Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin-1 (ET-1) is known as an aggravating factor of the failing cardiomyocytes and, therefore, a therapeutic method is indispensable to decrease cardiac ET-1 expression. To study the mechanisms of how cardiac ET-1 gene expression can be modified, we investigated the effect of electrical stimulation against cardiomyocytes. Considering the physiology of cardiomyocytes, in vitro cultured cardiomyocytes demonstrate distinctive features from in vivo cardiomyocytes (i.e. the absence of a stretch along with electrical stimulation). In this study, we especially focused on the effect of electrical stimulation. The electrical stimulation reduced the gene expression of ET-1 mRNA in rat primary cultured cardiomyocytes. Furthermore, this effect on the transcriptional modification of ET-1 was also identified in H9c2 cells. Luciferase activity using H9c2 cells was decreased by electrical stimulation in the early phase, suggesting that the attenuation of the ET-1 gene transcription by electrical stimulation should be due to a transcriptional repression. To further investigate a trigger signal involved in the transcriptional repression, phosphorylation of 5'-AMP-activated protein kinase (AMPK) was evaluated. It was revealed that AMPK was phosphorylated in the early phase of electrical stimulation of H9c2 cells as well as in rat primary cultured cardiomyocytes, and that AMPK phosphorylation was followed by ET-1 transcriptional repression, suggesting that electrical stimulation directly regulates AMPK. This study suggests that AMPK activation in cardiomyocytes plays a crucial role in the transcriptional repression of ET-1.
J Cardiovasc Pharmacol 2004 Nov
PMID:Effect of electrical modification of cardiomyocytes on transcriptional activity through 5'-AMP-activated protein kinase. 1583 42

AMP-activated protein kinase (AMPK) is activated during exercise and ischemia and is emerging as an important regulatory mechanism in the heart. AMPK promotes adenosine triphosphate-generating pathways, including glucose transport, glycolysis, and fatty acid oxidation, while inhibiting energy-consuming anabolic pathways. After ischemia-reperfusion, AMPK-deficient hearts from transgenic mice have severe left ventricular contractile dysfunction with increased apoptosis and necrosis. Mutations in the AMPKgamma(2) subunit lead to cardiac glycogen overload, Wolff-Parkinson-White syndrome, arrhythmias, and heart failure. This review focuses on the molecular mechanisms of activation and cardiovascular actions of AMPK in the heart.
Trends Cardiovasc Med 2005 Apr
PMID:AMP-activated protein kinase: a key stress signaling pathway in the heart. 1603 71

Wolff-Parkinson-White (WPW) syndrome is the most common cause of ventricular pre-excitation, a condition where, due to defects in the conduction pathway, all or part of the ventricle is excited earlier than would normally be expected, often leading to ventricular fibrillation and sudden cardiac death. It was recently discovered that many of the underlying mutations responsible for the familial form of WPW syndrome are located in the gene encoding for the regulatory gamma(2)-subunit (PRKAG2) of the AMP-activated protein kinase. The cellular mechanisms for the observed arrhythmias are currently being studied and may involve glycogen storage with associated hypertrophy as well as alterations in the properties of cardiac ion channels such as voltage-gated sodium channel. It is the aim of this review to discuss our current knowledge of the cellular disturbances underlying the induction of arrhythmias in patients with PRKAG2 mutations.
J Cardiovasc Electrophysiol 2006 May
PMID:Familial Wolff-Parkinson-White Syndrome: a disease of glycogen storage or ion channel dysfunction? 1668 73

Obesity is an important contributor to the risk of developing insulin resistance, diabetes, and heart disease. Alterations in tissue levels of malonyl-CoA have the potential to impact on the severity of a number of these disorders. This review will focus on the emerging role of malonyl-CoA as a key "metabolic effector" of both obesity and cardiac fatty acid oxidation. In addition to being a substrate for fatty acid biosynthesis, malonyl-CoA is a potent inhibitor of mitochondrial carnitine palmitoyltransferase (CPT) 1, a key enzyme involved in mitochondrial fatty acid uptake. A decrease in myocardial malonyl-CoA levels and an increase in CPT1 activity contribute to an increase in cardiac fatty acid oxidation. An increase in malonyl-CoA degradation due to increased malonyl-CoA decarboxylase (MCD) activity may be one mechanism responsible for this decrease in malonyl-CoA. Another mechanism involves the inhibition of acetyl-CoA carboxylase (ACC) synthesis of malonyl-CoA, due to AMP-activated protein kinase (AMPK) phosphorylation of ACC. Recent studies have demonstrated a role of malonyl-CoA in the hypothalamus as a regulator of food intake. Increases in hypothalamic malonyl-CoA and inhibition of CPT1 are associated with a decrease in food intake in mice and rats, while a decrease in hypothalamic malonyl-CoA increases food intake and weight gain. The exact mechanism(s) responsible for these effects of malonyl-CoA are not clear, but have been proposed to be due to an increase in the levels of long chain acyl CoA, which occurs as a result of malonyl-CoA inhibition of CPT1. Both hypothalamic and cardiac studies have demonstrated that control of malonyl-CoA levels has an important impact on obesity and heart disease. Targeting enzymes that control malonyl-CoA levels may be an important therapeutic approach to treating heart disease and obesity.
Cardiovasc Res 2007 Jan 15
PMID:Role of malonyl-CoA in heart disease and the hypothalamic control of obesity. 1712 22

Obesity is strongly associated with the pathogenesis of type 2 diabetes, hypertension, and cardiovascular disease. Levels of the hormone adiponectin are downregulated in obese individuals, and several experimental studies show that adiponectin protects against the development of various obesity-related metabolic and cardiovascular diseases. Adiponectin exhibits favorable effects on atherogenesis, endothelial function, and vascular remodeling by modulation of signaling cascades in cells of the vasculature. More recent findings have shown that adiponectin directly affects signaling in cardiac cells and is beneficial in the setting of pathological cardiac remodeling and acute cardiac injury. Several of these effects of adiponectin have been attributed to the activation of the 5' AMP-activated protein kinase signaling cascade and other signaling proteins. This review will discuss the epidemiological and experimental studies that have elucidated the role of adiponectin in a variety of cardiovascular diseases.
Cardiovasc Res 2007 Apr 01
PMID:Adiponectin actions in the cardiovascular system. 1714 May 53

The main role of insulin in the heart under physiological conditions is obviously the regulation of substrate utilization. Indeed, insulin promotes glucose uptake and its utilization via glycolysis. In addition, insulin participates in the regulation of long-chain fatty acid uptake, protein synthesis, and vascular tonicity. Significant advancements have been made over the last 20 years in the understanding of the signal transduction elements involved in these insulin effects. Among these molecular mechanisms, the phosphatidylinositol 3-kinase/protein kinase B (Akt) pathway is thought to play a crucial role. Under pathological conditions, such as type-2 diabetes, myocardial ischaemia, and cardiac hypertrophy, insulin signal transduction pathways and action are clearly modified. These molecular signalling alterations are often linked to atypical crosstalks with other signal transduction pathways. On the other hand, pharmacological modifications of parallel and interdependent signalling components, such as the AMP-activated protein kinase pathway, are now considered to be a good therapeutic approach to treat insulin-signalling defects such as insulin resistance and type-2 diabetes. In this review, we will focus on the description of the molecular signalling elements involved in insulin action in the heart and vasculature under these different physiological, pathological, and therapeutical conditions.
Cardiovasc Res 2008 Jul 15
PMID:Insulin signalling in the heart. 1839 Aug 97

Cardiovascular disease is the leading cause of death and disability for people living in western societies, with ischaemic heart disease accounting for the majority of this health burden. The primary treatment for ischaemic heart disease consists of either improving blood and oxygen supply to the heart or reducing the heart's oxygen demand. Unfortunately, despite recent advances with these approaches, ischaemic heart disease still remains a major health problem. Therefore, the development of new treatment strategies is still required. One exciting new approach is to optimize cardiac energy metabolism, particularly by decreasing the use of fatty acids as a fuel and by increasing the use of glucose as a fuel. This approach is beneficial in the setting of ischaemic heart disease, as it allows the heart to produce energy more efficiently and it reduces the degree of acidosis associated with ischaemia/reperfusion. Malonyl CoA is a potent endogenous inhibitor of cardiac fatty acid oxidation, secondary to inhibiting carnitine palmitoyl transferase-I, the rate-limiting enzyme in the mitochondrial uptake of fatty acids. Malonyl CoA is synthesized in the heart by acetyl CoA carboxylase, which in turn is phosphorylated and inhibited by 5'AMP-activated protein kinase. The degradation of myocardial malonyl CoA occurs via malonyl CoA decarboxylase (MCD). Previous studies have shown that inhibiting MCD will significantly increase cardiac malonyl CoA levels. This is associated with an increase in glucose oxidation, a decrease in acidosis, and an improvement in cardiac function and efficiency during and following ischaemia. Hence, the malonyl CoA axis represents an exciting new target for the treatment of ischaemic heart disease.
Cardiovasc Res 2008 Jul 15
PMID:The malonyl CoA axis as a potential target for treating ischaemic heart disease. 1849 82

Adiponectin is an abundant plasma protein secreted from adipocytes that elicits protective effects in the vasculature and myocardium. In obesity and insulin-resistant states, adiponectin levels are reduced and loss of its protective effects might contribute to the excess cardiovascular risk observed in these conditions. Adiponectin ameliorates the progression of macrovascular disease in rodent models, consistent with its correlation with improved vascular outcomes in epidemiological studies. The mechanisms of adiponectin signaling are multiple and vary among its cellular sites of action. In endothelial cells, adiponectin enhances production of nitric oxide, suppresses production of reactive oxygen species, and protects cells from inflammation that results from exposure to high glucose levels or tumor necrosis factor, through activation of AMP-activated protein kinase and cyclic AMP-dependent protein kinase (also known as protein kinase A) signaling cascades. In the myocardium, adiponectin-mediated protection from ischemia-reperfusion injury is linked to cyclo-oxygenase-2-mediated suppression of tumor necrosis factor signaling, inhibition of apoptosis by AMP-activated protein kinase, and inhibition of excess peroxynitrite-induced oxidative and nitrative stress. In this Review, we provide an update of studies of the signaling effects of adiponectin in endothelial cells and cardiomyocytes.
Nat Clin Pract Cardiovasc Med 2009 Jan
PMID:Protective vascular and myocardial effects of adiponectin. 1902 92

Activation of AMP-activated protein kinase (AMPK) results in glucose transporter 4 (GLUT4) translocation from the cytosol to the cell membrane, and glucose uptake in the skeletal muscles. This increased activation of AMPK can be stimulated by a pharmacological agent, AICAR (5' -aminoimidazole-4-carboxamide ribonucleoside), which is converted intracellularly into ZMP (5' -aminoimidazole-4-carboxamideribonucleosidephosphate), an AMP analogue. We utilised AICAR and ZMP to study GLUT4 translocation and glucose uptake in isolated cardiomyocytes. Adult ventricular cardiomyocytes were treated with AICAR or ZMP, and glucose uptake was measured via [3H] -2-deoxyglucose accumulation. PKB/Akt, AMPK and acetyl-CoA-carboxylase phosphorylation and GLUT4 translocation were detected by Western blotting or flow cytometry. AICAR and ZMP promoted AMPK phosphorylation. Neither drug increased glucose uptake but on the contrary, inhibited basal glucose uptake, although GLUT4 translocation from the cytosol to the membrane occurred. Using flow cytometry to detect the exofacial loop of the GLUT4 protein, we showed ineffective insertion in the membrane under these conditions. Supplementing with nitric oxide improved insertion in the membrane but not glucose uptake. We concluded that activation of AMPK via AICAR or ZMP was not sufficient to induce GLUT4-mediated glucose uptake in isolated cardiomyocytes. Nitric oxide plays a role in proper insertion of the protein in the membrane but not in glucose uptake.
Cardiovasc J Afr
PMID:AMP kinase activation and glut4 translocation in isolated cardiomyocytes. 2053 30

The urokinase-type plasminogen activator receptor (uPAR) is a glycosylphosphatidylinositol-anchored membrane protein with multiple functions. In the present study, we examined whether the uPAR plays any role in the regulation of glucose metabolism. The experiments were performed using male wild-type (uPAR) and uPAR knockout (uPAR) C57BL/6J mice. The blood glucose levels after the intraperitoneal injection of glucose were significantly decreased in uPAR mice compared with uPAR mice. On the other hand, there were no differences in the insulin secretion induced by glucose injection and the reactivity of insulin between uPAR and uPAR mice. The expression levels of glucose transporter 2 (GLUT2) in the liver and GLUT4 in the skeletal muscles from the uPAR mice were significantly increased compared with those of the uPAR mice. In addition, we found that the level of phosphorylation of AMP-activated protein kinase in skeletal muscles and myoblasts from the uPAR mice increased compared with those in uPAR mice. These data suggest that the increase in the GLUT2 and GLUT4 expression and the activation of AMP-activated protein kinase by uPAR deficiency enhances the glucose intake. These findings therefore provide new insights into the role of uPAR in the glucose metabolism.
J Cardiovasc Pharmacol 2011 Mar
PMID:The absence of urokinase-type plasminogen activator receptor plays a role in the insulin-independent glucose metabolism. 2116 56


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