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      RAGE Regulating Vascular Remodeling in Diabetes by Regulating Mitochondrial Dynamics with JAK2/STAT3 Pathway


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          In this research, we will explore the role and modulation of mitochondrial dynamics in diabetes vascular remodeling. Only a few cell types express the pattern recognition receptor, also known as the AGE receptor (RAGE). However, it is triggered in almost all of the cells that have been investigated thus far by events that are known to cause inflammation. Here, Type 2 diabetes was studied in both cellular and animal models. Elevated Receptor for advanced glycation end products (RAGE), phosphorylated JAK2 (p-JAK2), phosphorylated STAT3 (p-STAT3), transient receptor potential ion channels (TRPM), and phosphorylated dynamin-related protein 1 (p-DRP1) were observed in the context of diabetes. In addition, we found that inhibition of RAGE was followed by a remarkable decrease in the expression of the above proteins. It has also been demonstrated by western blotting and immunofluorescence results in vivo and in vitro. Suppressing STAT3 and DRP1 phosphorylation produced effects similar to those of RAGE inhibition on the proliferation, cell cycle, migration, invasion, and expression of TRPM in VSMCs and vascular tissues obtained from diabetic animals. These findings indicate that RAGE regulates vascular remodeling via mitochondrial dynamics through modulating the JAK2/STAT3 axis in diabetes. The findings could be crucial in gaining a better understanding of diabetes-related vascular remodeling. It also contributes to a better cytopathological understanding of diabetic vascular disease and provides a theoretical foundation for novel targets that aid in the prevention and treatment of diabetes-related cardiovascular problems.

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              Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission

              Metformin is a widely used antidiabetic drug that exerts cardiovascular protective effects in patients with diabetes. How metformin protects against diabetes-related cardiovascular diseases remains poorly understood. Here, we show that metformin abated the progression of diabetes-accelerated atherosclerosis by inhibiting mitochondrial fission in endothelial cells. Metformin treatments markedly reduced mitochondrial fragmentation, mitigated mitochondrial-derived superoxide release, improved endothelial-dependent vasodilation, inhibited vascular inflammation, and suppressed atherosclerotic lesions in streptozotocin (STZ)-induced diabetic ApoE−/− mice. In high glucose–exposed endothelial cells, metformin treatment and adenoviral overexpression of constitutively active AMPK downregulated mitochondrial superoxide, lowered levels of dynamin-related protein (Drp1) and its translocation into mitochondria, and prevented mitochondrial fragmentation. In contrast, AMPK-α2 deficiency abolished the effects of metformin on Drp1 expression, oxidative stress, and atherosclerosis in diabetic ApoE−/−/AMPK-α2−/− mice, indicating that metformin exerts an antiatherosclerotic action in vivo via the AMPK-mediated blockage of Drp1-mediated mitochondrial fission. Consistently, mitochondrial division inhibitor 1, a potent and selective Drp1 inhibitor, reduced mitochondrial fragmentation, attenuated oxidative stress, ameliorated endothelial dysfunction, inhibited inflammation, and suppressed atherosclerosis in diabetic mice. These findings show that metformin attenuated the development of atherosclerosis by reducing Drp1-mediated mitochondrial fission in an AMPK-dependent manner. Suppression of mitochondrial fission may be a therapeutic approach for treating macrovascular complications in patients with diabetes.

                Author and article information

                Comput Intell Neurosci
                Comput Intell Neurosci
                Computational Intelligence and Neuroscience
                22 April 2022
                : 2022
                : 2685648
                Department of Cardiology, Huashan Hospital Fudan University, No.12 Urumqi Middle Road, Shanghai 200040, China
                Author notes

                Academic Editor: Rahim Khan

                Author information
                Copyright © 2022 Shengjia Sun et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 11 January 2022
                : 6 March 2022
                : 18 March 2022
                Research Article



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