FTH) and ferritin light chain (FTL), and downregulated Matrix Gla Protein (MGP) and divalent metal transporter 1 (DMT1). The results also showed that FeSO 4 induced cell apoptosis by TUNEL method. The elevated Bcl2-associated death protein (Bad) and Bcl2-associated X protein (Bax) and the reduction in Bcl-2, p-Bad, p-AKT, and t-AKT were found. DFO and ferrostatin significantly reduced the iron-induced calcification and apoptosis of endothelial cells. DFO significantly increased the expression level of Bcl-2, and reduced the expression level of Bad. Conclusions: Iron overload contributes to the process of endothelial cell calcification by inducing apoptosis and ferroptosis. Iron chelators and ferroptosis inhibitors alleviate endothelial cell apoptosis, ferroptosis, and calcification induced by iron overload.

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Section: Relative Protein Expression Of Ferritin Relative Protein Expression Of Dmt1supporting

confidence: 64%

Effect of iron overload on endothelial cell calcification and its mechanism

Zhao¹,

Yang²,

Song³

et al. 2021

Ann Transl Med

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“…Metformin is a commonly used anti-diabetic agent ( 121 ). Metformin attenuates hyperlipidemia/PA-induced vascular calcification through anti-ferroptosis effects ( 122 ). It is possible that metformin may also exert its anti-diabetic effects through this pathway, but further studies are needed to confirm this hypothesis.…”

Section: Ferroptosis Inhibitors In Diabetes and Diabetic Complicationsmentioning

confidence: 99%

Ferroptosis as a Novel Therapeutic Target for Diabetes and Its Complications

Yang

2022

Front. Endocrinol.

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The global diabetes epidemic and its complications are increasing, thereby posing a major threat to public health. A comprehensive understanding of diabetes mellitus (DM) and its complications is necessary for the development of effective treatments. Ferroptosis is a newly identified form of programmed cell death caused by the production of reactive oxygen species and an imbalance in iron homeostasis. Increasing evidence suggests that ferroptosis plays a pivotal role in the pathogenesis of diabetes and diabetes-related complications. In this review, we summarize the potential impact and regulatory mechanisms of ferroptosis on diabetes and its complications, as well as inhibitors of ferroptosis in diabetes and diabetic complications. Therefore, understanding the regulatory mechanisms of ferroptosis and developing drugs or agents that target ferroptosis may provide new treatment strategies for patients with diabetes.

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“…Treating VSMCs with palmitic acid (PA) upregulates the expression of extracellular matrix protein periostin (POSTN), which inhibits SLC7A11 expression by suppresses the expression of P53 gene in VSMCs, and therefore reduces the synthesis of GSH, leading to ferroptosis. However, pretreating with metformin activates Nrf2 pathway, a powerful antioxidant system, significantly reducing ferroptosis in VSMCs [57]. All of these indicate that we can target ferroptosis to protect VSMCs.…”

Section: Vascular Smooth Muscle Cellsmentioning

confidence: 89%

Ferroptosis in Cardiovascular Diseases: Current Status, Challenges, and Future Perspectives

Guo

Lü

et al. 2022

Biomolecules

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Cardiovascular diseases (CVDs) are still a major cause of global mortality and disability, seriously affecting people’s lives. Due to the severity and complexity of these diseases, it is important to find new regulatory mechanisms to treat CVDs. Ferroptosis is a new kind of regulatory cell death currently being investigated. Increasing evidence showed that ferroptosis plays an important role in CVDs, such as in ischemia/reperfusion injury, heart failure, cardiomyopathy, and atherosclerosis. Protecting against CVDs by targeting ferroptosis is a promising approach; therefore, in this review, we summarized the latest regulatory mechanism of ferroptosis and the current studies related to each CVD, followed by critical perspectives on the ferroptotic treatment of CVDs and the future direction of this intriguing biology.

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Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects

Cited by 97 publications

References 59 publications

Effect of iron overload on endothelial cell calcification and its mechanism

Effect of iron overload on endothelial cell calcification and its mechanism

Ferroptosis as a Novel Therapeutic Target for Diabetes and Its Complications

Ferroptosis in Cardiovascular Diseases: Current Status, Challenges, and Future Perspectives

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