Posts in Category: 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]

Mitochondrial Metabolism in Aging Heart

Mitochondrial Metabolism in Aging Heart

Edward J. Lesnefsky, Qun Chen, Charles L. Hoppel

Schematic of the interfibrillar mitochondrial defects in the aged heart. ETC indicates electron transport chain; IMM, mitochondrial inner membrane; NADH, nicotinamide adenine dinucleotide; PPL, phospholipid, proposed defect affecting subunit VIIa in complex IV; and Q, ubiquinone; Qo site, ubiquinol-binding site on cytochrome bl with proposed defect in Y132. Illustration credit, Ben Smith. [Powerpoint File]

Mitochondrial Metabolism in Aging Heart

Mitochondrial Metabolism in Aging Heart

Edward J. Lesnefsky, Qun Chen, Charles L. Hoppel

A schematic of a cardiomyocyte to highlight the location of subsarcolemmal (SSM) and interfibrillar mitochondria (IFM). Illustration credit: Ben Smith. [Powerpoint File]

Mitochondrial Metabolism in Aging Heart

Mitochondrial Metabolism in Aging Heart

Edward J. Lesnefsky, Qun Chen, Charles L. Hoppel

A schematic of a cardiomyocyte to show defects present in global and mitochondrial metabolism with age in concert with mechanisms of mitochondria-driven cellular injury. The aged heart exhibits impaired fatty acid oxidation (FAO) and preserved oxidation of glucose. Aging leads to defects in the electron transport chain that involve complexes III (CIII) and IV (CIV). Monoamine oxidase (MAO) and p66shc are significant sources of oxidants. There is a decrease in cardiolipin (CL). Antioxidant contents are relatively unchanged although a decrease in matrix antioxidant capacity leads to mitochondrial damage. Age-related damage enhances the production of reactive oxygen species (ROS) that lead to mitochondrial and cell damage. In addition, effector mechanisms of age-induced mitochondrial damage discussed include an increased susceptibility to mitochondrial permeability transition pore opening (MPTP; MPTP Opening in the Aged Heart: Relationship With ROS Production section), impaired mitochondrial dynamics favoring fusion over fission (Mitochondrial Fission and Fusion section), likely impaired mitophagy (Mitochondrial Biogenesis, Dynamics, and Removal section), and enhanced oxidant-derived signaling to activate cell death programs (Mitochondrial Metabolism–Based Signaling in Response to ROS Production section). Illustration credit: Ben Smith. ETC indicates electron transport chain. [Powerpoint File]

The Ubiquitin-Like SUMO System and Heart Function: From Development to Disease

The Ubiquitin-Like SUMO System and Heart Function: From Development to Disease

Luca Mendler, Thomas Braun, Stefan Müller

Pathway of small ubiquitin-like modifier (SUMO) conjugation/deconjugation and the SUMO-dependent recruitment of SUMO interacting motif (SIM)–containing interaction partners. SUMO is covalently attached to specific lysine (Lys) residues of target proteins in an enzymatic process that involves an E1 activating enzyme (SAE1/SAE2), a single E2 conjugating enzyme (Ubc9), and different SUMO E3 ligases, such as Protein inhibitors of activated STATs (PIAS) proteins, ras-related nuclear protein (Ran)–binding protein 2 (RanBP2), and possibly others. As a result, an isopeptide bond is formed between the C-terminal glycine residues of SUMO and an ε-amino group of a Lys residue of the target protein. Attachment of additional SUMO moieties to internal Lys residues of SUMO induces polymeric chains (mainly by SUMO2/3). SUMO is deconjugated from target proteins by SUMO-specific isopeptidases (SUMO/sentrin-specific protease [SENP]). SUMO conjugates are specifically recognized by interaction partners that possess a specific binding module termed SIM (SUMO interaction motif). SAE1/2 indicates SUMO activating enzyme 1 and 2. [Powerpoint File]

Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis

Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis

Geerte Hoeke, Sander Kooijman, Mariëtte R. Boon, Patrick C.N. Rensen*, Jimmy F.P. Berbée*

Activated brown adipose tissue (BAT) takes up triglyceride (TG)–derived fatty acids after lipolysis. In response to cold, norepinephrine (NE) is released from the sympathetic nervous system and binds to the β3-adrenergic receptor on brown and beige adipocytes. This results in activation of adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP) that activates protein kinase A (PKA). PKA phosphorylates and activates cAMP response element-binding protein (CREB) resulting in enhanced transcription of uncoupling protein-1 (Ucp-1) and peroxisome proliferator-activated receptor-gamma co-activator (Pgc-1α). In addition, activation of PKA enhances the activity of lipolytic enzymes that are associated with the intracellular lipid droplets, leading to release of fatty acids (FA) that enter the mitochondria for β-oxidation. The produced acetyl-CoA is used in the citric acid cycle where reducing equivalents are formed that donate electrons to the electron transport chain. UCP-1 is a proton channel that uncouples respiration, which results in the generation of heat instead of ATP. Upon prolonged activation of brown and beige adipocytes, intracellular lipid droplets become depleted and are replenished via the uptake of TG-derived FA, mainly via selective delipidation of TG-rich lipoproteins (TRLs) through the hydrolyzing action of lipoprotein lipase (LPL). The released FA are taken up by cluster of differentiation 36 (CD36) and FA transport proteins (FATP) and stored in the lipid droplets as TG. Furthermore, glucose is taken up as well via glucose transporter (GLUT) 1 and 4 and used for, among others, de novo lipogenesis. ATGL indicates adipose triglyceride lipase; DAG, diacylglycerol; HSL, hormone-sensitive lipase; MAG, monoacylglycerol; and MGL, monoglyceride lipase (Illustration credit: Ben Smith). [Powerpoint Point]

Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis

Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis

Geerte Hoeke, Sander Kooijman, Mariëtte R. Boon, Patrick C.N. Rensen*, Jimmy F.P. Berbée*

Brown adipose tissue (BAT) activation reduces hypercholesterolemia and atherosclerosis development. A, When BAT is inactive, triglyceride–rich lipoproteins (TRLs) in the circulation donate small amounts of triglyceride-derived fatty acids (FA) to BAT, leading to slow formation of TRL remnants. While circulating, these TRL remnants can infiltrate the vessel wall and induce atherosclerosis development. B, Upon BAT activation, we propose a model in which BAT takes up substantial amounts of TRL-derived FA, resulting in accelerated formation of cholesterol-rich remnants that acquire abundant quantities of apoE (E). As a consequence, these remnants are efficiently cleared by the liver via the low-density lipoprotein receptor (LDLR), thereby reducing hypercholesterolemia and atherosclerosis development. B indicates apoB (Illustration credit: Ben Smith). [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]

DPP4 in Cardiometabolic Disease: Recent Insights From the Laboratory and Clinical Trials of DPP4 Inhibition

DPP4 in Cardiometabolic Disease: Recent Insights From the Laboratory and Clinical Trials of DPP4 Inhibition

Jixin Zhong, Andrei Maiseyeu, Stephen N. Davis, Sanjay Rajagopalan

Mechanisms by which dipeptidyl peptidase-4 (DPP4) modulates immune response of relevance to cardiovascular disease. DPP4 regulates immune response via multiple mechanisms that involve both adaptive and innate immune function. These include (1) control of pericellular adenosine levels: ATP or ADP is converted into AMP by membrane-bound CD39. AMP is further catalyzed by CD73 and produce adenosine. Adenosine is degraded by adenosine deaminase (ADA) bound to membrane-anchored DPP4. Accumulation of adenosine suppresses T-cell activation and proliferation; (2) ADA–DPP4 interaction provides costimulatory signaling for T-cell activation. By signaling through CD45, DPP4 enhances T-cell receptor signals to promote T-cell activation; (3) inactivation of glucagon-like peptide-1 (GLP-1). GLP-1 binds to GLP-1R and increases cAMP resulting in protein kinase A (PKA)–mediated suppression of ERK, JNK, and nuclear factor (NF)-κB; (4) activation of APCs by interaction with caveolin-1. DPP4 binds to caveolin-1 and activates IRAK and NF-κB, leading to the activation of APCs. APC indicates antigen-presenting cell; ERK, extracellular signal-regulated kinase; IRAK, IL-1 receptor-associated kinase; and JNK, c-Jun N-terminal kinase. [Poweropint File]

DPP4 in Cardiometabolic Disease: Recent Insights From the Laboratory and Clinical Trials of DPP4 Inhibition

DPP4 in Cardiometabolic Disease: Recent Insights From the Laboratory and Clinical Trials of DPP4 Inhibition

Jixin Zhong, Andrei Maiseyeu, Stephen N. Davis, Sanjay Rajagopalan

Dipeptidyl peptidase-4 (DPP4) functions and structure. DPP4 consists of a 6-amino-acid (AA) cytoplasmic tail, a 22-AA transmembrane domain and a large extracellular domain. The extracellular domain is responsible for the dipeptidase activity and binding to its ligands such as adenosine deaminase (ADA) and fibronectin. BNP indicates brain natriuretic peptide; G-CSF, granulocyte colony-stimulating factor; GIP, gastric inhibitory peptide; GLP, glucagon-like peptide-1; GM-CSF, granulocyte-macrophage colony-stimulating factor; GRP, gastrin-releasing peptide; IP-10, interferon gamma-induced protein 10; MDC, macrophage derived chemokine; MIG, monokine induced by IFN-γ; NPY, neuropeptide Y; PYY, peptide YY; RANTES, regulated on activation, normal T-cell expressed and secreted; and SDF-1, stromal-cell-derived factor-1. [Powerpoint File]

Endothelial Cell Metabolism in Normal and Diseased Vasculature

Endothelial Cell Metabolism in Normal and Diseased Vasculature

Guy Eelen, Pauline de Zeeuw, Michael Simons, Peter Carmeliet

General metabolism in healthy endothelial cells (ECs). Schematic and simplified overview of general EC metabolism. 3PG indicates 3-phosphogylcerate; α-KG, α-ketoglutarate; CoA, coenzyme A; DHAP, dihydroxyacetone phosphate; ETC, electron transport chain; F1,6P2, fructose-1,6-bisphosphate; F2,6P2, fructose-2,6-bisphosphate; F6P, fructose-6-phosphate; FA, fatty acid; G3P, glyceraldehyde-3-phosphate; G6P, glucose-6-phosphate; GLS, glutaminase; GlucN6P, glucosamine-6-phosphate; GSH, reduced glutathione; hCYS, homocysteine; mTHF, 5-methyltetrahydrofolate; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; OAA, oxaloacetate; OXPHOS, oxidative phosphorylation; PFK1, phosphofructokinase-1; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; R5P, ribose-5-phosphate; ROS, reactive oxygen species; Ru5P, ribulose-5-phosphate; SAM, S-adenosylmethionine; SLC1A5, solute carrier family 1 member 5; TCA, tricarboxylic acid; THF, tetrahydrofolate; and UDP-GlucNAc, uridine diphosphate N-acetylglucosamine. [Poweropint File]