Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling
Abstract
OBJECTIVE: Clinical studies have reported that metformin reduces cardiovascular end points of type 2 diabetic subjects by actions that cannot solely be attributed to glucose-lowering effects. The therapeutic effects of metformin have been reported to be mediated by its activation of AMP-activated protein kinase (AMPK), a metabolite sensing protein kinase whose activation following myocardial ischemia has been suggested to be an endogenous protective signaling mechanism. We investigated the potential cardioprotective effects of a single, low-dose metformin treatment (i.e., 286-fold less than the maximum antihyperglycemic dose) in a murine model of myocardial ischemia-reperfusion (I/R) injury. RESEARCH DESIGN AND METHODS: Nondiabetic and diabetic (db/db) mice were subjected to transient myocardial ischemia for a period of 30 min followed by reperfusion. Metformin (125 microg/kg) or vehicle (saline) was administered either before ischemia or at the time of reperfusion. RESULTS: Administration of metformin before ischemia or at reperfusion decreased myocardial injury in both nondiabetic and diabetic mice. Importantly, metformin did not alter blood glucose levels. During early reperfusion, treatment with metformin augmented I/R-induced AMPK activation and significantly increased endothelial nitric oxide (eNOS) phosphorylation at residue serine 1177. CONCLUSIONS: These findings provide important information that myocardial AMPK activation by metformin following I/R sets into motion events, including eNOS activation, which ultimately lead to cardioprotection.
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Administration of metformin before ischemia or at reperfusion decreased myocardial injury in mice.
“Administration of metformin before ischemia or at reperfusion decreased myocardial injury in mice [183].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [183]
Beneficial actions of metformin disappeared in cardiac-specific dominant-negative AMPKα2 transgenic mice or eNOS deficient mice.
“The beneficial actions of metformin disappeared in cardiac-specific dominant-negative AMPKα2 transgenic mice or eNOS deficient mice [183].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [183]
During early reperfusion, treatment with metformin augmented I/R-induced AMPK activation and significantly increased eNOS phosphorylation at ser1177.
“During early reperfusion, treatment with metformin augmented I/R-induced AMPK activation and significantly increased eNOS phosphorylation at ser1177 [183].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [183]
Cardioprotective effects of metformin on I/R are mediated by its activation of AMPK.
“Recent studies suggest that the cardioprotective effects of metformin on I/R are mediated by its activation of AMPK.”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [183]
Metformin failed to increase eNOS Ser1177 phosphorylation at reperfusion in AMPKα2 deficient mice.
“Further, metformin failed to increase eNOS Ser1177 phosphorylation at reperfusion in AMPKα2 deficient mice [183].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [183]
Myocardial AMPK-eNOS activation by metformin following I/R led to cardioprotection.
“These findings provide important information that myocardial AMPK–eNOS activation by metformin following I/R led to cardioprotection [183].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [183]
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- Authors
- Calvert, J. W., Gundewar, S., Jha, S., Greer, J. J. M., Bestermann, W. H., Tian, R., & Lefer, D. J.
- Affiliations
- Albert Einstein College of Medicine (US)
- Holston Valley Medical Center (US)
- Brigham and Women's Hospital (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2008-03-01
- Volume
- 57
- Issue
- 3
- Pages
- 696-705
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2097668381
- Cited by
- 422
- References
- 46
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 13 · 2023: 20 · 2022: 29 · 2021: 20 · 2020: 36 · 2019: 25 · 2018: 24 · 2017: 29 · 2016: 27 · 2015: 27 · 2014: 26 · 2013: 24 · 2012: 28
- FWCI
- 10.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (2 RO1 HL-060849-08, R01HL060849)
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK077380)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- metformin, cardioprotection, myocardial ischemia-reperfusion injury, AMPK, endothelial nitric oxide synthase, diabetic cardiomyopathy, db/db mice, myocardial infarction
- MeSH terms
- Adenylate Kinase, Animals, Blood Glucose, Diabetes Mellitus, Gene Expression Regulation, Hypoglycemic Agents, Male, Metformin, Mice, Inbred C57BL, Mice, Transgenic, Multienzyme Complexes, Myocardial Infarction, Myocardium, Signal Transduction, Reperfusion Injury, Mice, Inbred NOD, Protein Serine-Threonine Kinases, Gene Deletion, Mice, Nitric Oxide Synthase Type III, AMP-Activated Protein Kinases
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