Posts Tagged: metabolism

AMP-Activated Protein Kinase: An Ubiquitous Signaling Pathway With Key Roles in the Cardiovascular System

AMP-Activated Protein Kinase: An Ubiquitous Signaling Pathway With Key Roles in the Cardiovascular System

Ian P. Salt, D. Grahame Hardie

Structure of human AMP-activated protein kinase (AMPK; α1β2γ1 complex).8 The model was created in space-filling mode using PyMol v1.7.4.2 with the co-ordinates in PDB file 4RER and with color coding similar to that in Figure 1. The heterotrimer was crystallized in the presence of β-cyclodextrin, which occupies the glycogen-binding site, staurosporine, which occupies the active site, and AMP, which occupies sites 1, 3, and 4 on the γ subunit (sites 1 and 4 are round the back in this view). Although Thr172 was phosphorylated, it is not visible in this view but lies in the cleft between the kinase domain C lobe and the β-CTD, just over the right-hand shoulder of the C-lobe. ADaM indicates Allosteric Drug and Metabolite; AID, autoinhibitory domain; CBM, carbohydrate-binding module; CBS1, cystathionine beta-synthase motif-1, etc; CTD, C-terminal domain; and NTD, N-terminal domain. [Powerpoint File]

Circadian Influence on Metabolism and Inflammation in Atherosclerosis

Circadian Influence on Metabolism and Inflammation in Atherosclerosis

Cameron S. McAlpine, Filip K. Swirski

Circadian influence on atherosclerosis. Circadian rhythms influence the supply of leukocytes and lipids in the circulation and the behavior of endothelial cells, smooth muscle cells, and macrophages in the vessel wall. Together, these systemic factors and local cellular events mediate atherosclerosis. HSC indicates hematopoietic stem cell. [Powerpoint File]

Mechanisms of Sudden Cardiac Death: Oxidants and Metabolism

Mechanisms of Sudden Cardiac Death: Oxidants and Metabolism

Kai-Chien Yang, John W. Kyle, Jonathan C. Makielski, Samuel C. Dudley Jr

Effects of metabolic stresses on cardiac ion channel/transporter function. Schematic illustration of the impact of acute (ischemia/hypoxia) and chronic (heart failure and diabetes mellitus) metabolic stresses on cardiac ion channel/transporter function and the electrophysiological consequences. Acidosis during acute ischemia leads to opening of sarcKATP channels, increased activity of Na+/H+ exchanger (NHE), and increased late Na+-current (INa). ATP depletion during ischemia contributes to the opening of sarcKATP channels, as well as impairs the function of Na/K ATPase. Other electrophysiological effects from ischemia include the reduction of peak INa, increased connexin (Cx) conduction, and reduced ryanodine receptor 2 (RyR2) activity. Reduced RyR2 activity during acute ischemia is rapidly reversed on reperfusion, contributing to the spontaneous waves of Ca2+ release and delayed afterdepolarizations (DADs). A few examples of electrophysiological impact from chronic metabolic stresses associated with heart failure and diabetes mellitus are also illustrated: heart failure reduces peak INa and multiple Kv (Ito, IK) currents. Diabetes mellitus is also associated with reduction in Kv currents. The increase in sarcKATP currents lead to action potential duration (APD) shortening, whereas reduced Kv currents and increased late INa lead to prolonged APD and early afterdepolarizations (EADs). Finally, reduced Na/K ATPase activity, increased RyR2 activity, and increased gap junction conduction during ischemia predispose to arrhythmogenic DADs. [Powerpoint File]

Mechanisms of Sudden Cardiac Death: Oxidants and Metabolism

Mechanisms of Sudden Cardiac Death: Oxidants and Metabolism

Kai-Chien Yang, John W. Kyle, Jonathan C. Makielski, Samuel C. Dudley Jr

Oxidative phosphorylation and reactive oxygen species (ROS) production in mitochondria. The diagrams of the mitochondrial inner membrane show key components of the electron transport chain (ETC) above, and channels and transporters (below). Reducing equivalents nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) produced from the tricarboxylic acid (TCA) cycle feed electrons to the ETC along the mitochondrial inner membrane. The electrons flow through the ETC with the following sequence: complex I and II→coenzyme Q [Q]→complex III→cytochrome C [Cyt C]→complex IV→O2, during which coupled redox reactions drive H+ across the inner membrane, forming the proton gradient and the negative mitochondrial membrane potential (ΔΨm=−150 to −180 mV). The free energy stored in the proton gradient and ΔΨm then drive H+ through the mitochondrial ATP synthase (complex V), converting ADP to ATP. An estimated 0.1% to 1% of the electrons leak prematurely to O2 at complexes I, II, or III, resulting in the formation of superoxide (O2•−). Multiple important mitochondrial channels located on the inner membrane including mitochondrial KATP channels (mito-KATP), the mitochondrial Na+/Ca2+ exchanger (mito-NCX), the inner membrane anion channel (IMAC), the permeability transition pore (PTP), and the mitochondrial calcium uniporter (MCU) also contribute to the regulation of mitochondrial function, myocardial ROS, and cellular cation homeostasis. [Powerpoint File]

Pathogenesis of the Limb Manifestations and Exercise Limitations in Peripheral Artery Disease

Pathogenesis of the Limb Manifestations and Exercise Limitations in Peripheral Artery Disease

William R. Hiatt, Ehrin J. Armstrong, Christopher J. Larson, Eric P. Brass

Metabolic and mitochondrial abnormalities in peripheral artery disease. FAD indicates flavin adenine dinucleotide; and NAD, nicotine adenine dinucleotide. Reprinted from Hiatt and Brass [Powerpoint File]

Pathogenesis of the Limb Manifestations and Exercise Limitations in Peripheral Artery Disease

Pathogenesis of the Limb Manifestations and Exercise Limitations in Peripheral Artery Disease

William R. Hiatt, Ehrin J. Armstrong, Christopher J. Larson, Eric P. Brass

Hemodynamic alterations in peripheral artery disease. Top, A healthy arterial bed with normal large vessel and microcirculatory flow characteristics. Bottom, A peripheral artery with atherosclerotic occlusive disease. ABI indicates ankle-brachial index. Reprinted from Hiatt and Brass. [Powerpoint File]

Epigenetics and Metabolism

Epigenetics and Metabolism

Samuel T. Keating, Assam El-Osta

The chromatin code. Gene function is primarily regulated by chromatin accessibility. Cytosine bases covalently modified by addition of methyl groups are recognized by methyl-binding proteins that associate with chromatin remodeling factors to establish transcriptionally incompetent chromatin architectures. The nucleosome is comprised of ≈147 bp of DNA encircling an octamer of 2 copies of each of the 4 core histone proteins H2A, H2B, H3, and H4. Post-translational modification (PTM) of nucleosomal histones further regulates transition between active euchromatin and silent heterochromatin. Shown here is a summary of acetyl (green) and methyl (red) modifications of specific arginine (R) and lysine (K) residues on N-terminal tails of the heavily modified H3 and H4 histones. Adding a greater level of complexity, arginine residues can be mono- and di-methylated, and lysines mono-, di-, or trimethylated. CR indicates chromatin remodelling; and ME, methylation. [Powerpoint File]

Epigenetics and Metabolism

Epigenetics and Metabolism

Samuel T. Keating, Assam El-Osta

Genome-wide distribution of histone methylation. Graphical representation of the aorta showing the endothelial cell layer and flow of CD14+ monocytes and blood cells. The circos plot shows the genomic distribution of histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 27 trimethylation (H3K27me3) on human autosomes of vascular endothelial cells and primary CD14+ monocytes. Genome-wide maps are derived from chromatin immunoprecipitation combined with sequencing (ChIP-seq) data accessed from the ENCODE project using the UCSC browser. H3K4me3 and H3K27me3 peaks were considered overlapping using a minimum of 5% coverage. The percentage of genome coverage for each peak represents the sum of the total length of all peaks divided by the total number of base pairs in the genome. Alignability scores used were derived from ENCODE (UCSC assession: wgEncodeEH000318). Base pairs with an alignability score of ≥1 were considered mappable. Histone methylation unique to vascular endothelial cells are shown in blue and those unique to monocytes are shown in orange. Regions of histone methylation overlap in vascular endothelial and monocytes (minimum 5% overlap) are shown in yellow. [Powerpoint File]

The Metabolic Theory of Pulmonary Arterial Hypertension

The Metabolic Theory of Pulmonary Arterial Hypertension

Roxane Paulin, Evangelos D. Michelakis

Pulmonary arterial hypertension (PAH) involves many organs. Several organs are involved in PAH in addition to the resistance pulmonary arteries, which are characterized by an obliterative vascular remodeling (top left: smooth muscle actin staining of a small pulmonary artery from a patient with PAH; used with permission from Michelakis et al188). The right ventricle (RV) undergoes remodeling in response to increased afterload (top right: autopsy specimen form a patient with severe PAH showing hypertrophy and dilatation of the RV). Activated circulating (bone marrow–derived) immune cells infiltrate the lung parenchyma and significantly contribute to the pathology of the disease (bottom right: a remodeled pulmonary artery from a patient with PAH showing intense infiltration of mononuclear immune cells around and within the vascular wall). Reprinted from Stacher et al1 with permission of the publisher. Patients with PAH also have evidence of insulin resistance, resembling the metabolic syndrome. The skeletal muscle is a major target organ in the metabolic syndrome in humans. In the left lower corner, a biopsy of skeletal muscle from transgenic mice carrying a human bone morphogenic protein receptor II mutation is shown. The lipid droplets (arrow) are characteristic of insulin resistance. These signs appeared even before spontaneous pulmonary hypertension was detectable in these mice. Reprinted from West et al2 with permission from the publisher. Remarkably, as discussed in the text, all of these tissues have evidence of mitochondrial suppression and inhibited glucose oxidation. [Powerpoint File]

The Metabolic Theory of Pulmonary Arterial Hypertension

The Metabolic Theory of Pulmonary Arterial Hypertension

Roxane Paulin, Evangelos D. Michelakis

The disruption of the mitochondria/endoplasmic reticulum (ER) unit induced by ER stress, results in suppression of mitochondrial function. ER stress is a result of many known triggers of pulmonary arterial hypertension (PAH) including bone morphogenic protein receptor II and other mutations (like in Kv channels; such mutations have been shown to disturb intracellular cell trafficking and induce the unfolded protein response), viral infections, hypoxia, or inflammation. At least in pulmonary artery, smooth muscle cells ER stress activates the activating transcription factor 6 (ATF6) that enhances the expression of the reticulon protein Nogo. Nogo alters the shape of the ER, disrupting the functional mito-ER unit at points where the exchange of calcium occurs, thus decreasing calcium supply for mitochondrial calcium-dependent enzymes and resulting in decreased glucose oxidation and an overall mitochondrial suppression. The ER is the largest supplier of calcium for the mitochondria. Animals lacking Nogo are resistant to the development of pulmonary hypertension, and ER stress inhibitors have been shown to reverse PAH in animal models, as discussed in the text. Pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (IDH), and α-ketoglutarate dehydrogenase (αKGDH) are all important mitochondrial enzymes that are dependent on intramitochondrial calcium levels. MCU indicates mitochondrial calcium uniporter; and TCA, tricarboxylic acid cycle. [Powerpoint File]

G Protein–Coupled Receptor Kinase 2: A Link Between Myocardial Contractile Function and Cardiac Metabolism

G Protein–Coupled Receptor Kinase 2: A Link Between Myocardial Contractile Function and Cardiac Metabolism

Meryl C. Woodall, Michele Ciccarelli, Benjamin P. Woodall, Walter J. Koch

The role of G protein–coupled receptor kinase 2 (GRK2) in cardiac insulin receptor signaling and myocyte glucose uptake. A, Normally, insulin binding to its receptor activates a downstream signaling process involving insulin receptor substrate-1 (IRS1) that ultimately results in the movement of glucose transporter 4 (GLUT4) from the cytosol to the membrane, allowing for increased glucose uptake. B, Excess GRK2, as in heart failure, attenuates the insulin response via phosphorylation of IRS1 and inhibition of GLUT4 membrane translocation. The net result of GRK2’s action on the insulin signaling pathway in the myocyte is insulin resistance and glucose intolerance. GRB2 indicates growth factor receptor-bound protein 2; GSK, glycogen synthase kinase; and mTOR, mammalian target of rapamycin. [Powerpoint File]

G Protein–Coupled Receptor Kinase 2: A Link Between Myocardial Contractile Function and Cardiac Metabolism

G Protein–Coupled Receptor Kinase 2: A Link Between Myocardial Contractile Function and Cardiac Metabolism

Meryl C. Woodall, Michele Ciccarelli, Benjamin P. Woodall, Walter J. Koch

Mechanism for how G protein–coupled receptor kinase 2 (GRK2) moves to the mitochondria after cardiac injury. Reactive oxygen species (ROS) produced as a result of ischemia–reperfusion injury or oxidative stress can activate extracellular signal–regulated kinase (ERK) mitogen-activated protein kinase, which is able to phosphorylate GRK2 at Serine 670, facilitating the interaction of GRK2 with the chaperone protein heat shock protein 90 (Hsp90). Hsp90 aids in the movement of GRK2 to the mitochondria where it induces its prodeath actions in myocytes. The change in GRK2 localization can be prevented in multiple ways including expression of carboxyl terminus of β-adrenergic receptor kinase (βARKct; through competition with Hsp90 binding as the βARKct has Ser670), the Hsp90 inhibitor geldanamycin, and the antioxidant N-acetyl-cysteine (NAC). [Poewrpoint File]

Matrix Revisited: Mechanisms Linking Energy Substrate Metabolism to the Function of the Heart

Matrix Revisited: Mechanisms Linking Energy Substrate Metabolism to the Function of the Heart

Andrew N. Carley, Heinrich Taegtmeyer, E. Douglas Lewandowski

Calcium regulation of mitochondrial metabolism. Calcium (Ca2+) released by the sarcoplasmic reticulum is taken up by the mitochondria via the mitochondrial calcium uniporter (MCU). Mitochondria are found in close association with the calcium release channels in the sarcoplasmic reticulum, the ryanodine receptors (RyR), creating a Ca2+ microdomain. Mitofusin2 (Mfn2) acts to bring the mitochondria and sarcoplasmic reticulum (SR) into close communication. Ca2+ activates (designated by the dashed purple lines) mitochondrial metabolism by increasing the activities of pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (ICDH), and α-ketoglutarate (α-KG) dehydrogenase (α-KDH) resulting in increased metabolism of pyruvate and fatty acyl CoA and increased NADH formation. Ca2+ also increases the exchange rate of malate/aspartate (Malate/ASP) shuttle by increasing the activity of the ASP/glutamate (GLUT) exchangers 1 and 2 (AGC1/2), while inhibiting (indicated by the dotted red line) net efflux of citric acid cycle (CAC) intermediates out of the mitochondria via the oxaloacetate (OAA)/malate cotransporter (OMC). The malate/ASP shuttle is responsible for maintaining the cytoplasmic NAD+ pool. The 2 spans of the CAC are indicated by blue (reductive span) and green (oxidative span) lines. Pyruvate can feed into the reductive span through PDH or feed into OAA and malate pools in the oxidative span via anaplerotic flux. Ca2+ is cleared from the mitochondrial matrix by the actions of the Na+/Ca2+ exchanger (NCX). The magnitude of the calcium release by the SR is dependent on the actions of SR Ca2+-ATPase (SERCA2a), which facilitates Ca2+ reuptake into the SR (illustration credit: Ben Smith). FA-CoA indicates fatty acyl-carnitine. [Powerpoint File]

Matrix Revisited: Mechanisms Linking Energy Substrate Metabolism to the Function of the Heart

Matrix Revisited: Mechanisms Linking Energy Substrate Metabolism to the Function of the Heart

Andrew N. Carley, Heinrich Taegtmeyer, E. Douglas Lewandowski

Phosphotransfer systems in the heart. ATP is formed within the mitochondria by ATP synthase, which uses the proton gradient across the inner mitochondrial membrane (IMM) to catalyze ATP formation from ADP and Pi (not depicted). The proton gradient is generated by actions of the electron transport chain (shown as complexes I–IV) after donation of an electron by NADH at complex I. Once formed ATP can cross the IMM via the adenine nucleotide transporter (ANT). ANT also brings ADP into the mitochondria from the cytoplasm. The energy contained within ATP is then transferred to the cytoplasmic phosphocreatine (PCr) pool through the actions of a mitochondrial isoform of creatine kinase (CK). PCr is less diffusion limited than ATP and is therefore an efficient means of transmitting energy to the peripheral sites of ATP utilization, depicted as sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a)–dependent calcium reuptake by the sarcoplasmic reticulum and myosin ATPase-dependent cross-bridge cycling within the sarcomere. PCr is converted back to free creatine (Cr) by cytoplasmic CK with the freed energy used for ATP formation and driving the peripheral ATPases. An alternative phosphotransfer pathway (depicted by a dashed line) is for ATP to directly travel from the mitochondria to the sites of utilization independent of the PCr:CK system. As ATP is diffusion limited, the direct transfer of ATP from the mitochondria to a site of utilization requires close localization between the mitochondria and the peripheral ATPase (illustration credit: Ben Smith). [Powerpoint File]

Mammalian Target of Rapamycin Signaling in Cardiac Physiology and Disease

Mammalian Target of Rapamycin Signaling in Cardiac Physiology and Disease

Sebastiano Sciarretta, Massimo Volpe, Junichi Sadoshima

General cellular functions of mammalian target of rapamycin complex 1 (mTORC1) and mTORC2. The figure summarizes the most well-characterized functions of mTORC1 and mTORC2. mTORC1 regulates protein synthesis and autophagy in response to growth factors and stress. mTORC2 is known to regulate cell growth, survival, and polarity. Akt indicates protein kinase B; and AMPK, adenosine monophosphate-activated protein kinase. [Powerpoint File]