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AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury
Open accessAbstract
AMP-activated protein kinase (AMPK) is an important regulator of diverse cellular pathways in the setting of energetic stress.Whether AMPK plays a critical role in the metabolic and functional responses to myocardial ischemia and reperfusion remains uncertain.We examined the cardiac consequences of long-term inhibition of AMPK activity in transgenic mice expressing a kinase dead (KD) form of the enzyme.The KD mice had normal fractional shortening and no heart failure, cardiac hypertrophy, or fibrosis, although the in vivo left ventricular (LV) dP/dt was lower than that in WT hearts.During low-flow ischemia and postischemic reperfusion in vitro, KD hearts failed to augment glucose uptake and glycolysis, although glucose transporter content and insulin-stimulated glucose uptake were normal.KD hearts also failed to increase fatty acid oxidation during reperfusion.Furthermore, KD hearts demonstrated significantly impaired recovery of LV contractile function during postischemic reperfusion that was associated with a lower ATP content and increased injury compared with WT hearts.Caspase-3 activity and TUNEL-staining were increased in KD hearts after ischemia and reperfusion.Thus, AMPK is responsible for activation of glucose uptake and glycolysis during low-flow ischemia and plays an important protective role in limiting damage and apoptotic activity associated with ischemia and reperfusion in the heart.Nonstandard abbreviations used: acetyl-CoA carboxylase (ACC); 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR); AMP-activated protein kinase (AMPK); carnitine palmitoyltransferase-1 (CPT-1); kinase dead (KD); left ventricular (LV); LV developed pressure (LVDP); 6-phosphofructo-2-kinase (PFK-2). Conflict of interest:The authors have declared that no conflict of interest exists.
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“Mechanically, AMPK increased glucose uptake and glucose transporter 4 translocation [171], decreased apoptosis, improved post-ischemic recovery, and limited myocardial infarction (MI) [172,173].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [173]
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Metadata
- Authors
- Russell, R. R., Li, J., Coven, D. L., Pypaert, M., Zechner, C., Palmeri, M., Giordano, F. J., Mu, J., Birnbaum, M. J., & Young, L. H.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Young, Lawrence H.
- Venue
- Journal of Clinical Investigation
- Published
- 2004-08-16
- Volume
- 114
- Issue
- 4
- Pages
- 495-503
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC503766
- OpenAlex
- W2073534977
- Cited by
- 738
- References
- 74
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 16 · 2023: 19 · 2022: 28 · 2021: 30 · 2020: 23 · 2019: 26 · 2018: 28 · 2017: 31 · 2016: 40 · 2015: 36 · 2014: 42 · 2013: 34 · 2012: 52
- FWCI
- 24.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- American Heart Association
- Yale University
- Deutscher Akademischer Austauschdienst
- Raymond and Beverly Sackler Institute for Biological, Physical and Engineering Sciences, Yale University
- U.S. Public Health Service (U24 DK59635)
- National Heart, Lung, and Blood Institute (R01HL063811, R01-HL-63811, HL 10301, F32HL010301)
- National Institute of Diabetes and Digestive and Kidney Diseases (U24DK59635, U24DK059635)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- AMPK, myocardial ischemia, ischemia-reperfusion injury, glucose uptake, glycolysis, cardiac contractile function, apoptosis, caspase-3, fatty acid oxidation, ATP levels, cardioprotection, energy metabolism
- MeSH terms
- Animals, Glucose, Glycolysis, Mice, Inbred C57BL, Mice, Transgenic, Multienzyme Complexes, Myocardial Reperfusion Injury, Myocardial Ischemia, Apoptosis, Protein Serine-Threonine Kinases, Mice, AMP-Activated Protein Kinases
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