AMP-activated protein kinase control of energy metabolism in the ischemic heart

Lopaschuk, Gary D.

doi:10.1038/ijo.2008.120

Cited by 68 publications

(55 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, adverse effects of AMPK in the proceeding of ischemia reperfusion injury have also been reported. In hearts from AMPK dominate negative mutant of the α2 subunit (DNα2) of mice showed an actual increase in cardiac functional recovery during reperfusion after ischemia (Lopaschuk, 2008). Moreover, suppression of cardiac AMPK activity did not affect baseline cardiac function but may in fact improve the recovery of cardiac function after ischemia (Folmes et al, 2009).…”

Section: Discussionmentioning

confidence: 98%

Berberine alleviates cardiac ischemia/reperfusion injury by inhibiting excessive autophagy in cardiomyocytes

Huang

Han

et al. 2015

European Journal of Pharmacology

136

110

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 98%

Berberine alleviates cardiac ischemia/reperfusion injury by inhibiting excessive autophagy in cardiomyocytes

Huang

Han

et al. 2015

European Journal of Pharmacology

136

110

View full text Add to dashboard Cite

“…This surprising observation provides additional support for the conclusion that a metabolic adaptation is triggered in response to the chronic inhibition of the pyruvate dehydrogenase complex. It is possible that the observed increase in AMPK activity or respiratory uncoupling, both of which have been proposed to improve the reperfusion response (42), counteract the effects of reduced GO after ischemic insult. Future studies aimed at the mechanisms involved in triggering the adaptive responses could yield novel therapeutic targets aimed at the prevention of diabetic cardiac dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Chronic Inhibition of Pyruvate Dehydrogenase in Heart Triggers an Adaptive Metabolic Response

Chambers

Leone

Sambandam

et al. 2011

Journal of Biological Chemistry

104

View full text Add to dashboard Cite

Diabetic cardiac dysfunction is associated with decreased rates of myocardial glucose oxidation (GO) and increased fatty acid oxidation (FAO), a fuel shift that has been shown to sensitize the heart to ischemic insult and ventricular dysfunction. We sought to evaluate the metabolic and functional consequences of chronic suppression of GO in heart as modeled by transgenic mice with cardiac-specific overexpression of pyruvate dehydrogenase kinase 4 (myosin heavy chain (MHC)-PDK4 mice), an inhibitor of pyruvate dehydrogenase. Hearts of MHC-PDK4 mice were shown to exhibit an insulin-resistant substrate utilization profile, characterized by low GO rates and high FAO flux. Surprisingly, MHC-PDK4 mice were not sensitized to cardiac ischemia-reperfusion injury despite a fuel utilization pattern that phenocopied the diabetic heart. In addition, MHC-PDK4 mice were protected against high fat diet-induced myocyte lipid accumulation, likely related to increased capacity for FAO. The high rates of mitochondrial FAO in the MHC-PDK4 heart were related to heightened activity of the AMP-activated protein kinase, reduced levels of malonyl-CoA, and increased capacity for mitochondrial uncoupled respiration. The expression of the known AMP-activated protein kinase target, peroxisome proliferator-activated receptor ␥ coactivator-1␣ (PGC-1␣), a master regulator of mitochondrial function and biogenesis, was also activated in the MHC-PDK4 heart. These results demonstrate that chronic activation of PDK4 triggers transcriptional and post-transcriptional mechanisms that re-program the heart for chronic high rates of FAO without the expected deleterious functional or metabolic consequences.The emerging pandemic of obesity is driving a dramatic increase in the incidence of type 2 diabetes mellitus and "metabolic syndrome" (1, 2). Diabetic individuals are more sensitive to co-morbidities known to cause heart failure, such as myocardial ischemic injury (3-5). The term "diabetic cardiomyopathy" has been coined to capture this unique condition. Although many factors certainly contribute, recent evidence suggests that diabetic cardiac dysfunction is driven at least in part by abnormalities in myocardial fuel metabolism (6 -8).The healthy adult mammalian heart exhibits energy substrate flexibility, utilizing a variety of energy substrates including fatty acids (FAs), 3 glucose, ketones, and lactate to yield ATP to meet the high energy demands of a constant pump (9, 10). In most conditions, FAs are the preferred substrate for myocardial ATP production, although a significant proportion of ATP is derived from glycolysis and glucose oxidation (GO) (8). The insulin-resistant diabetic heart loses this substrate flexibility due to reduced insulin responsive glucose uptake and oxidation, together with increased delivery of FAs, resulting in near complete reliance on fatty acid oxidation (FAO) for ATP production (7,11,12). GO is inhibited in the insulin-resistant heart at the step catalyzed by the pyruvate dehydrogenase complex, due in part to increased e...

show abstract

“…AMPK also stimulates glycolysis in cardiomyocytes (and hepatocyes) by activating 6-phosphofructo-2-kinase (PFK2) [62,63]. AMPK (predominantly complexes with the α2 isoform) has a cardioprotective role in augmenting glucose transport and glycolysis in ischemic hearts [64,65]. Increased myocardial ischemia injury due to enhanced post ischemic myocardial apoptosis, extended infarct size and worsened cardiac functional recovery were inflicted in mice bearing a dominant negative AMPKα2 in their cardiomyocytes [66].…”

Section: Skeletal Muscles and Heartmentioning

confidence: 99%

Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Review on Metabolic, Pharmacological and Chemical Considerations

Babai²,

2009

View full text Add to dashboard Cite

■ AbstractIn view of the epidemic nature of type 2 diabetes and the substantial rate of failure of current oral antidiabetic drugs the quest for new therapeutics is intensive. The adenosine monophosphate-activated protein kinase (AMPK) is an important regulatory protein for cellular energy balance and is considered a master switch of glucose and lipid metabolism in various organs, especially in skeletal muscle and liver. In skeletal muscles, AMPK stimulates glucose transport and fatty acid oxidation. In the liver, it augments fatty acid oxidation and decreases glucose output, cholesterol and triglyceride synthesis. These metabolic effects induced by AMPK are associated with lowering blood glucose levels in hyperglycemic individuals. Two classes of oral antihyperglycemic drugs (biguanidines and thiazolidinediones) have been shown to exert some of their therapeutic effects by directly or indirectly activating AMPK. However, side effects and an acquired resistance to these drugs emphasize the need for the development of novel and efficacious AMPK activators. We have recently discovered a new class of hydrophobic Dxylose derivatives that activates AMPK in skeletal muscles in a non insulin-dependent manner. One of these derivatives (2,4;3,5-dibenzylidene-D-xylose-diethyl-dithioacetal) stimulates the rate of hexose transport in skeletal muscle cells by increasing the abundance of glucose transporter-4 (GLUT-4) in the plasma membrane through activation of AMPK. This compound reduces blood glucose levels in diabetic mice and therefore offers a novel strategy of therapeutic intervention strategy in type 2 diabetes. The present review describes various classes of chemically-related compounds that activate AMPK by direct or indirect interactions and discusses their potential for candidate antihyperglycemic drug development.

show abstract

AMP-activated protein kinase control of energy metabolism in the ischemic heart

Cited by 68 publications

References 48 publications

Berberine alleviates cardiac ischemia/reperfusion injury by inhibiting excessive autophagy in cardiomyocytes

Berberine alleviates cardiac ischemia/reperfusion injury by inhibiting excessive autophagy in cardiomyocytes

Chronic Inhibition of Pyruvate Dehydrogenase in Heart Triggers an Adaptive Metabolic Response

Adenosine Monophosphate-Activated Protein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Review on Metabolic, Pharmacological and Chemical Considerations

Contact Info

Product

Resources

About