Metformin modulates hyperglycaemia‐induced endothelial senescence and apoptosis through SIRT1
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BACKGROUND AND PURPOSE: Endothelial dysfunction can be detected at an early stage in the development of diabetes-related microvascular disease and is associated with accelerated endothelial senescence and ageing. Hyperglycaemia-induced oxidative stress is a major contributing factor to the development of endothelial dysfunction. Clinical data indicate that the hypoglycaemic agent, metformin, has an endothelial protective action; however, its molecular and cellular mechanisms remain elusive. In the present study, we have investigated the protective effect of metformin during hyperglycaemia-induced senescence in mouse microvascular endothelial cells (MMECs). EXPERIMENTAL APPROACH: MMECs were cultured in normal glucose (11 mM) and high glucose (HG; 40 mM) in the presence and absence of metformin (50 μM) for 72 h. The expression of sirtuin-1 (SIRT1) and senescence/apoptosis-associated markers was determined by immunoblotting and immunocyto techniques. SIRT1 expression was inhibited with appropriate siRNA. KEY RESULTS: Exposure of MMECs to HG significantly reduced SIRT1 protein expression, increased forkhead box O1 (FoxO-1) and p53 acetylation, increased p21 and decreased Bcl2 expression. In addition, senescence-associated β-galactosidase activity in MMECs was increased in HG. Treatment with metformin attenuated the HG-induced reduction of SIRT1 expression, modulated the SIRT1 downstream targets FoxO-1 and p53/p21, and protected endothelial cells from HG-induced premature senescence. However, following gene knockdown of SIRT1 the effects of metformin were lost. CONCLUSIONS AND IMPLICATIONS: HG-induced down-regulation of SIRT1 played a crucial role in diabetes-induced endothelial senescence. Furthermore, the protective effect of metformin against HG-induced endothelial dysfunction was partly due to its effects on SIRT1 expression and/or activity.
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Sirtuin-1 expression is required for metformin to protect endothelial cells against hyperglycemia-induced senescence.
“sirtuin-1 expression is required for metformin to protect endothelial cells against hyperglycemia-induced senescence (110).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [110]
The positive effects of metformin to offset hyperglycemia-induced endothelial dysfunction reflect an increase in generation of NO.
“The positive effects of metformin to offset hyperglycemia-induced endothelial dysfunction reflect an increase in the generation of NO (110, 111).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [110]
Metformin directly protects the endothelium from hyperglycemia-induced dysfunction and premature senescence and implicates a crucial role for the SIRT1-derived deacetylase, sirtuin-1.
“metformin directly protects the endothelium from hyperglycemia-induced dysfunction and premature senescence and implicates a crucial role for the SIRT1-derived deacetylase, sirtuin-1 (110, 111).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [110]
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- Authors
- Arunachalam, G., Samuel, S. M., Marei, I., Ding, H., & Triggle, C. R.
- Affiliations
- Weill Cornell Medical College in Qatar (QA)
- Corresponding author
- Triggle, Chris R
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2013-12-23
- Volume
- 171
- Issue
- 2
- Pages
- 523-535
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC3904269
- OpenAlex
- W1588051322
- Cited by
- 221
- References
- 59
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 15 · 2023: 15 · 2022: 15 · 2021: 26 · 2020: 17 · 2019: 25 · 2018: 14 · 2017: 13 · 2016: 21 · 2015: 28 · 2014: 11
- FWCI
- 9.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- British Journal of Pharmacology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Qatar Foundation
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- metformin, endothelial cell senescence, endothelial cell apoptosis, SIRT1, hyperglycemia, endothelial dysfunction, FOXO1, p53 acetylation, p21, Bcl-2, senescence-associated β-galactosidase, oxidative stress, microvascular endothelial cells
- MeSH terms
- Forkhead Box Protein O1, Acetylation, Adenylate Kinase, Animals, beta-Galactosidase, Capillaries, Diabetes Mellitus, Type 2, Endothelium, Vascular, Fluorescent Antibody Technique, Hyperglycemia, Hypoglycemic Agents, Metformin, Mice, Inbred C57BL, Blotting, Western, Signal Transduction, Cellular Senescence, Apoptosis, Reactive Oxygen Species, Gene Silencing, Mice, Forkhead Transcription Factors, Sirtuin 1
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