23ªAula

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•  Aterogénese: estudo dos mecanismos envolvidos na formação da placa 
aterosclerótica; papel da oxidação das LDL; Antioxidantes e aterosclerose; 
Factores de risco. 
Bibliografia 
•  Lodish H., Baltimore D., Berk A., Zipursky S.L., Matsudaira P., and Darnell J., Molecular 
Cell Biology (4ª Ed.), Freeman W.H. and Company (USA) (2000). 
•  Voet D. and Voet J.G. (2011) Biochemistry, 4 th edition, Wiley. Inc. 
•  Baynes J., and Dominiczak M.H., Medical Biochemistry (1ª Ed.), Mosby Int. Ltd (1999). 
Aterosclerose 
Obstrução das artérias dependente de colesterol, caracteriza-
se pela deposição progressiva de lípidos, células e material 
da matriz extracelular na camada interna da artéria 
Aterosclerose 
Teoria da aterogénese 
“Teoria da Oxidação das LDL” 
Processo mediado por ROS 
  Estudos epidemiológicos (Vit E) 
  Dieta Mediterrânica 
  Paradoxo Francês 
ANTIOXIDANTES ! 
Estrutura da artéria 
Initiating Events, LDL Modification 
Foam Cells 
•  Macrophages that contains massive amounts of 
cholesterol esters 
•  Cholesterol accumulation is mediated primarily 
by uptake of oxLDL via scavenger receptors on 
macrophages 
•  Hallmark of both early and late atherosclerotic 
lesions 
Lesion Progression 
Plaque Rupture and Thrombosis 
NO synthase (NOS) 
Coronary Heart Disease 
High LDL levels can lead to 
cardiovascular disease. 
•  LDL can be oxidized to form oxLDL 
•  oxLDL is taken up by immune cells called 
macrophages. 
•  Macrophages become engorged to form foam cells. 
•  Foam cells become trapped in the walls of blood 
vessels and contribute to the formation of 
atherosclerotic plaques. 
•  Causes narrowing of the arteries which can lead to 
heart attacks. 
Stroke (AVC) 
•  Development is strongly correlated to high LDL levels and 
low HDL levels 
•  Form of chronic inflammation resulting from interaction 
between: 
–  modified lipoproteins, monocyte-derived macrophages, T-cells, 
and the normal cellular elements of the arterial wall 
•  Ultimately lead to the development of complex lesions or 
plaques in the lumen of the artery 
•  Plaque rupture and thrombosis can occur and result in 
myocardial infarction (heart attack) and stroke 
Atherosclerosis 
Formation of Fatty Streaks 
•  Atherosclerotic lesions begin as fatty streaks underlying 
the endothelium of large arteries 
•  Initial formation of fatty streaks is driven by oxidative 
modifications of LDL, ranges from minimal modification, 
(mmLDL) to extensively oxidized (oxLDL) where LDL 
receptors cannot recognize it but instead taken up by 
scavenger receptors that are expressed on the 
macrophage 
•  Recruitment of macrophages and their subsequent 
uptake of oxLDL cholesterol are the major cellular 
events contributing to fatty streak formation 
•  HDL/LDL ratios are used as a diagnostic tool for 
signs of cardiovascular disease 
•  LDL = “Bad Cholesterol” 
•  HDL = “Good Cholesterol” 
•  A good HDL/LDL ratio is 3.5 
•  Protective role of HDL not clear. 
•  An esterase that breaks down oxidized lipids is 
associated with HDL. It is possible (but not 
proven) that this enzyme helps destroy oxLDL 
HDLs/LDLs and Cardiovascular Disease