Posts in Category: 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]

Gut Microbiota in Cardiovascular Health and Disease

Gut Microbiota in Cardiovascular Health and Disease

W.H. Wilson Tang, Takeshi Kitai, Stanley L. Hazen

Gut microbiota and possible molecular pathways linked to cardiovascular and cardiometabolic diseases. BAT indicates brown adipose tissue; FXR, farnesoid X receptor; GLP, glucagon-like peptide; GPR, G-protein–coupled receptor; LPS, lipopolysaccharide; PYY, peptide YY; TLR, toll-like receptor; TMA, trimethylamine; and TMAO, trimethylamine N-oxide. [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]

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]

Stroke Caused by Atherosclerosis of the Major Intracranial Arteries

Stroke Caused by Atherosclerosis of the Major Intracranial Arteries

Chirantan Banerjee, Marc I. Chimowitz

Histological cross-section of intracranial atherosclerosis in basilar artery. Image courtesy Dr Tanya Turan. Red arrow—fibrous tissue, blue arrow—vessel wall, and green arrow—lipid [Powerpoint File]

Pleiotropic Effects of Statins on the Cardiovascular System

Pleiotropic Effects of Statins on the Cardiovascular System

Adam Oesterle, Ulrich Laufs, James K. Liao

Regulation of the Rho GTPase cycle. Rho cycles between an inactive, cytoplasmic, GDP bound form and after geranylgeranylation is translocated to the plasma membrane and activated when it is bound to GTP. Inhibition of mevalonate synthesis by statins decreases geranylgeranyl (GG) pyrophosphate and prevents the geranylgeranylation of Rho and therefore its activation of Rho kinase (ROCK). ROCK mediates the downstream effects of Rho and has effect on endothelial cells, inflammatory cells, fibroblasts, cardiomyocytes, and vascular smooth muscle cells (SMC) that promote atherosclerosis and cardiac remodeling and may be responsible for the pleiotropic effects of statins. CRD indicates cysteine-rich domain; eNOS, endothelial nitric oxide synthase; GAP, GTPase-activating proteins; GDI, guanine nucleotide dissociation inhibitors; GEF, guanine nucleotide exchange factors; PI3K, phosphatidylinositol 3-kinase; and RBD, Rho-binding domain. Illustration Credit: Ben Smith. [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]

Prognostic Determinants of Coronary Atherosclerosis in Stable Ischemic Heart Disease: Anatomy, Physiology, or Morphology?

Prognostic Determinants of Coronary Atherosclerosis in Stable Ischemic Heart Disease: Anatomy, Physiology, or Morphology?

Amir Ahmadi, Gregg W. Stone, Jonathon Leipsic, Leslee J. Shaw, Todd C. Villines, Morton J. Kern, Harvey Hecht, David Erlinge, Ori Ben-Yehuda, Akiko Maehara, Eloisa Arbustini, Patrick Serruys, Hector M. Garcia-Garcia, Jagat Narula

Modification of the natural history of coronary disease by local implantation of a bioresorbable scaffold. From left to right: Intimal thickening (a), intimal xanthoma (b), pathological intimal thickening (c), fibroatheroma (d), thin-capped fibroatheroma (e) (reprinted from García-García et al92 with permission of the publisher. Copyright © 2009, Europa Digital & Publishing). As coronary disease progresses, does the endothelial function worsen. After the implantation of the scaffold, it can be seen that the 3-dimensional (3D) structure of the device can be delineated by means of optical coherence tomography (OCT) (f). In histology, it can be appreciated the polymeric struts overlying on the vessel wall (black arrow). On the 2D OCT image, the squared-shape struts are translucent and therefore their whole thickness can be appreciated (f′). At 5 o clock, the metallic marker can be seen (*). Invasive imaging by means of angiography and OCT allows the reconstruction of the scaffolded artery (f″). Thereafter, blood flow simulation was performed on the luminal surface and around struts at baseline and the local shear stress conditions were measured. As times goes by, the struts are integrated into the vessel wall and cover by neointima (g and g′). When the shear stress at baseline is portrayed into the follow-up OCT images (g″), it became apparent that the low shear stress areas at baseline (blue) correlate with thicker neointima thickness at follow-up as compared to high shear stress areas (on top of struts in red color), which showed thinner neointima thickness (reprinted from Bourantas et al93 with permission of the publisher. Copyright © 2014, American College of Cardiology Foundation. Published by Elsevier Inc.). Eventually, the polymeric struts will disappear (h) and somewhat vessel wall thinning is observed (i). As the bioresorbable vascular scaffold (BVS) integrates and dissolves, there is some vasomotion restoration (reprinted from Serruys et al94 with permission of the publisher. Copyright © 2014, American College of Cardiology Foundation. Published by Elsevier Inc.). EL indicates extracellular lipid; FC, fibrous cap; NC, necrotic core. BVS is a product of Abbott Vascular, Santa Clara, CA. [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]

Transcathether Valve Replacement and Valve Repair: Review of Procedures and Intraprocedural Echocardiographic Imaging

Transcathether Valve Replacement and Valve Repair: Review of Procedures and Intraprocedural Echocardiographic Imaging

Rebecca T. Hahn

Recommended surgical view for a mitral valve replacement. A, A schematic of mitral valve replacement (MVR) in the surgical view. B, A bioprosthetic MVR with an Agilis catheter across the interatrial septum and directed toward a paravalvular regurgitant leak at the 5 o’clock position (red dotted line). Ao indicates aorta; IAS, interatrial septum; LAA, left atrial appendage; and RA, right atrium. [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]