Atherosclerosis

ATHEROSCLEROSIS Normal Atherosclerosis Factors such as high plasma cholesterol, smoking, hypertension, diabetes and family history are all associated with atherosclerosis. Normal Atherosclerosis Intima Medis Adventitis Proliferation of intimal connective tissue Lipid accumulation Tissue breakdown

Progression Of Atherosclerosis

The Lipid Hypothesis and components of the plaque Diagrammatic representation of an atheromatous plaque showing outer cap containing collagen and smooth muscle cells, and inner core containing foam cells and extracellular cholesterol crystals. Collagen Smooth muscle cells Cholesterol crystals Foam cells

The Lipid Hypothesis

Response – to – Injury Hypothesis Monocycle Cholesteryl ester Foam cells Platelets LDL Endothelial injury

Development of Atherosclerosis Acute occlusion caused by blood clot, fragment or spasm Progressive Reduction in blood flow R Lumen Diameter 100% (Endothelial damage) Intima Fatty lesion Progression to fibrolipid plaque formation Risk factors Regression Development of Atherosclerosis Fibrous cap Ground substance Collagen fibers Reticulum fibrils Thrombosis Ulceration Calcification Haemorrhage Complicated lesion Intercellular lipid Fatty streak Lipid core Fibrous plaque Foam cells Smooth Muscle 1 2 3

Arterial Wall Permeability  LDL Large % serum cholesterol - High influx Lp characteristics: Type (Lipids & apoP) Size Number Most cholesterol VLDL Lipoprotein (a) LDL HDL IDL Chylomicrons

High LDL Levels Receptor Mediated Pathway Non-Specific

Lipoprotein Trafficking Relationship between arterial intimal influx, efflux, degradation, and retention of plasma lipoproteins. Increased retention in intima of intact atherogenic lipoproteins, or increased deposition of cholesterol from lipoproteins degraded by macrophages, or both, are important characteristics of atherosclerosis. Influx Efflux Plasma Intima Media Adventitia Degradation Retention

LDL Heterogeneity: Small vs. large LDL:

Production of Small Dense LDL Although size (& lipid content) changes, there is always 1 molecule apo B protein / particle Oxidation & modification TG CE Lipase B (CETP) Lipids transferred dense large 1 2 3 VLDL remnants IDL LDL Lipoprotein receptors

Relative Atherogenicity of Large and Small LDL Particles B Tg CE Relative Atherogenicity of Large and Small LDL Particles

N-LDL OX-LDL B

? Oxidized LDL Concentration Residence time in arterial wall Modified protein & lipid = immunogenicity Concentration Residence time in arterial wall Opportunity to be oxidized, taken up by macrophage, glycated and be trapped MEDIA INTIMA Endothelium LUMEN LDL, VLDL IEL Free radicals Initial Lipoprotein Oxidation ?

Permeability Arterial Wall Characteristics Oxidized LDL can: 1-  leucocyte influx 5-  response acetylcholine 2-  chemotactic factors 6-  macrophage foam cells 3-  thrombosis 7-  cytokine factors 4-  toxicity 3 major cell types: - Foam cells - Endothelial cells - Smooth muscle SMC EC LDL ↑ Lipoprotein size ↓ Efflux ↑ Influx ↑ Foam cells leave intima Plasma Intima ↓ Estrogen ↑ Athero sclerosis ↑ Retention ↑ Degradation ↑ Oxidation ↓ Lipoprotein size ↑ Plasma concentration ↑ Arterial wall injury ↑ Blood pressure ↑ Permeability

LDL C 3.5 3.5 Apo B 75 150 CE B Tg

Because small dense LDL is more toxic ( oxidation etc.) but has less cholesterol per particle, measuring LDL cholesterol doesn’t give the whole complete picture. Measuring apoB provides a better index of particle number, and an additional discriminator. Percent 40 30 20 10 40 60 80 100 120 140 160 180 200 220 240 260 280 mg/dl LDL cholesterol 25 15 5 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 mmol/l Controls CHD patients LDL apoB

Biological Determinants of Protracted Instability in Unstable Angina: Endothelium Platelets Smooth Muscle Cells Sympathetic Nerve Injury Inflammation

Cellular Components of Atherosclerotic Lesion Development

Endothelial Cells ACTIVATION Oxidized lipids/ Free radicals Cytokines (dietary fats) Nicotine (smoking) EC damage  EDRF  Endothelin 3 Altered surface  anticoagulants,  plasminogen activators,  PAI - 1 2  chemoattractants to: - platelets & Mø, - growth factors for SMC Viral infection Homocysteine Hypoxia Shear stress Cytokines EC Oxidized lipids/ Free radicals Leukocyte adhesion Altered permeability Procoagulant activity Vasoactive substances Growth factors/ chemoattractants ACTIVATION RESPONSE

Macrophages 1.  VCAM,  Monocytes 2.  Monocyte 3.  Differentiation to Mø 4.  Scavenger Receptor  LDL oxidation  PDGF, bFGF  Enzymes (metalloproteinases) 5.  Foam cells (fatty streak) 6.  Effect on SMC (by M-CSF / 1L–1) 7. Rupture releases factors that  clotting &  PAI-1 4 7 5 3 1 2 6 Rupture Endothelium Adhesion Monocyte LDL Fatty streak Lipid Oxidation MM-LDL Ox-LDL Modified LDL uptake ROS Smooth Muscle cells Macrophage X-LAM Entry M-CSF IL-1 Differentiation MCP-1 muscle cell proliferation

Smooth Muscle Cells * Normal Developing lesion Predominant cell type In Atherosclerosis  deviate from N behaviour:  proliferation &  migration due to  bFGF & PDGF production by Mø & dysfunctional EC but also SMC become responsive (see  next O / H) * Smooth Muscle Cells Normal Developing lesion PDGF (exon 6) PDGF Migration Intimal growth t-PA Ang II SMC migration β3 integrin replication bFGF SMC AT1 α adrenergic Receptor inhibitor (e.g.: prazosin) TGF β PDGF antibody Heparin

Normal Developing lesion Addition bFGF no response (no receptor) Normal Developing lesion SMC Released bFGF SMC replication SMC death bFGF FGF-r FGF-toxin No enhanced replication No injury +bFGF PCNA antisense c-myb antisense Heparin Membrane disruption Mechanical injury EC

FIBRINOGEN & FIBRINOLYSIS Clot size = Balance formation & lysis Factors that influence: EC -  PAI–1 (therefore inhibits clot lysis)  plasminogen activators (therefore inhibits clot lysis) -Mø -  factors that  clotting (therefore  formation)  PAI–1 Lp (a) is LDL with a tail - “mimics” plasminogen (therefore interferes with clot lysis) [ ]  risk factor Lesions SMC proliferation interact LDL (active) Lp (a) FIBRINOGEN & FIBRINOLYSIS Plasminogen activators Fibrogen Fibren FDP Antiactivators Plasmin t-Pa Pro-UK-UK FXII-PreK-HMWK PAI-1 PAI-2 C1 inh α2-AP

Lp (a) (LDL with a tail) Present at very low to very high levels Concentration is strongly influenced by hereditary Not influenced by Rx Lp (a) (LDL with a tail) B100 apo (a) S-S (lp a+) (lp a-) S S S S S Kringle 4 5 3 2 1 Plasminogen

OXIDIZED LDL INTERPLAY Oxidation of LDL changes its properties and the way it interacts with cells. 1- It can injure or kill cells, particularly those going through the cell cycle. 2- It may recruit monocytes by acting as a chemoattractant itself, 3- By inducing endothelial cells to produce monocyte chemoattractants, and causing the expression of a monocyte-binding protein on the endothelial cell surface. OXIDIZED LDL INTERPLAY Monocyte Chemoattractants Monocytes Cell Death Oxidised LDL Increased LDL, VLDL Entry

OXIDIZED LDL INTERPLAY (cont’d) 4- With further oxidation, oxidized LDL can become a ligand for scavenger receptors on monocyte-derived macrophages. 5- Aggregated oxidized LDL may be taken up by phagocytotic processes. 6-Oxidized LDL may also be a chemoattractant for smooth-muscle cells from the media. Receptor Mediated uptake Cell Death SMC Chemoattraction Monocyte Derived Macrophage (From Cells) Agrogate Fprmation And Phagocytosis