RnDSy-lu-2945 Atherosclerosis Disease Progression

Healthy Endothelial Damage Cellular uptake of lipids Intracellular cholesterol metabolism LDL oxidation Reverse cholesterol transport Foam cell development

LDL OXIDATION Minimally modified (mmLDL) to oxidized (oxLDL) Agents Substrates Products Lipoxygenase ApoA1,ApoB Aldehydes (HNE,MDA) Myeloperoxidase Cholesteryl esters Free fatty acids NADPH oxidase Phospholipids Lipid hydroperoxides Phospholipases Polyunsaturated fatty acids Lysophosphatidic acid (LPA) Xanthine oxidase Lysophosphatidyl choline (LPC) TBARS

Cathepsin K IFN-γ E2 CCL2,3,4,5,8,11,19,20,22 IL-6,10,17,18 PLA2G7 CX3CL1 MMPs Thromboxane A2 CXCL2,8,9,10,16 Prostaglandin D2 TNF-α

NITRIC OXIDE EFFECTS  Vasoconstriction DC-SIGN CD11b CCL2  Fcγ RII/III Endothelial permeability CD14 IL-12,23  Angiogenesis NO IFN-γ R1 α  Platelet aggregation TNF- AT1  SMC proliferation RAGE TLR4-MD2-CD14 PDGF R  Leukocyte adhesion ApoA1 LOX-1 Dendritic DEC205 Cell RAGE SREBP  HMG Co A PTGER2 CD11c Low Sterol Conditions SCAP SREBP Cholesterol MARCO Reductase CD36 Cholesteryl esters Activation Synthesis GM-CSF INSIG  LDL R TLR4 ligation Triglycerides CX3CR1 γ LOX-1 Monocyte LOX-1 RAGE Fc RII/III LXRα or β  ABCA1, G1 NO TLR2 Phospholipids P-Selectin Integrin α4β1 High Sterol Conditions ROR  PLTP, CETP, LPL E-Selectin CCR5 +  eNOS ApoE2,C1,C2,C4 Integrin αLβ2 CD36 Oxysterols CCR2  IDOL LDL PGI2 Macrophage degradation (M1 polarized) SR-A TLR4-MD2-CD14 CCL2,3,4,5,8,11,15,19,20,22 IL-6,10,15,17,18,23 CXCL1,2,3,5,8,9,10,11,13,16 Cathepsin K Mature HDL Macrophage ABCA1 TLR3,9 ABCG1 CX3CL1 PLA2G7 Cholesteryl Cholesterol ICAM-1 ester storage Efflux ABCA1 ABCG1 IFN-γ TNF-α Triglyceride VCAM-1 Monocyte hydrolysis ACAT SR-BI TNF R1 Integrin αLβ2 Cholesterol γ α Capillary LIPE Integrin α4β1 AdipoR IFN- , TNF- SR-A mmLDL Free Cholesterol Cellular lipids Kv1.3 TLR3,4,9 ligation oxLDL SR-BI NCEH ST2 ApoA1 EL Mature HDL Monocyte LOX-1 IFN-γ R1 Cholesterol IL-1ra LOX-1 ABCG1 ABCA1 IL-33 Pre-beta HDL Reverse cholesterol AGEs ABCA1 CX3CR EL, HL transport CRP RAGE Foam Cells Cholesterol mmLDL CD36 Lipids LCAT ABCG1 AGEs Mature CCR2 CCR5 AGEs SR-BI SR-BI HDL Transfer of Cholesteryl Esters Cholesterol SMC proliferation & migration acLDL Transdifferentiation to foam cells CETP, PLTP oxLDL AGEs HDL EFFECTS CETP, PLTP ADVANCED GLYCATION END PRODUCTS (AGEs) acLDL  NO production Transfer of Phospholipids ● Non-enzymatic conjugation of sugars to macromolecules  NADPH oxidase oxLDL Sympathetic neuron and Triglycerides ● Accelerated under hyperglycemic and oxidative conditions  Endothelial cell, macrophage apoptosis ● Increased production in diabetes and chronic inflammation  Leukocyte adhesion SR-BI VLDL Leptin R  Monocyte activation MMP-1,2,12,13,14,25 Digestion of  Platelet aggregation LDL EL, HL DYSFUNCTIONAL ENDOTHELIUM-DERIVED FACTORS elastic lamina  Matrix degradation Fas/CD95 EL, HL LPL, PLTP BMP-2,4 FGF basic ● Removes oxidized lipids from LDL and cells CCL2,5 Follistatin Cathepsin K Elastic lamina LPL, PLTP AT1 Collagen ● Protects LDL from oxidative modification PCSK9 Crossveinless-2 M-CSF IL-6,33 LDL R CX3CL1 MMP-1,3,9 M-CSF Tunica media IDL CXCL1,2,3,8 Noggin CD40 Cholesterol MMP-1,9 (smooth muscle) Cholesterol Endothelial lipase Serpin E1/PAI-1 CD40 Ligand Endothelial lipase Phospholipids Phospholipids Endothelin-1 PDGF Adventitia LDL NADPH oxidase ROS Remnants Intima Vascular Endothelium Arterial Lumen

Fibrin clot Creatinine Kinase MM/CKMM Activated Platelets Troponins TnI,TnT

CIRCULATING VASOACTIVE FACTORS Monocyte Th1 Constrictors Dilators Macrophage Monocyte ADP Epinephrine TBXA2R (M1 polarized) Endothelin-A Histamine Integrin α2bβ3 Epinephrine PGD2 Histamine PGE2 LOX-1 Azurocidin NADPH oxidase PGE2 PGI2 Cathepsin G Neutrophil elastase Macrophage S1P CCL2,3,19,20 Nitric oxide Neoangiogenesis (M1 polarized) α Thrombin CD36 Neutrophil -Defensins PLA2G2A TXA2 CAMP/LL37 S100A8,A9 SMC apoptosis Myeloperoxidase VEGF

Coagulation Factor III/ Platelets Tissue Factor CD8+ Macrophage T cell (M1 polarized) Fibrous cap thinning CCL3 MMP-1,2,12,13,14,25 CCR6 Intra-plaque Granzymes hemorrhage IFN-γ Integrin αMβ2 IL-17 TNF-α CD8+ Integrin αXβ2 CXCR1,2 T cell Fatty Streak CCR3 Th1 L-Selectin IFN-γ R

Th1 Macrophage Macrophage (M1 polarized) (M1 polarized) PSGL-1 IL-1β IFN-γ CCR1,5 α IGF-1R IL-12 Rβ1,2 IL-2 TNF- IL-18 Rα,β Clotting Cascade IL-27 Rα Macrophage Neutrophil Factor XII (M1 polarized) Mast Cell Alkaline phosphatase Pre-Kallikrein AT1 BMP-2,4,6 ST2 Matrix Gla HMW Kininogen IL-4 Rα EDNRA,B CCL2 PLA2G2A IL-5 Rα Necrotic cells Chymase TNF-α Osteoprotegerin CXCL8 Tryptase IL-9 R EP1,3,4 Factor XII activation Mast Cell GM-CSF VEGF IL-13 Rα1 IL-3,4,5,13 S1PR2,3

Mast Cell CysLT1 Intima thickening Factor XI activation Factor III/Tissue Factor TLR3,9 ACELLULAR NECROTIC CORE PTGDR Osteogenic differentiation Factor VIIIa Calcium nodules Calcification of SMC Cholesterol Fibrin P2Y Factor IX activation Factor X activation Glycophorin A TBXA2R Factor VIIIa Hypoxic Fibrinogen Necrotic foam cells PAR1 Aneurysm of arterial wall Factor X activation Factor Xa Pro Thrombin activation FIBROUS CAP RAGE Factor Va Biglycan Fibrin Collagen I,III Macrophage Decorin (M1 polarized) Hyaluronan Versican

Adenosine R A1,2a,2b 5-HT1B,2A,7 Aneurysm rupture and M1,3 Acetylcholine Adenosine Arterial hemorrhage H1,2 D1 Dopamine Serotonin Adrenergic Receptors alpha 1a,1b,1d,2a,2b,2c beta 1,2,3 RISK FACTORS FOR ATHEROSCLEROSIS Advanced age Hypertension PLATELET-DERIVED FACTORS CIRCULATING FACTORS Diabetes  LDL cholesterol 5-HT/serotonin Protein S Adiponectin IGF-1 Genetics Obesity ADP,ATP,GDP Prothrombin  Leukocyte adhesion  SMC proliferation  HDL cholesterol Sedentary lifestyle CXCL4,7 TFPI  EC apoptosis  NO production in EC High fat diet Smoking Endostatin Thrombospondin-1  Foam cell development  ROS production in EC Factors V,XI,XIII Thromboxane A2  Thrombosis ● SMC apoptosis Fas Ligand TRAIL Fibrinogen TWEAK Leptin Plasmin VEGF  Leukocyte adhesion Plasminogen vWF  Platelet aggregation & activation Polyphosphates  Foam cell development Plaque Rupture  SMC responsiveness to Arg II Plaque Progression Foam cell accumulation and necrosis Thrombosis and arterial blockage Smooth muscle cell (SMC) proliferation and migration Aneurysm rupture

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