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Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission
Open accessAbstract
Impaired cardiac microvascular function contributes to diabetic cardiovascular complications although effective therapy remains elusive. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor recently approved for treatment of type 2 diabetes, promotes glycosuria excretion and offers cardioprotective actions beyond its glucose-lowering effects. This study was designed to evaluate the effect of empagliflozin on cardiac microvascular injury in diabetes and the underlying mechanism involved with a focus on mitochondria. Our data revealed that empagliflozin improved diabetic myocardial structure and function, preserved cardiac microvascular barrier function and integrity, sustained eNOS phosphorylation and endothelium-dependent relaxation, as well as improved microvessel density and perfusion. Further study suggested that empagliflozin exerted its effects through inhibition of mitochondrial fission in an adenosine monophosphate (AMP)-activated protein kinase (AMPK)-dependent manner. Empagliflozin restored AMP-to-ATP ratio to trigger AMPK activation, suppressed Drp1 S616 phosphorylation, and increased Drp1 S637 phosphorylation, ultimately leading to inhibition of mitochondrial fission. The empagliflozin-induced inhibition of mitochondrial fission preserved cardiac microvascular endothelial cell (CMEC) barrier function through suppressed mitochondrial reactive oxygen species (mtROS) production and subsequently oxidative stress to impede CMEC senescence. Empagliflozin-induced fission loss also favored angiogenesis by promoting CMEC migration through amelioration of F-actin depolymerization. Taken together, these results indicated the therapeutic promises of empagliflozin in the treatment of pathological microvascular changes in diabetes.
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“Empagliflozin exerted its protective roles via inhibition of AMPK-dependent mitochondrial fission [229].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [229]
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“Empagliflozin recovered the AMP-to-ATP ratio that is necessary for triggering AMPK activation [229].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [229]
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“In the meantime, DRP1-S616 phosphorylation was decreased, while DRP1-S637 phosphorylation was increased, ultimately leading to mitochondrial fission [229].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [229]
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1 retracted
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AMP-activated protein kinase mediates mitochondrial fission in response to energy stress
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Background
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Metadata
- Authors
- Zhou, H., Wang, S., Zhu, P., Hu, S., Chen, Y., & Ren, J.
- Affiliations
- Chinese PLA General Hospital (CN)
- University of Wyoming (US)
- Corresponding author
- Zhou, Hao
- Chen, Yundai
- Ren, Jun
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 15
- Pages
- 335-346
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC5756062
- OpenAlex
- W2777514005
- Cited by
- 550
- References
- 63
- Citations by year
- 2026: 34 · 2025: 53 · 2024: 87 · 2023: 71 · 2022: 71 · 2021: 65 · 2020: 63 · 2019: 53 · 2018: 50
- FWCI
- 35.91
- Type
- journal article
- Language
- en
- Update notices
- erratum (2024-05-01)
- Open access
- gold
- doi.org
- Licence
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81441008, 81030002, 81102079, 81270186)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- empagliflozin, SGLT2 inhibitors, diabetic cardiomyopathy, mitochondrial fission, AMPK, Drp1 phosphorylation, endothelial barrier function, endothelial cell senescence, mitochondrial reactive oxygen species, oxidative stress, angiogenesis, endothelial cell migration, F-actin depolymerization, eNOS phosphorylation, type 2 diabetes
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Animals, Benzhydryl Compounds, Diabetes Mellitus, Type 2, Glucosides, Heart Injuries, Humans, Mitochondria, Protein Kinases, Endothelial Cells, Mice, Mitochondrial Dynamics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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