AMP-activated protein kinase: Role in metabolism and therapeutic implications

AMP-activated protein kinase (AMPK) is an enzyme that works as a fuel gauge which becomes activated in situations of energy consumption. AMPK functions to restore cellular ATP levels by modifying diverse metabolic and cellular pathways. In the skeletal muscle, AMPK is activated during exercise and is involved in contraction-stimulated glucose transport and fatty acid oxidation. In the heart, AMPK activity increases during ischaemia and functions to sustain ATP, cardiac function and myocardial viability. In the liver, AMPK inhibits the production of glucose, cholesterol and triglycerides and stimulates fatty acid oxidation. Recent studies have shown that AMPK is involved in the mechanism of action of metformin and thiazolidinediones, and the adipocytokines leptin and adiponectin. These data, along with evidence that pharmacological activation of AMPK in vivo improves blood glucose homeostasis, cholesterol concentrations and blood pressure in insulin-resistant rodents, make this enzyme an attractive pharmacological target for the treatment of type 2 diabetes, ischaemic heart disease and other metabolic diseases.     

Heart spotting

Cardiac function depends upon several factors, including adequate cellular mass, intact contractile machinery, and adequate production of ATP. An appropriate homeostasis on all these levels is crucial for the daunting life-long task the myocardium faces. Not surprisingly, many alterations in the above factors have been spotted when the heart fails and hypothesized to play a causal role in the genesis of the failing heart. Indeed, development of cardiac hypertrophy and failure is associated with chamber remodeling as well as with changes of the phenotype at the level of the individual myocyte. Disturbed energy metabolism with impaired fatty acid oxidation and lower expression of proteins involved in ATP synthesis occurs during myocardial hypertrophy and heart failure. The altered expression of proteins from metabolic pathways may reflect mitochondrial dysfunction as a feature of the transition from compensated myocardial hypertrophy with preserved fatty acid metabolism to impaired energy metabolism in heart failure.     

Cardiac energetics during ischaemia and the rationale for metabolic interventions

Cardiac work is supported by high rates of combustion of carbon fuel and oxygen consumption. Fatty acids are the main fuel for the healthy heart, supplying approximately 60-80% of the energy. The balance of the energy comes from the oxidation of glucose and lactate. ATP is broken down to fuel contractile work. ATP is resynthesized in the mitochondria using energy from the oxidation of fatty acids, glucose, and lactate. Myocardial ischaemia dramatically alters fuel metabolism. Ischaemia occurs when the coronary blood flow is insufficient to supply enough oxygen to combust carbon fuels and resynthesize ATP at the normal rate. During partial reductions in coronary blood flow (30-60% of normal) there is a proportional decrease in the rates of oxygen consumption and production of ATP, and an increase in uptake of glucose by the heart. However, unlike under normal aerobic conditions, the glucose taken up by the ischaemic myocardium is not readily oxidized in the mitochondria, but rather is converted to lactate and there is a switch from uptake of lactate by the heart to lactate production. This causes a dramatic disruption in cell homeostasis: ATP content decreases; there is accumulation of lactate and H+, a fall in intracellular pH and a decrease in contractile work. Paradoxically, the ischaemic tissue continues to derive most of its energy (50-70%) from the oxidation of fatty acids despite there being a high rate of lactate production. This ischaemia-induced disruption of cardiac metabolism can be minimized by metabolic agents that decrease oxidation of fatty acids and increase the rates of combustion of glucose and lactate, resulting in clinical benefit to the ischaemic patient.     

The Pathophysiological Basis of Diabetic Cardiomyopathy Development

Diabetes mellitus (DM) provokes widely known structural and functional dyscoordination of the myocardium performance. A cascade of pathophysiological changes occurs due to metabolic disorders caused by hyperglycemia, insulin resistance, and dyslipidemia. Free fatty acids can stimulate oxidation and accumulate in the cytosol, leading to lipotoxic effects by forming ceramides, diacylglycerol, and reactive oxygen species (ROS). Hyperglycemia also causes an increase in the content of reactive oxygen species and the formation of advanced glycation end (AGE) products, which is accompanied by the development of cardiac glucotoxicity. The combination of these pathophysiological processes, ATP deficiency, and the development of myocardial fatty degeneration induce calcium stress, as well as dysfunction of mitochondria and endoplasmic reticulum, activation of signaling pathways of protein kinase C (PKC), mitogen-activated protein kinases (MAPK), etc., causing chronic sluggish inflammation, as well as first diastolic and further systolic dysfunction, and myocardial fibrosis. This article reviews the data on diabetic alteration of the cardiovascular system.     

Disruption of sarcolemmal ATP-sensitive potassium channel activity impairs the cardiac response to systolic overload

Sarcolemmal ATP-sensitive potassium channels (K(ATP)) act as metabolic sensors that facilitate adaptation of the left ventricle to changes in energy requirements. This study examined the mechanism by which K(ATP) dysfunction impairs the left ventricular response to stress using transgenic mouse strains with cardiac-specific disruption of K(ATP) activity (SUR1-tg mice) or Kir6.2 gene deficiency (Kir6.2 KO). Both SUR1-tg and Kir6.2 KO mice had normal left ventricular mass and function under unstressed conditions. Following chronic transverse aortic constriction, both SUR1-tg and Kir6.2 KO mice developed more severe left ventricular hypertrophy and dysfunction as compared with their corresponding WT controls. Both SUR1-tg and Kir6.2 KO mice had significantly decreased expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha and a group of energy metabolism related genes at both protein and mRNA levels. Furthermore, disruption of K(ATP) repressed expression and promoter activity of PGC-1alpha in cultured rat neonatal cardiac myocytes in response to hypoxia, indicating that K(ATP) activity is required to maintain PGC-1alpha expression under stress conditions. PGC-1alpha gene deficiency also exacerbated chronic transverse aortic constriction-induced ventricular hypertrophy and dysfunction, suggesting that depletion of PGC-1alpha can worsen systolic overload induced ventricular dysfunction. Both SUR1-tg and Kir6.2 KO mice had decreased FOXO1 after transverse aortic constriction, in agreement with the reports that a decrease of FOXO1 can repress PGC-1alpha expression. Furthermore, inhibition of K(ATP) caused a decrease of FOXO1 associated with PGC-1alpha promoter. These data indicate that K(ATP) channels facilitate the cardiac response to stress by regulating PGC-1alpha and its target genes, at least partially through the FOXO1 pathway.     

Biochemical derangements in ischemic myocardium: the role of carnitine

The most important biochemical derangements in ischemic myocardium are the decrease of energy rich phosphates (ATP and phosphocreatine) and intracellular acidosis, both of which contribute to a rapid loss of the contractile function. How and to which extent the alterations of carbohydrate and lipid metabolism are involved in these derangements is briefly discussed. In conditions of oxygen restriction the synchronism between the cytosolic and mitochondrial phase of carbohydrate metabolism is disrupted and beta-oxidation of long chain fatty acids is prevented. Consequently less ATP and more lactate is produced and fatty acids accumulate together with their activation products, acyl CoA in particular. In ischemia free carnitine is also decreased and the carnitine dependent functions (acyl transfer across mitochondrial membrane and pyruvate and alpha ketoglutarate dehydrogenase stimulation) impaired. The meaning of the altered carnitine dependent functions is considered together with the possible (demonstrated and supposed) metabolic effects of carnitine administration in cardiac ischemia.     

Enhancing the metabolic substrate: PPAR-alpha agonists in heart failure

The prognosis for patients diagnosed with heart failure has significantly improved over the past three decades; however, the disease still confers a high degree of morbidity and mortality. Current treatments for chronic heart failure have focused primarily on blocking neurohormonal signaling and optimizing hemodynamic parameters. Although significant resources have been devoted toward the development of new pharmaceutical therapies for heart failure, few new drugs have been designed to target myocardial metabolic pathways despite growing evidence that on a fundamental level chronic heart failure can be characterized as an imbalance between myocardial energy demand and supply. Disruptions in myocardial energy pathways are evident as the myocardium is unable to generate sufficient amounts of ATP with advancing stages of heart failure. Down-regulation of fatty acid oxidation likely contributes to the phenotype of the “energy starved” heart. Fibrates are small molecule agonists of PPARα pathways that have been used to treat dyslipidemia. Although never used therapeutically in clinical heart failure, PPARα agonists have been shown to enhance fatty acid oxidation, improve endothelial cell function, and decrease myocardial fibrosis and hypertrophy in animal models of heart failure. In light of their excellent clinical safety profile, PPARα agonists may improve outcomes in patients suffering from systolic heart failure by augmenting myocardial ATP production in addition to targeting maladaptive hypertrophic pathways.