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      Gypenoside Inhibits Endothelial Cell Apoptosis in Atherosclerosis by Modulating Mitochondria through PI3K/Akt/Bad Pathway

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          Abstract

          Atherosclerosis remains the most common cause of deaths worldwide. Endothelial cell apoptosis is an important process in the progress of atherosclerosis, as it can cause the endothelium to lose their capability in regulating the lipid homeostasis, inflammation, and immunity. Endothelial cell injury can disrupt the integrity and barrier function of an endothelium and facilitate lipid deposition, leading to atherogenesis. Chinese medicine techniques for preventing and treating atherosclerosis are gaining attention, especially natural products. In this study, we demonstrated that gypenoside could decrease the levels of serum lipid, alleviate the formation of atherosclerotic plaque, and lessen aortic intima thickening. Gypenoside potentially activates the PI3K/Akt/Bad signal pathway to modulate the apoptosis-related protein expression in the aorta. Moreover, gypenoside downregulated mitochondrial fission and fusion proteins, mitochondrial energy-related proteins in the mouse aorta. In conclusion, this study demonstrated a new function of gypenoside in endothelial apoptosis and suggested a therapeutic potential of gypenoside in atherosclerosis associated with apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway.

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          Most cited references45

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          Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane

          In this study, O'Neill et al. used genome editing to generate cells deficient for all eight proapoptotic BH3-only proteins (OctaKO) and cells that lack the entire Bcl-2 family (Bcl-2 allKO). Their findings suggest that the outer mitochondrial membrane (OMM), not BH3-only proteins or p53/Rb, is the direct activator of Bax/Bak following BH3-only-mediated neutralization of anti-apoptotic Bcl-2 proteins. The mechanism of Bax/Bak activation remains a central question in mitochondria-dependent apoptotic signaling. While it is established that all proapoptotic Bcl-2 homology 3 (BH3)-only proteins bind and neutralize the anti-apoptotic Bcl-2 family proteins, how this neutralization leads to Bax/Bak activation has been actively debated. Here, genome editing was used to generate cells deficient for all eight proapoptotic BH3-only proteins (OctaKO) and those that lack the entire Bcl-2 family (Bcl-2 allKO). Although the OctaKO cells were resistant to most apoptotic stimuli tested, they underwent Bax/Bak-dependent and p53/Rb-independent apoptosis efficiently when both Bcl-xL and Mcl-1, two anti-apoptotic Bcl-2 proteins, were inactivated or eliminated. Strikingly, when expressed in the Bcl-2 allKO cells, both Bax and Bak spontaneously associated with the outer mitochondrial membrane (OMM) through their respective helix 9, and this association triggered their homo-oligomerization/activation. Together, these results strongly suggest that the OMM, not BH3-only proteins or p53/Rb, is the long-sought-after direct activator of Bax/Bak following BH3-only-mediated neutralization of anti-apoptotic Bcl-2 proteins.
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            Exosome-Mediated miR-155 Transfer from Smooth Muscle Cells to Endothelial Cells Induces Endothelial Injury and Promotes Atherosclerosis.

            The vascular response to pro-atherosclerotic factors is a multifactorial process involving endothelial cells (ECs), macrophages (MACs), and smooth muscle cells (SMCs), although the mechanism by which these cell types communicate with each other in response to environmental cues is yet to be understood. Here, we show that miR-155, which is significantly expressed and secreted in Krüppel-like factor 5 (KLF5)-overexpressing vascular smooth muscle cells (VSMCs), is a potent regulator of endothelium barrier function through regulating endothelial targeting tight junction protein expression. VSMCs-derived exosomes mediate the transfer of KLF5-induced miR-155 from SMCs to ECs, which, in turn, destroys tight junctions and the integrity of endothelial barriers, leading to an increased endothelial permeability and enhanced atherosclerotic progression. Moreover, overexpression of miR-155 in ECs inhibits endothelial cell proliferation/migration and re-endothelialization in vitro and in vivo and thus increases vascular endothelial permeability. Blockage of the exosome-mediated transfer of miR-155 between these two cells may serve as a therapeutic target for atherosclerosis.
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              DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C. elegans.

              Genetic analyses in Caenorhabditis elegans have been instrumental in the elucidation of the central cell-death machinery, which is conserved from C. elegans to mammals. One possible difference that has emerged is the role of mitochondria. By releasing cytochrome c, mitochondria are involved in the activation of caspases in mammals. However, there has previously been no evidence that mitochondria are involved in caspase activation in C. elegans. Here we show that mitochondria fragment in cells that normally undergo programmed cell death during C. elegans development. Mitochondrial fragmentation is induced by the BH3-only protein EGL-1 and can be blocked by mutations in the bcl-2-like gene ced-9, indicating that members of the Bcl-2 family might function in the regulation of mitochondrial fragmentation in apoptotic cells. Mitochondrial fragmentation is independent of CED-4/Apaf-1 and CED-3/caspase, indicating that it occurs before or simultaneously with their activation. Furthermore, DRP-1/dynamin-related protein, a key component of the mitochondrial fission machinery, is required and sufficient to induce mitochondrial fragmentation and programmed cell death during C. elegans development. These results assign an important role to mitochondria in the cell-death pathway in C. elegans.
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                Author and article information

                Contributors
                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi
                2314-6133
                2314-6141
                2020
                20 June 2020
                : 2020
                : 2819658
                Affiliations
                1Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China
                2National Local Joint Engineering Laboratory for the Prevention and Treatment of Cardioencephalopathy with Integrated Traditional Chinese and Western Medicine, Shenyang 110847, China
                Author notes

                Academic Editor: Luis Loura

                Author information
                https://orcid.org/0000-0003-0923-6987
                https://orcid.org/0000-0001-6652-0680
                Article
                10.1155/2020/2819658
                7327587
                32685460
                d32bde5f-3b99-4b9e-94a5-70487579eccf
                Copyright © 2020 Nan Song 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.

                History
                : 4 December 2019
                : 13 April 2020
                : 21 April 2020
                Funding
                Funded by: Natural Science Foundation of Liaoning Province
                Award ID: 2019-ZD-0966
                Funded by: National Natural Science Foundation of China
                Award ID: 81774022
                Funded by: Liaoning Provincial Central Committee Guides Local Science and Technology Development Project
                Award ID: 2017105002
                Categories
                Research Article

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