Posts Tagged: atherosclerosis

Autophagy and Mitophagy in Cardiovascular Disease

Autophagy and Mitophagy in Cardiovascular Disease

José Manuel Bravo-San Pedro, Guido Kroemer, Lorenzo Galluzzi

Detrimental effects of autophagy or mitophagy inhibition on cardiovascular health. Multiple genetic interventions that limit autophagic or mitophagic flux at the whole-body level or in specific compartments of the cardiovascular system have been associated with the spontaneous development of cardiovascular disorders. AP indicates autophagosome; APL, autophagolysosome; Atg5, autophagy related 5; Bnip3l, BCL2 interacting protein 3 like; Dnml1, dynamin 1 like; Fbxo32, F-box protein 32; L, lysosome; Lamp2, lysosomal-associated membrane protein 2; Mfn1, mitofusin 1; Park2, Parkinson disease (autosomal recessive, juvenile) 2, parkin; Pink1, PTEN-induced putative kinase 1; Sirt6, sirtuin 6; Tfrc, transferrin receptor; and Trp53, transformation-related protein 53. [Powerpoint File]

Neutrophil Extracellular Traps in Atherosclerosis and Atherothrombosis

Neutrophil Extracellular Traps in Atherosclerosis and Atherothrombosis

Yvonne Döring, Oliver Soehnlein, Christian Weber

Emerging roles of neutrophil extracellular traps (NETs) in atherosclerosis and atherothrombosis. (A) Luminally netting neutrophils activate leukocytes, platelets, and endothelial cells creating a proinflammatory milieu presumably resulting in endothelial dysfunction, the initial trigger of lesion development. (B/C) Lesional NETs may initiate a interleukin-1β/TH17 (T helper 17) and type I interferon response, which leads to further activation of lesional leukocytes, releasing more proinflammatory mediators. (D/E) Furthermore, it may be assumed that NET-driven proinflammatory responses will cause an inflammatory environment that favors plaque destabilization and rupture. During atherothrombosis, NETs may trigger activation of the coagulation cascade and increase thrombus stability thus orchestrating arterial occlusion. [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]

Noninvasive Molecular Imaging of Disease Activity in Atherosclerosis

Noninvasive Molecular Imaging of Disease Activity in Atherosclerosis

Marc R. Dweck, Elena Aikawa, David E. Newby, Jason M. Tarkin, James H.F. Rudd, Jagat Narula, Zahi A. Fayad

The link between inflammation, microcalcification, and macrocalcification. A large necrotic core, a thin fibrous cap, and an intense inflammation are key precipitants of acute plaque rupture and myocardial infarction. Intimal calcification is thought to occur as a healing response to this intense necrotic inflammation. However, the early stages of microcalcification (detected by 18F-fluoride positron emission tomography) are conversely associated with an increased risk of rupture. In part, this is because of residual plaque inflammation and in part because microcalcification itself increases mechanical stress in the fibrous cap further increasing propensity to rupture. With progressive calcification, plaque inflammation becomes pacified and the necrotic core walled off from the blood pool. The latter stages of macrocalcification (detected by computed tomographic) are, therefore, associated with plaque stability and a lower risk of that plaque rupturing (Illustration credit: Ben Smith). [Powerpoint FIle]

Thirty Years of Saying NO: Sources, Fate, Actions, and Misfortunes of the Endothelium-Derived Vasodilator Mediator

Thirty Years of Saying NO: Sources, Fate, Actions, and Misfortunes of the Endothelium-Derived Vasodilator Mediator

Paul M. Vanhoutte, Yingzi Zhao, Aimin Xu, Susan W.S. Leung

Regulation of vascular tone by endothelium-derived nitric oxide (NO). Top, Physical factors (increases in shear stress and temperature lowering) and neurohumoral mediators (through activation of specific endothelial cell membrane receptors) cause instantaneous increases in the release of endothelium-derived NO by endothelial nitric oxide synthase (eNOS). Color code: Signals leading to activation of eNOS dependent mainly on increases in Ca2+ concentration, mainly on post-translational modifications or on both are indicated by blue, yellow, and green, respectively. Image derived from Vanhoutte et al14 and modified from Zhao et al29 (Copyright ©2015, The Authors). Bottom, The contraction of vascular smooth muscle cells is initiated by increases in the intracellular calcium (Ca2+) concentration either from internal stores (sarcoplasmic reticulum [SR]) or by influx into the cell after opening of calcium channels in the cell membrane. The intracellular free calcium ions bind to calmodulin (CaM) and the calcium–calmodulin complex activates myosin light-chain kinase; when activated the latter phosphorylates myosin light chain, which leads to cross-bridge formation between the myosin heads and the actin filaments. Cross-bridge formation results in contraction of the smooth muscle cell. NO modulates the contraction process in different ways: (A) NO stimulates soluble guanylyl cyclase (sGC) in the vascular smooth muscle cells which produces cGMP. Cyclic GMP activates protein kinase G (PKG), preventing calcium influx through voltage-dependent calcium channels and calcium release mediated by inositol 1,4,5-trisphosphate (IP3) receptors (IP3R). In addition, PKG not only activates the calcium-ATPase on the cell membrane and the sarco/endoplasmic reticulum calcium-ATPase (SERCA) accelerating the efflux of cytosolic calcium outside the cell and its reuptake into the sarcoplasmic reticulum (SR), respectively, but also opens large-conductance calcium-activated potassium channels resulting in hyperpolarization, which in turn prevents the opening of voltage-dependent L-type channels and hence calcium influx. The resulting decrease in free intracellular calcium ion concentration inactivates calmodulin and thus myosin light-chain kinase. Calcium depletion also augments the activity of myosin light-chain phosphatase (MLCP). The actin–myosin cross-bridges are interrupted and the vascular smooth muscle cell relaxes and (B) NO also S-nitrosylates (SNO) intracellular proteins: (1) SERCA with resulting accelerated calcium depletion; NO also facilitate the S-glutathionylation (SSG) of SERCA; (2) G-protein–coupled receptors (GPCR) with reduced binding of ligands (A) or blunted G-protein coupling; (3) G-protein–coupled receptor kinase 2 (GRK2) preventing desensitization and internalization of β-adrenoceptors; and (4) β-arrestin 2 increasing receptor-internalization. Modified from Zhao et al29 (Copyright ©2015, The Authors). α indicates α-adrenergic receptor; 5HT, serotonin (5-hydroxytryptamine); 5HT1d, serotoninergic (5 hydroxytryptamine) receptor 1D subtypes; ACh, acetylcholine; Ang1–7, angiotensin1–7; AdipoR, adiponectin receptor; AVP, arginine vasopressin; B, kinin receptor; E, epinephrine; EP4, prostaglandin E2-receptor 4; ER, nongenomic estrogen receptor; ET, endothelin-1; ETb, endothelin-receptor B subtypes; GLP, glucagon-like peptide-1, glucagon-like peptide receptor; GPR55, G-protein–coupled receptor 55; H, histaminergic receptor; HDL,_wp_link_placeholder high-density lipoproteins; IP, prostacyclin receptor; IR1, insulin receptor; M, muscarinic receptor; Mas, Mas receptor; MC, melanocortin receptor; NE, norepinephrine; P, purinergic receptor; PAR, protease activated receptor; PGE2, prostaglandin E2; PGI2, prostacyclin; SP1, sphingosine 1-phosphate; TRP, transient potential receptor V4; V, vasopressin receptor; VEGF, vascular endothelial growth factor; VEGFR, VEGF-receptor; VD, vitamin D; and VDR, vitamin D receptor. [Powerpoint File]

Thirty Years of Saying NO: Sources, Fate, Actions, and Misfortunes of the Endothelium-Derived Vasodilator Mediator

Thirty Years of Saying NO: Sources, Fate, Actions, and Misfortunes of the Endothelium-Derived Vasodilator Mediator

Paul M. Vanhoutte, Yingzi Zhao, Aimin Xu, Susan W.S. Leung

Dysfunction of endothelial nitric oxide synthase (eNOS): protein changes. Examples of factors increasing or reducing the mRNA expression, the protein presence and the degree of dimerization of endothelial NO synthase (eNOS). The green and red arrows indicate facilitation or inhibition of NO-dependent dilatations, respectively. ALK1 indicates transforming growth factor-β receptor; ALK5, transforming growth factor-β3 receptor; α-CGRP, α-calcitonin gene–related peptide; AP-1, activator protein-1; BH4, tetrahydrobiopterin; CaMKII, calcium/calmodulin-dependent protein kinases II; eEF1-α, eukaryotic translation elongation factor 1 α; ER, estrogen receptor; GLP, glucagon-like peptide; H2O2, hydrogen peroxide; IR1, insulin receptor 1; JAK2, janus kinase II; KLF2, Krüppel-like factor-2; KDM, histone demethylase; LCN2, lipocalin-2; JNK, c-Jun NH2-terminal mitogen-activated protein kinase; MAPK, mitogen-activated protein kinase; L-arg, L-arginine; MC1, melanocortin 1 receptor; miR, microribonucleic acid; NFκB, nuclear factor κB; ox-LDL, oxidized low-density lipoproteins; P-Akt, phosphor-protein kinase B; PI3K, phosphoinositide 3-kinase; PHLPP2, phosphotyrosine-binding domain and leucine-rich repeat protein phosphatase 2; PTBP-1, polypyrimidine tract-binding protein 1; R, receptor; ROS, reactive oxygen species; SIRT1, silent mating-type information regulation 2 homologue 1; SNO, S-nitrosylation; Sp1, specificity protein 1; SSG, S-glutathionylation; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; TH, thyroid hormone; THR, thyroid hormone receptor; and VDR, vitamin D receptor. [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]

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Manasi S. Shah, Michael Brownlee

Increased cardiac fatty acid oxidation, reactive oxygen species (ROS) formation, and cardiolipin remodeling. Insulin resistance–induced increased cardiac β oxidation of free fatty acids (FFAs) causes greater H2O2 production than does increased glucose oxidation because of increased electron leakage from the electron transfer flavoprotein (ETF) complex. These ROS activate Acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1) transcription. ALCAT1, located in the mitochondrial-associated membrane of the endoplasmic reticulum, causes pathological remodeling of cardiolipin from tetra 18:2 cardiolipin to cardiolipin with highly unsaturated fatty acid side chains and cardiolipin deficiency because of oxidative damage. This reduces ETC (electron transport chain) electron flux, ATP synthesis, and further increases ROS. [Powerpoint File]

Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease

Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease

José J. Fuster, Noriyuki Ouchi, Noyan Gokce, Kenneth Walsh

Functional adipose tissue (left), predominantly found in lean organisms, tends to express anti-inflammatory adipokines that protect against cardiovascular disease. In contrast, excess adipose tissue expansion promotes dysfunction (right), leading to the expression of proinflammatory adipokines that promote cardiovascular disease. Dysfunctional adipose tissue is characterized by enlarged adipocytes, vascular rarefaction, increased inflammatory cell infiltrate, and the appearance of crown-like structures. [Powerpoint File]

Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease

Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease

José J. Fuster, Noriyuki Ouchi, Noyan Gokce, Kenneth Walsh

Obesity leads to adipose tissue dysfunction, triggering the release of proinflammatory adipokines that can directly act on cardiovascular tissues to promote disease. The adipokine imbalance can also affect the function of metabolically important tissues and the microvasculature, promoting insulin resistance and indirectly contributing to cardiovascular disease. [Powerpoint File]

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Manasi S. Shah, Michael Brownlee

Hyperglycemia-induced myocardial protein modification by O-GlcNAc causes increased intracellular Ca++ and delayed after polarizations. Increased intracellular glucose flux provides more substrate for the enzyme O-GlcNAc-transferase (OGT). This increases O-GlcNAc modification of calcium/calmodulin-dependent protein kinase IIδ (CaMKII), causing autonomous CaMKII activation. CaMKII increases intracellular Ca++ by phosphorylating ryanodine receptor 2 (RyR). OGT also modifies transcription complex factors regulating expression of sarcoplasmic reticulum Ca2+-ATPase (SERCA2), reducing SERCA2A expression and contributing to increased intracellular Ca++. Increased O-GlcNAc modification of these proteins causes delayed afterdepolarizations in cardiomyocytes. PLB indicates phospholamban. [Powerpoint File]

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Manasi S. Shah, Michael Brownlee

Increased mitochondrial oxidation of glucose or fatty acids activates nuclear factor of activated T cells (NFAT)–mediated transcription of genes promoting diabetic atherosclerosis and heart failure. Mitochondrial overproduction of reactive oxygen species (ROS) causes increased intracellular Ca++, which activates the calcium-activated neutral cysteine protease calpain. Calpain then activates the Ca2+/calmodulin-dependent (CaM; Ca2+)serine/threonine phosphatase calcineurin. Dephosphorylation facilitates nuclear translocation of the transcription factor NFAT. In the nucleus, NFAT interacts with polyADP-ribose polymerase (PARP), which increases NFAT transcriptional activity via NFAT polyADP-ribosylation. ICAM-1 indicates intercellular adhesion molecule-1; IL-6, interleukin-6; and MCP-1, monocyte chemoattractant protein-1. [Powerpoint File]

Epigenetic Changes in Diabetes and Cardiovascular Risk

Epigenetic Changes in Diabetes and Cardiovascular Risk

Samuel T. Keating, Jorge Plutzky, Assam El-Osta

Interpreting chromatin and constituent residues subject to modification. Chromatin regulates gene structure and function. DNA is packaged into a 30-nm macromolecular structure consisting of the chromatin fiber. Together with post-translational modifications (PTM) of histone residues, chromatin regulates the functions involving transcription, repair, replication, and condensation. The nucleosome at 11 nm is comprised of ≈147 bp of DNA comprising an octamer of 2 copies of each of the 4 core histone proteins: H2A, H2B, H3, and H4. The histone tail is subject to immense interpretation by writing enzymes that add PTM shown such as histone methyltransferase, Set7. Histone tails are also subject to erasing enzymes that specifically remove these modifications and interpreted by reader proteins that identify histone tail modifications. Cytosine residues of the DNA duplex are subject to 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications interpreted by methyl-CpG binding domain (MBD) and ten-eleven translocation (TET) enzyme. Methylation-mediated gene suppression events involve targeted MBD recruitment whereas TET proteins are implicated in active DNA demethylation and regulation of gene expression. [Powerpoint File]

Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease

Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease

José J. Fuster, Noriyuki Ouchi, Noyan Gokce, Kenneth Walsh

Adipose tissue depots occur throughout the body. Studies suggest that visceral adipose tissue accumulation is a major risk factor for cardiometabolic disease, whereas subcutaneous fat seems to be neutral or protective. Other adipose tissue depots of note include the epicardium, the perivascular space, and bone marrow, but the functional significance of these tissues is largely unknown. Brown adipose tissue occurs in the supraclavicular and paraspinal regions. In contrast to white adipose tissue, brown adipose tissue is metabolically active, and it functions to utilize fuel to produce heat. In addition, ectopic lipid can accumulate in tissues, such as liver, in metabolically dysfunctional organisms. [Powerpoint File]

Epigenetic Changes in Diabetes and Cardiovascular Risk

Epigenetic Changes in Diabetes and Cardiovascular Risk

Samuel T. Keating, Jorge Plutzky, Assam El-Osta

Epigenomic profiling of human monocytes and endothelial cells. Distinguishing epigenomic profiles from distinct cell populations in the vasculature. In this example, histone modifications and genomic DNA methylation sequences are derived from human monocyte and endothelial cells using epigenomic profiling methodology combined with computational analyses and integration. Histone acetylation data from human CD14+ monocytes was accessed from the Encyclopedia of DNA Elements portal. Histone acetylation and DNA methylation data from human aortic endothelial cells were obtained from GEO (Gene Expression Omnibus; ID: GSE37378). This circos plot shows histone acetylation and DNA methylation patterns on chromosome 17. Peaks were uniformly generated using MACS (Model-based Analysis of ChIP-Seq) peak calling by comparing the samples to sequenced input for both cell types. The length of the peaks is proportional to the strength of the peak (calculated based on P value). Monocyte acetylation is shown in purple. Endothelial cell acetylation is shown in blue, whereas methylated regions are shown in red. The innermost track represents gene promoters from HAECs with differential histone acetylation (green) and deacetylation (orange) induced by the histone deacetylase inhibitor suberoylanilide hydroxamic acid. All RefSeq (hg19) genes on chr17 are represented in the outer most track (blue with red outline). Names of genes associated with differential histone acetylation at the promoter are included. [Powerpoint File]