ArticleToxicological sciences : an official journal of the Society of Toxicology2019
Dichloroacetate Ameliorates Cardiac Dysfunction Caused by Ischemic Insults Through AMPK Signal Pathway-Not Only Shifts Metabolism.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 46 citations in OpenAlex.
- Animal models of pyruvate dehydrogenase complex deficiency: insight into mechanisms of cerebral abnormalities and tissue-specific role in metabolism.Frontiers in medicine · 2026Review
- Emerging therapy strategies for energy metabolism in acute myocardial infarction.Journal of translational medicine · 2025Review
- Dichloroacetate Prevents Sepsis Associated Encephalopathy by Inhibiting Microglia Pyroptosis through PDK4/NLRP3.Inflammation · 2025Article
- Cardiomyocytes in Hypoxia: Cellular Responses and Implications for Cell-Based Cardiac Regenerative Therapies.Bioengineering (Basel, Switzerland) · 2025Review
- The Role of Short-Chain Fatty Acids in Myocardial Ischemia-Reperfusion Injury.Current nutrition reports · 2024Review
- Heart Failure: A Deficiency of Energy-A Path Yet to Discover and Walk.Biomedicines · 2024Review
- Post-translational modifications of pyruvate dehydrogenase complex in cardiovascular disease.iScience · 2024Review
- Regulating mitochondrial metabolism by targeting pyruvate dehydrogenase with dichloroacetate, a metabolic messenger.Biochimica et biophysica acta. Molecular basis of disease · 2023Review
- Administration of metformin rescues age-related vulnerability to ischemic insults through mitochondrial energy metabolism.Biochemical and biophysical research communications · 2023Article
- Sestrin2 Mediates Metformin Rescued the Age-Related Cardiac Dysfunctions of Cardiorenal Syndrome Type 3.Cells · 2023Article
- Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation.Cell reports · 2023Article
- Temporal changes in glucose metabolism reflect polarization in resident and monocyte-derived macrophages after myocardial infarction.Frontiers in cardiovascular medicine · 2023Article
- Neuroprotective Effects and Therapeutic Potential of Dichloroacetate: Targeting Metabolic Disorders in Nervous System Diseases.International journal of nanomedicine · 2023Review
- Combined Treatment of Dichloroacetic Acid and Pyruvate Increased Neuronal Survival after Seizure.Nutrients · 2022Article
- Dichloroacetate as a metabolic modulator of heart mitochondrial proteome under conditions of reduced oxygen utilization.Scientific reports · 2022Article
- Age-Independent Cardiac Protection by Pharmacological Activation of Beclin-1 During Endotoxemia and Its Association With Energy Metabolic Reprograming in Myocardium-A Targeted Metabolomics Study.Journal of the American Heart Association · 2022Article
- Activated Protein C Strengthens Cardiac Tolerance to Ischemic Insults in Aging.Circulation research · 2022Article
- The Cardiac Dysfunction Caused by Metabolic Alterations in Alzheimer's Disease.Frontiers in cardiovascular medicine · 2022Article
- MG53 suppresses NF-κB activation to mitigate age-related heart failure.JCI insight · 2021Article
- Alterations in mitochondrial dynamics with age-related Sirtuin1/Sirtuin3 deficiency impair cardiomyocyte contractility.Aging cell · 2021Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), regulates substrate metabolism in the heart. AMP-activated protein kinase (AMPK) is an age-related energy sensor that protects the heart from ischemic injury. This study aims to investigate whether DCA can protect the heart from ischemic injury through the AMPK signaling pathway. Young (3-4 months) and aged (20-24 months) male C57BL/6J mice were subjected to ligation of the left anterior descending coronary artery (LAD) for an in vivo ischemic model. The systolic function of the hearts was significantly decreased in both young and aged mice after 45 min of ischemia and 24 h of reperfusion. DCA treatment significantly improved cardiac function in both young and aged mice. The myocardial infarction analysis demonstrated that DCA treatment significantly reduced the infarction size caused by ischemia/reperfusion (I/R) in both young and aged mice. The isolated-cardiomyocyte experiments showed that DCA treatment ameliorated contractile dysfunction and improved the intracellular calcium signal of cardiomyocytes under hypoxia/reoxygenation (H/R) conditions. These cardioprotective functions of DCA can be attenuated by inhibiting AMPK activation. Furthermore, the metabolic measurements with an ex vivo working heart system demonstrated that the effects of DCA treatment on modulating the metabolic shift response to ischemia and reperfusion stress can be attenuated by inhibiting AMPK activity. The immunoblotting results showed that DCA treatment triggered cardiac AMPK signaling pathway by increasing the phosphorylation of AMPK's upstream kinase liver kinase B1 (LKB1) under both sham operations and I/R conditions. Thus, except from modulating metabolism in hearts, the cardioprotective function of DCA during I/R was mediated by the LKB1-AMPK pathway.
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