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Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux
INTRODUCTION: Vascular smooth muscle cell (VSMC) senescence in the vasculature results in vascular aging as well as age-related diseases, while metformin improves the inflamm-aging profile by enhancing autophagy. However, metformin’s impact on VSMC senescence is largely undefined. OBJECTIVES: To tes...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9637479/ https://www.ncbi.nlm.nih.gov/pubmed/36328749 http://dx.doi.org/10.1016/j.jare.2021.12.009 |
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author | Tai, Shi Sun, Jiaxing Zhou, Yuying Zhu, Zhaowei He, Yuhu Chen, Mingxian Yang, Hui Xiao, Yichao Tu, Tao Tang, Liang Li, Xuping Zeng, Jianping Zheng, Xilong Zhou, Shenghua |
author_facet | Tai, Shi Sun, Jiaxing Zhou, Yuying Zhu, Zhaowei He, Yuhu Chen, Mingxian Yang, Hui Xiao, Yichao Tu, Tao Tang, Liang Li, Xuping Zeng, Jianping Zheng, Xilong Zhou, Shenghua |
author_sort | Tai, Shi |
collection | PubMed |
description | INTRODUCTION: Vascular smooth muscle cell (VSMC) senescence in the vasculature results in vascular aging as well as age-related diseases, while metformin improves the inflamm-aging profile by enhancing autophagy. However, metformin’s impact on VSMC senescence is largely undefined. OBJECTIVES: To test the hypothesis that metformin exerts an anti-senescence role by restoring autophagic activity in VSMCs and vascular tissues. METHODS: Animal models established by angiotensin II (Ang II) induction and physiological aging and senescent primary VSMCs from the aortas of elderly patients were treated with metformin. Cellular and vascular senescence were assessed by measuring the amounts of senescence-associated β-galactosidase and senescence markers, including p21 and p53. Autophagy levels were assessed by autophagy-related protein expression, transmission electron microscope, and autolysosome staining. In order to explore the underlying mechanism of the anti-senescence effects of metformin, 4D label-free quantitative proteomics and bioinformatic analyses were conducted, with subsequent experiments validating these findings. RESULTS: Ang II-dependent senescence was suppressed by metformin in VSMCs and vascular tissues. Metformin also significantly improved arterial stiffness and alleviated structural changes in aged arteries, reduced senescence-associated secretory phenotype (SASP), and improved proliferation and migration of senescent VSMCs. Mechanistically, the proteomic analysis indicated that autophagy might contribute to metformin’s anti-senescence effects. Reduced autophagic flux was observed in Ang II-induced cellular and vascular senescence; this reduction was reversed by metformin. Specifically, metformin enhanced the autophagic flux at the autophagosome-lysosome fusion level, whereas blockade of autophagosome-lysosome fusion inhibited the anti-senescence effects of metformin. CONCLUSIONS: Metformin prevents VSMC and vascular senescence by promoting autolysosome formation. |
format | Online Article Text |
id | pubmed-9637479 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-96374792022-11-07 Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux Tai, Shi Sun, Jiaxing Zhou, Yuying Zhu, Zhaowei He, Yuhu Chen, Mingxian Yang, Hui Xiao, Yichao Tu, Tao Tang, Liang Li, Xuping Zeng, Jianping Zheng, Xilong Zhou, Shenghua J Adv Res Original Article INTRODUCTION: Vascular smooth muscle cell (VSMC) senescence in the vasculature results in vascular aging as well as age-related diseases, while metformin improves the inflamm-aging profile by enhancing autophagy. However, metformin’s impact on VSMC senescence is largely undefined. OBJECTIVES: To test the hypothesis that metformin exerts an anti-senescence role by restoring autophagic activity in VSMCs and vascular tissues. METHODS: Animal models established by angiotensin II (Ang II) induction and physiological aging and senescent primary VSMCs from the aortas of elderly patients were treated with metformin. Cellular and vascular senescence were assessed by measuring the amounts of senescence-associated β-galactosidase and senescence markers, including p21 and p53. Autophagy levels were assessed by autophagy-related protein expression, transmission electron microscope, and autolysosome staining. In order to explore the underlying mechanism of the anti-senescence effects of metformin, 4D label-free quantitative proteomics and bioinformatic analyses were conducted, with subsequent experiments validating these findings. RESULTS: Ang II-dependent senescence was suppressed by metformin in VSMCs and vascular tissues. Metformin also significantly improved arterial stiffness and alleviated structural changes in aged arteries, reduced senescence-associated secretory phenotype (SASP), and improved proliferation and migration of senescent VSMCs. Mechanistically, the proteomic analysis indicated that autophagy might contribute to metformin’s anti-senescence effects. Reduced autophagic flux was observed in Ang II-induced cellular and vascular senescence; this reduction was reversed by metformin. Specifically, metformin enhanced the autophagic flux at the autophagosome-lysosome fusion level, whereas blockade of autophagosome-lysosome fusion inhibited the anti-senescence effects of metformin. CONCLUSIONS: Metformin prevents VSMC and vascular senescence by promoting autolysosome formation. Elsevier 2021-12-22 /pmc/articles/PMC9637479/ /pubmed/36328749 http://dx.doi.org/10.1016/j.jare.2021.12.009 Text en © 2022 The Authors. Published by Elsevier B.V. on behalf of Cairo University. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Tai, Shi Sun, Jiaxing Zhou, Yuying Zhu, Zhaowei He, Yuhu Chen, Mingxian Yang, Hui Xiao, Yichao Tu, Tao Tang, Liang Li, Xuping Zeng, Jianping Zheng, Xilong Zhou, Shenghua Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux |
title | Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux |
title_full | Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux |
title_fullStr | Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux |
title_full_unstemmed | Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux |
title_short | Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux |
title_sort | metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9637479/ https://www.ncbi.nlm.nih.gov/pubmed/36328749 http://dx.doi.org/10.1016/j.jare.2021.12.009 |
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