Posts Tagged: oxidative stress

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Steven J. Forrester, Daniel S. Kikuchi, Marina S. Hernandes, Qian Xu, Kathy K. Griendling

Cytosolic reactive oxygen species (ROS) production and regulation of cytosolic metabolic pathways. Cytosolic ROS are formed most notably through NOX (nicotinamide adenine dinucleotide phosphate [NADPH] oxidase) activity and influence metabolic processes including glycolysis and downstream oxidative phosphorylation, pentose phosphate pathway activity, and autophagy. ACC indicates acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; ATM, ataxia-telangiectasia mutated; CAMKKβ, Ca2+/calmodulin-dependent protein kinase β; CoA, coenzyme A; CRAC, calcium release–activated channel; ER, endoplasmic reticulum; GLUT1, glucose transporter 1; HIF1α, hypoxia-inducible factor 1α; HK, hexokinase; IP3R, inositol 1,4,5-trisphosphate receptor; LKB1, liver kinase B1; mTOR, mammalian target of rapamycin; NADPH, nicotinamide adenine dinucleotide phosphate; NOS, nitric oxide synthase; OONO, peroxynitrite; OxPL, oxidized phospholipid; PDK-1, phosphoinositide-dependent kinase-1; PFK, phosphofructo kinase; PI3K, phosphoinositide 3-kinase; PKM2, pyruvate kinase 2; PPP, pentose phosphate pathway; STIM1, stromal interaction molecule 1; and TSC2, tuberous sclerosis protein 2. [Powerpoint File]

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Steven J. Forrester, Daniel S. Kikuchi, Marina S. Hernandes, Qian Xu, Kathy K. Griendling

Peroxisomal reactive oxygen species (ROS) and metabolism. Peroxisomal ROS are produced as by-products of enzymatic reactions within β-oxidation, polyamine synthesis, d-amino acid deamination, and hypoxanthine oxidation and have been found to be key regulators of pexophagy. ACOX indicates acyl-coenzyme A (CoA) oxidases; ATM, ataxia-telangiectasia mutated; CAT, catalase; CoA, coenzyme A; DAO, d-amino acid oxidase; GPX, glutathione peroxidase; LC3, light chain 3; mTOR, mammalian target of rapamycin; PAO, polyamine oxidase; PEX, peroxin; PRDX, peroxiredoxin; SOD, superoxide dismutase; TSC1, tuberous sclerosis protein 1; ULK1, uncoordinated 51-like kinase 1; and XAO, xanthine oxidase. [Powerpoint File]

 

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Reactive Oxygen Species in Metabolic and Inflammatory Signaling

Steven J. Forrester, Daniel S. Kikuchi, Marina S. Hernandes, Qian Xu, Kathy K. Griendling

Endoplasmic reticulum and reactive oxygen species (ROS). The endoplasmic reticulum (ER) is highly sensitive to redox status, and altered ROS signaling can influence protein folding, Ca2+ release, and mitochondrial respiration. ATF6 indicates activating transcription factor 6; CAMKKII, Ca2+/calmodulin-dependent protein kinase II; Cyto, cytoplasm; ER, endoplasmic reticulum; ERO1, ER oxidoreductin 1; GPX, glutathione peroxidase; GRP78, glucose-regulated protein, 78 kDa; GSH, glutathione; GSSG, glutathione disulfide; IMS, intermembrane space; IP3R, inositol 1,4,5-trisphosphate receptor; IRE1α, inositol-requiring enzyme 1α; MCU, mitochondrial calcium uniporter; NOX, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; OxPL, oxidized phospholipid; p66shc, SHC-transforming protein 1 isoform p66; PDI, protein disulfide isomerase; PERK, protein kinase R (PKR)–like endoplasmic reticulum kinase; and Prdx, peroxiredoxin [Powerpoint File]

Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis

Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis

Ulrich Förstermann, Ning Xia, Huige Li

Enzymes involved in the generation and inactivation of reactive oxygen species (ROS). Superoxide anion (O2·-) can be produced in the vascular wall by NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidases (Nox1 and Nox2), xanthine oxidase, uncoupled endothelial nitric oxide synthase (eNOS), and the mitochondrial respiration chain. O2·- can be converted to hydrogen peroxide (H2O2) by the enzyme superoxide dismutase (SOD). H2O2 can undergo spontaneous conversion to hydroxyl radical (OH·) via the Fenton reaction. OH· is extremely reactive and attacks most cellular components. H2O2 can be detoxified via glutathione (GSH) peroxidase, catalase or thioredoxin (Trx) peroxidase to H2O and O2. The enzyme myeloperoxidase can use H2O2 to oxidize chloride to the strong-oxidizing agent hypochlorous acid (HOCl). HOCl can chlorinate and thereby inactivate various biomolecules including lipoproteins and the eNOS substrate L-arginine. Besides HOCl generation, myelo-peroxidase can oxidize (and thus inactivate) NO to nitrite (NO2−) in the vasculature. Paraoxonase (PON) isoforms 2 and 3 can prevent mitochondrial O2·- generation. Reprinted from Li et al67 with permission of the publisher. Copyright © 2013, Elsevier. [Powerpoint File]

The Human Microcirculation: Regulation of Flow and Beyond

The Human Microcirculation: Regulation of Flow and Beyond

David D. Gutterman, Dawid S. Chabowski, Andrew O. Kadlec, Matthew J. Durand, Julie K. Freed, Karima Ait-Aissa, Andreas M. Beyer

In a healthy heart (left), arteriolar endothelium produces NO, prostacyclin (PGI2), and epoxyeicosatrienoic acids (EETs) as well as low levels of hydrogen peroxide, which support a quiescent nonproliferative state. With onset of disease, flow through the microvasculature releases hydrogen peroxide, creating a proinflammatory environment throughout the organ, potentially leading to hypertrophy, fibrosis, and atherosclerosis. NO indicates nitric oxide. [Powerpoint File]

The Human Microcirculation: Regulation of Flow and Beyond

The Human Microcirculation: Regulation of Flow and Beyond

David D. Gutterman, Dawid S. Chabowski, Andrew O. Kadlec, Matthew J. Durand, Julie K. Freed, Karima Ait-Aissa, Andreas M. Beyer

Proposed mechanism for the stress-induced switch in the mediator of flow-induced dilation. In arterioles from healthy subjects, shear activates production of NO to stimulate dilation and vascular homeostasis (left side of diagram). Vascular stress or presence of coronary disease stimulates pathological basal levels of oxidants and initiates a switch in the mediator of flow-induced dilation from NO to hydrogen peroxide. This switch requires ceramide and a reduction in telomerase. Dilation is maintained but at the expense of vascular inflammation and its consequences. Ang II indicates angiotensin II; CAD, coronary artery disease, HTN, hypertension; NO, nitric oxide; and TERT, catalytic subunit of telomerase. [Powerpoint File]

RhoA/Rho-Kinase in the Cardiovascular System

RhoA/Rho-Kinase in the Cardiovascular System

Hiroaki Shimokawa, Shinichiro Sunamura, Kimio Satoh

Rho-kinase activation and multiple targets. Rho GTPases, including RhoA, is activated by the guanine nucleotide exchange factors (GEFs) that catalyze exchange of GDP for GTP and inactivated by the GTPase-activating proteins (GAPs). Rho-kinase is an effector of the active form of Rho. Many substrates of Rho-kinase have been identified, including myosin light chain (MLC), MLC phosphatase (MLCP), ezrin/radixin/moesin (ERM) family, adducin, and LIM kinases. 5-HT indicates 5-hydroxytryptamine; AC, adenylyl cyclase; CRMP2, collapsin response mediator protein 2; eNOS, endothelial NO synthase; Epac, exchange protein directly activated by cAMP; ET-1, endothelin; GDI, guanine nucleotide dissociation inhibitor; GPCR, G-protein–coupled receptor; NE, norepinephrine; and PDGF-BB, platelet-derived growth factor-BB. [Powerpoint File]

RhoA/Rho-Kinase in the Cardiovascular System

RhoA/Rho-Kinase in the Cardiovascular System

Hiroaki Shimokawa, Shinichiro Sunamura, Kimio Satoh

Input from endothelial cells (ECs) to vascular smooth muscle cells (VSMCs) through endothelium-derived relaxing factors. Rho-kinase is a downstream effector of the active form of RhoA. Phosphorylation of myosin light chain (MLC) is a key event in the regulation of VSMC contraction. MLC is phosphorylated by Ca2+-calmodulin-activated MLC kinase (MLCK) and dephosphorylated by MLC phosphatase (MLCP). Rho-kinase mediates agonist-induced VSMC contraction. H2O2 rapidly reaches VSMC, stimulates the 1-α isoform of cGMP-dependent protein kinase (PKG1α) to form the disulfide form, and opens Ca-activated K channels (KCa) with subsequent VSMC hyperpolarization and relaxation. CRMP2 indicates collapsin response mediator protein 2; DAG, diacylglycerol; GEF, guanine nucleotide exchange factor; GAP, GTPase-activating protein; IP3, 1,4,5-triphosphate; MCP, monocyte chemoattractant protein; PAI-1, plasminogen activator inhibitor type 1; PDE, phosphodiesterase; PGI2, prostacyclin; PKC, protein kinase C; PLC, phospholipase C; and PTEN, phosphatase and tensin homolog. [Powerpoint File]

RhoA/Rho-Kinase in the Cardiovascular System

RhoA/Rho-Kinase in the Cardiovascular System

Hiroaki Shimokawa, Shinichiro Sunamura, Kimio Satoh

Molecular structure of Rho-kinase isoforms. There are 2 isoforms of Rho-kinase, ROCK1 and ROCK2, which consist of 3 major domains, including a kinase domain in its N-terminal domain, a coiled-coil domain with Rho-binding domain in its middle portion, and a putative pleckstrin homology (PH) domain in its C-terminal domain. ROCK1 and ROCK2 are highly homologous with an overall amino acid sequence identity of 65%. There are 2 types of activation; Rho-dependent and Rho-independent activation. ROCK1 is specifically cleaved by caspase-3, whereas granzyme B cleaves ROCK2. GAP indicates GTPase-activating protein; and GEF, guanine nucleotide exchange factor. [Powerpoint File]

RhoA/Rho-Kinase in the Cardiovascular System

RhoA/Rho-Kinase in the Cardiovascular System

Hiroaki Shimokawa, Shinichiro Sunamura, Kimio Satoh

Interactions between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). Intracellular signaling pathways for Rho-kinase activation, ROS production, and cyclophilin A (CyPA) secretion are closely linked through VAMP2 vesicle formation. H2O2 has been reported to cause vasodilatation through several mechanisms. H2O2 rapidly reaches VSMC with subsequent VSMC hyperpolarization and relaxation. Oxidative stress promotes CyPA secretion from VSMC. Secreted CyPA promotes ROS production, contributing to the augmentation of oxidative stress. AMPK indicates AMP-activated protein kinase; CaMKK, Ca2+/calmodulin-dependent protein kinase kinase; EMMPRIN, extracellular matrix metalloproteinases inducer protein; IP3, 1,4,5-triphosphate; IRS, insulin receptor substrate; PGH2, prostaglandin H2; PGI2, prostacyclin; PI3K, phosphoinositide-3-kinase; PKG1α, protein kinase G, subunit 1α; PLC, phospholipase C; SOD, superoxide dismutase; and VAMP, vesicle-associated membrane protein. [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]

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]

Regulation of Signal Transduction by Reactive Oxygen Species in the Cardiovascular System

Regulation of Signal Transduction by Reactive Oxygen Species in the Cardiovascular System

David I. Brown, Kathy K. Griendling

Redox signaling pathways in migration and adhesion. Dark gray, redox modified proteins. AngII indicates angiotensin II; DAG, diacyl-glycerol; ECM, extracellular matrix; IP3, inositol trisphosphate; Jnk, c-Jun N-terminal kinase; LMW-PTP, low molecular weight protein tyrosine phosphatase; MLCP, myosin light chain phosphatase; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; ROK, Rho-associated protein kinase; ROS, reactive oxygen species; SOS, son of sevenless homolog 1; Src, Proto-oncogene tyrosine-protein kinase Src; and SSH1L, Slingshot homolog 1. [Powerpoint File]

Regulation of Signal Transduction by Reactive Oxygen Species in the Cardiovascular System

Regulation of Signal Transduction by Reactive Oxygen Species in the Cardiovascular System

David I. Brown, Kathy K. Griendling

Redox signaling pathways in hypertrophy and proliferation. Dark gray, Redox modified proteins. AngII indicates angiotensin II; AP1, activator protein 1; ASK1, apoptosis signal-regulating kinase 1; AT1R, angiotensin II type 1 receptor; DAG, diacyl-glycerol; ERK1/2, extracellular signal-regulated kinase 1/2; Ets-1, v-ets avian erythroblastosis virus E2 oncogene homolog 1; IP3, inositol triphosphate; JAK, janus kinase; MAPKAPK2, mitogen-activated protein kinase-activated protein kinase 2; MEK3/6, MAPK/ERK kinase 3/6; NF-κB, nuclear factor-κB; PDGF, platelet-derived growth factor; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; PP3, phosphatase calcineurin; PTEN, phosphatase and tensin homolog; RyR, ryanodine receptor; SOD, superoxide dismutase; SERCA, sarcoendoplasmic reticulum calcium transport ATPase; Src, Proto-oncogene tyrosine-protein kinase Src; STAT, signal transducer and activator of transcription; and Trx, thioredoxin (Illustration credit: Ben Smith). [Powerpoint File]

Mitochondria and Cardiovascular Aging

Mitochondria and Cardiovascular Aging

Dao-Fu Dai, Peter S. Rabinovitch, Zoltan Ungvari

Proposed signaling mechanism of angiotensin/Gαq and mitochondrial ROS amplification in aging and cardiovascular diseases. AT1-R, angiotensin receptor-1; Nnt, nicotinamide nucleotide transhydrogenase. Illustration credit: Cosmocyte/Ben Smith. [Powerpoint File]