Roles of lipoproteins transport of triglycerides from intestine & liver to peripheral tissues (dietary & stored fatty acids) transport of cholesterol & phospholipids to peripheral tissues, glands, and liver (« reverse ») transport of liposoluble vitamins transport of antioxidant enzymes neutralization of endotoxins effect of oxidised lipids on immune defenses, inflammation, and thrombosis passage of some particles from circulation to intimal space of arterial vessels (in both directions)

Structure of apolipoprotein B JP Segrest et al, J. Lipid Res., 2001

NORMAL REC. DEFICIENT LDL LDL IDL IDL VLDL VLDL FA FA

Passage intima fragilité LDL modifiées rétention intimale Sous-types de LDL LDL normales LDL rec sd LDL Passage intima fragilité cytotoxicité LDL modifiées rétention intimale cytotoxicité

Les lipoprotéines dans la paroi artérielle Nordestgaard BG and Nielsen LB, Curr. Opin. Lipidol., 1994

Cholesterol transport by HDL (normal) LpB receptors Other lipoproteins Peripheral Tissues CETP HDL Cholesterol ABC syst LCAT SR-B1/CLA Apo AI Apo AI Blood HDL Apo AI Cholesterol & bile acids Apo AI ABC syst SR-B1/CLA Arterial wall Steroidogenic tissues Cholesterol Steroid hormones

Roles of HDL: normal conditions Reverse cholesterol transport from periphery (including macrophages, endothelial cells, SMC, etc…) to liver Cholesterol transport to steroidogenic glands Transport of other lipid components & vitamins Protection of LDL against peroxidative damage Stabilization of prostacyclin Major carrier of LPS-binding protein (LBP)

LIPIDES ET LIPOPROTEINES PLASMATIQUES Les Gènes sont les briques et le mortier du corps, et le Comportement en est l’architecte RJ Deckelbaum

La Lésion Athéromateuse Maladie inflammatoire chronique de la paroi vasculaire Apparition récente dans évolution humaine Liée au mode de vie (nutrition, tabac, activité physique, ..) Liée au patrimoine génétique (familles, ethnies, …) Liée à autres pathologies (lipides, diabète, hypertension, inflammations, …) et traitements (stéroïdes, anti-rejets, ...) Distribution géographique (mode de vie occidental, centres urbains, …) Largement réversible  prévention efficace

La paroi artérielle normale Slide 1: The normal artery wall Cellules endotheliales The wall of a normal, healthy artery consists of three distinct layers1. The intima is the innermost layer. This comprises a monolayer of endothelial cells supported on a basement membrane and sub-endothelial matrix. Unlike that of other mammals, the human intima also contains a small number of vascular smooth muscle cells (VSMCs)2. The intermediate layer of the artery wall – the media – consists of concentrically arranged VSMCs in an extracellular matrix of collagen, elastic fibres and glycosaminoglycans1. The outermost structural layer of the artery wall is the adventitia. This comprises an extracellular matrix of longitudinally arranged collagen fibres and contains the vasa vasorum1. Endothelial cells synthesize and secrete a number of substances that control vascular tone. These include the vasodilators nitric oxide (NO), prostacyclin and the prostaglandins PGE2 and PGD2, as well as vasoconstrictors such as endothelin-1, thromboxane A2 and the prostaglandin endoperoxides PGG2 and PGH21,3. The endothelium also expresses substances that regulate the adhesion of monocytes and platelets, and control coagulation through a balance of inhibitory and promotional effects4. In the normal, healthy artery wall, the balance is such that antithrombotic, anti- inflammatory and vasodilatory characteristics predominate1,4. The endothelium is made up of three distinct layers: the intima, the media and the adventitia Endothelial cells secrete substances that control vascular tone Under basal conditions, the endothelium presents an antithrombotic surface, and vasodilatory tendencies predominate References 1 Vallance P. Vascular endothelium, its physiology and pathophysiology. In: Weatherall DJ, Ledingham JGG, Warrell DA. Oxford Textbook of Medicine, 3rd Edn, Oxford Medical Publications, Oxford, UK, 1996; 2: 2295–2300. 2 Schwartz SM, DeBlois D, O’Brien ER. The intima. Soil for atherosclerosis and restenosis. Circ Res 1995; 77: 445–465. 3 Celemajer DS. Endothelial dysfunction: does it matter? Is it reversible? J Am Coll Cardiol 1997; 30: 325– 333. 4 Verrier ED, Boyle EM. Endothelial cell injury in cardiovascular surgery: an overview. Ann Thorac Surg 1996; 64: S2–S8. CML contractiles

Début athérosclérose – Formation de la strie graisseuse Slide 4: Early atherosclerosis (III) – Formation of the fatty streak Les monocytes migrent dans l’intima, se differencient en macrophages, se gorgent de lipides, et forment cell. spumeuses On migrating into the intima, recruited monocytes differentiate into macrophages. This process is associated with the expression of the scavenger receptor; hence macrophage activation is accompanied by the uptake of modified oxLDL already present in the intima1,2. The uptake of oxLDL by macrophages results in the formation of cholesterol-rich foam cells which, together with T-lymphocytes that appear to accompany the monocytes during their entry into the vessel wall, comprise the earliest and most common atherosclerotic lesion: the fatty streak3. Adhesion molecules expressed by endothelial cells mediate monocyte recruitment and migration into the intima Intimal monocytes are activated to macrophages, which ingest lipid to produce foam cells Foam cells and T-lymphocytes combine to form fatty streaks in the artery wall References 1 Scott J. Atheroma, the vessel wall, and thrombosis. In: Weatherall DJ, Ledingham JGG, Warrell DA. Oxford Textbook of Medicine, 3rd Edn. Oxford Medical Publications, Oxford, UK, 1996; 2: 2289– 2295. 2 Davies MJ, Ho SY. Atherosclerosis: the process. In: Davies MJ, Ho SY. Atlas of Coronary Artery Disease. Lippincott-Raven, Philadelphia, USA, 1998: 23–61. 3 Ross R, Fuster V. The pathogenesis of atherosclerosis. In: Fuster V, Ross R, Topol EJ. Atherosclerosis and Coronary Artery Disease, Lippincott-Raven, Philadelphia, USA, 1996: 441–460. Lipid Des lymphocytes-T accompagnent les monocytes dans l’intima

La couche fibreuse et la plaque athéromateuse Slide 7: The fibrous cap of the developing atheromatous plaque Les CML qui ont migré changent de phénotype (de ‘contractile’ à ‘cicatrisation’), et produisent les composants de la couche fibreuse Noyau lipidique The most obvious difference between early and more developed atherosclerotic lesions is the incorporation into the latter of a fibrous cap. This cap covers the lipid-rich inner core and separates it from blood circulating through the lumen. The fibrous cap that characterizes the more advanced atheromatous lesion comprises a dense extracellular matrix generated by repair phenotype VSMCs1–3. Indeed, VSMCs are the only cells within an atherosclerotic plaque that are capable of synthesizing and maintaining the fibrous cap4. The fibrous cap is usually by far the largest component of the plaque, occupying more than 70% of the total volume of a typical stenotic coronary lesion5,6. The principal components are interstitial fibrillar collagen, elastin, proteoglycans and glycosaminoglycans3,5,7. Advanced plaques include a fibrous cap composed of extracellular matrix materials The fibrous cap separates the lipid-rich plaque core from the circulating blood, stabilizing the lesion VSMCs are the only cells capable of synthesizing the fibrous cap that stabilizes the atherosclerotic plaque References 1 Scott J. Atheroma, the vessel wall, and thrombosis. In: Weatherall DJ, Ledingham JGG, Warrell DA. Oxford Textbook of Medicine, 3rd Edn. Oxford Medical Publications, Oxford, UK, 1996; 2: 2289–2295. 2 Shanahan CM, Weissberg PL. Smooth muscle cell heterogeneity: patterns of gene expression in vascular smooth muscle cells in vitro and in vivo. Arterioscler Thromb Vasc Biol 1998; 18 (3): 333–338. 3 Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995; 91: 2844–2850. 4 Weissberg P. Mechanisms modifying atherosclerotic disease – from lipids to vascular biology. Atherosclerosis 1999; 147 (suppl 1): S3–S10. 5 Shah PK. New insights into the pathogenesis and prevention of acute coronary syndromes. Am J Cardiol 1997; 79: 17–23. 6 Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92: 657–671. 7 Crea F, Biasucci LM, Buffon A. Role of inflammation in the pathogenesis of unstable coronary artery disease. Am J Cardiol 1997; 80: 10E–16E. Adventice Weissberg, 1999