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.
“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]
Empagliflozin recovered the AMP-to-ATP ratio that is necessary for triggering AMPK activation.
“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]
DRP1-S616 phosphorylation was decreased, while DRP1-S637 phosphorylation was increased, ultimately leading to mitochondrial fission.
“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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- 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 · 2013: 1
- 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
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