Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE−/− mice
Abstract Background The protective effect of metformin (MET) on abdominal aortic aneurysm (AAA) has been reported. However, the related mechanism is still poor understood. In this study, we deeply investigated the role of metformin in AAA pathophysiology. Methods Angiotensin II (Ang-II) was used to...
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BMC
2019-08-01
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| Series: | Cell & Bioscience |
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| Online Access: | http://link.springer.com/article/10.1186/s13578-019-0332-9 |
| _version_ | 1818335185205198848 |
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| author | Zhu Wang Jingjing Guo Xinqiang Han Ming Xue Wenming Wang Lei Mi Yuguo Sheng Chao Ma Jian Wu Xuejun Wu |
| author_facet | Zhu Wang Jingjing Guo Xinqiang Han Ming Xue Wenming Wang Lei Mi Yuguo Sheng Chao Ma Jian Wu Xuejun Wu |
| author_sort | Zhu Wang |
| collection | DOAJ |
| description | Abstract Background The protective effect of metformin (MET) on abdominal aortic aneurysm (AAA) has been reported. However, the related mechanism is still poor understood. In this study, we deeply investigated the role of metformin in AAA pathophysiology. Methods Angiotensin II (Ang-II) was used to construct the AAA model in ApoE −/− mice. The related mechanism was explored using Western blot and quantitative real time PCR (qRT-PCR). We also observed the morphological changes in the abdominal aorta and the influence of metformin on biological behaviors of rat abdominal aortic VSMCs. Results The PI3K/AKT/mTOR pathway was activated in aneurysmal wall tissues of AAA patients and rat model. Treatment with metformin inhibited the breakage and preserved the elastin structure of the aorta, the loss of collagen, and the apoptosis of aortic cells. In addition, metformin significantly suppressed the activation of the PI3K/AKT/mToR pathway and decreased the mRNA and protein levels of LC3B and Beclin1, which were induced by Ang-II. Moreover, PI3K inhibitors enhanced the effect of metformin while PI3K agonists largely reversed this effect. Interestingly, the cell proliferation, apoptosis, migration and autophagy of vascular smooth muscle cells (VSMCs) induced by Ang-II were also decreased following metformin treatment. PI3K inhibitors and agonists strengthened and weakened the effects of metformin in VSMCs, respectively. Conclusions Metformin represses the pathophysiology of AAA by inhibiting the activation of PI3K/AKT/mTOR/autophagy pathway. This repression may be useful as a new therapeutic strategy for AAA. |
| first_indexed | 2024-12-13T14:19:24Z |
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| id | doaj.art-aa5e49178e86450da5bf92e7f1f3d0b1 |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-12-13T14:19:24Z |
| publishDate | 2019-08-01 |
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| series | Cell & Bioscience |
| spelling | doaj.art-aa5e49178e86450da5bf92e7f1f3d0b12022-12-21T23:42:09ZengBMCCell & Bioscience2045-37012019-08-019111510.1186/s13578-019-0332-9Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE−/− miceZhu Wang0Jingjing Guo1Xinqiang Han2Ming Xue3Wenming Wang4Lei Mi5Yuguo Sheng6Chao Ma7Jian Wu8Xuejun Wu9Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong UniversityDepartment of Obstetrics and Gynecology, Binzhou Medical University HospitalDepartment of Interventional Medicine and Vascular Surgery, Binzhou Medical University HospitalDepartment of Interventional Radiology, Weihai Municipal HospitalDepartment of Interventional Medicine and Vascular Surgery, Binzhou Medical University HospitalDepartment of General Surgery, Taian City Central HospitalDepartment of Interventional Medicine and Vascular Surgery, Binzhou Medical University HospitalDepartment of Interventional Medicine and Vascular Surgery, Binzhou Medical University HospitalDepartment of Interventional Medicine and Vascular Surgery, Binzhou Medical University HospitalDepartment of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong UniversityAbstract Background The protective effect of metformin (MET) on abdominal aortic aneurysm (AAA) has been reported. However, the related mechanism is still poor understood. In this study, we deeply investigated the role of metformin in AAA pathophysiology. Methods Angiotensin II (Ang-II) was used to construct the AAA model in ApoE −/− mice. The related mechanism was explored using Western blot and quantitative real time PCR (qRT-PCR). We also observed the morphological changes in the abdominal aorta and the influence of metformin on biological behaviors of rat abdominal aortic VSMCs. Results The PI3K/AKT/mTOR pathway was activated in aneurysmal wall tissues of AAA patients and rat model. Treatment with metformin inhibited the breakage and preserved the elastin structure of the aorta, the loss of collagen, and the apoptosis of aortic cells. In addition, metformin significantly suppressed the activation of the PI3K/AKT/mToR pathway and decreased the mRNA and protein levels of LC3B and Beclin1, which were induced by Ang-II. Moreover, PI3K inhibitors enhanced the effect of metformin while PI3K agonists largely reversed this effect. Interestingly, the cell proliferation, apoptosis, migration and autophagy of vascular smooth muscle cells (VSMCs) induced by Ang-II were also decreased following metformin treatment. PI3K inhibitors and agonists strengthened and weakened the effects of metformin in VSMCs, respectively. Conclusions Metformin represses the pathophysiology of AAA by inhibiting the activation of PI3K/AKT/mTOR/autophagy pathway. This repression may be useful as a new therapeutic strategy for AAA.http://link.springer.com/article/10.1186/s13578-019-0332-9MetforminAAAPI3K/AKT/mTOR pathwayAutophagy pathwayApoE −/− mice |
| spellingShingle | Zhu Wang Jingjing Guo Xinqiang Han Ming Xue Wenming Wang Lei Mi Yuguo Sheng Chao Ma Jian Wu Xuejun Wu Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE−/− mice Cell & Bioscience Metformin AAA PI3K/AKT/mTOR pathway Autophagy pathway ApoE −/− mice |
| title | Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE−/− mice |
| title_full | Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE−/− mice |
| title_fullStr | Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE−/− mice |
| title_full_unstemmed | Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE−/− mice |
| title_short | Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE−/− mice |
| title_sort | metformin represses the pathophysiology of aaa by suppressing the activation of pi3k akt mtor autophagy pathway in apoe mice |
| topic | Metformin AAA PI3K/AKT/mTOR pathway Autophagy pathway ApoE −/− mice |
| url | http://link.springer.com/article/10.1186/s13578-019-0332-9 |
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