Lipoproteinas y Aterogenesis
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Lipoproteinas y Aterogenesis
- 1. Papel de las Lipoproteínas en Aterosclerosis
- 2. Papel de la LDL en Aterosclerosis Las LDL ingresan a la pared arterial donde son modificadas Lumen del Vaso LDL Endotelio Oxidación de Lípidos LDL Hidólisis de fosfatidilcolina a y ApoB lisofosfatidilcolina Agregación Otras modificaciones químicas LDL Modificada LDL Modificadas son Proinflamatorias Intima Steinberg D et al. N Engl J Med 1989;320:915-924.
- 3. Papel de la LDL en Aterosclerosis Lumen del Vaso Monocito LDL Endotelio MCP-1 LDL LDL Modificada Intima Navab M et al. J Clin Invest 1991;88:2039-2046.
- 4. Papel de la LDL en Aterosclerosis Lumen del Vaso Monocito LDL Endotelio MCP-1 LDL Intima LDL Modificada LDL modificada promueve la diferenciación de Monocitos en Macrófago Macrófagos Steinberg D et al. N Engl J Med 1989;320:915-924.
- 5. Papel de la LDL en Aterosclerosis Monocito Lumen del Vaso Moléculas LDL Adhesión Endotelio MCP-1 LDL Citoquinas LDL Modificada Macrófago Intima Nathan CF. J Clin Invest 1987;79:319-326.
- 6. Papel de la LDL en Aterosclerosis Monocito Lumen del Vaso Moléculas LDL Adhesión Endotelio MCP-1 LDL LDL modificada tomada por macrófagos Intima Células Espumosas Macrófago Steinberg D et al. N Engl J Med 1989;320:915-924.
- 7. Papel de la LDL en Aterosclerosis Monocito Lumen del Vaso Lipoproteínas remanentes Moléculas Endotelio MCP-1 Adhesión Remanentes Remanentes Intima Citoquinas Modificados Factores de crecimiento Metaloproteinasas Macrófagos Proliferación celular Células Espumosas Degradación de la matriz Doi H et al. Circulation 2000;102:670-676.
- 8. HDL Previene la Formacion de Células Espumosas Monocito Lumen del Vaso LDL Moléculas Endotelio Adhesión MCP-1 LDL Citoquinas LDL Modificadas Celulas Espumosas Macrófagos HDL promueve eflujo de colesterol Intima Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80.
- 9. HDL Inhibe la Oxidación de LDL Monocito Lumen del Vaso LDL Moléculas Endotelio Adhesión MCP-1 LDL HDL Inhibe Oxidación de Citoquinas LDL Modificada LDL Células Espumosas Macrófago Intima HDL promueve eflujo de colesterol Mackness MI et al. Biochem J 1993;294:829-834.
- 10. HDL Inhibe Expresión de Moléculas d Adhesión Monocito HDL Inhibe Adhesión Moléculas de Expresión LDL Lumen del Vaso Molécules Endotelio Adhesión MCP-1 LDL HDL Inhibe Oxidación de Citoquinas LDL Modificada LDL Células Espumosas Macrófago Intima HDL promueve eflujo de colesterol Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.
- 11. Factores de Riesgo Sugeridos para Enfermedades Cardiovasculares v Oxidación de LDL v Injuria Endotelial v Inestabilidad de Placa LDL-C Triglicéridos/VLDL Metaloproteinasa-9 Anti-OxLDL apoA-1/apoB OxLDL HDL-2/HDL-3 v Formación de Trombos HDL-C Tamaño LDL Factor VII Paraoxonasa Postprandial TG Fibrinógeno PAF acetilhidrolasa IDL PAI-1 F2-Isoprostanas Quilomicrones remanentes Factor VII TBARS Presión sanguínea Activador tisular del ORAC Homocisteína plasminógeno Aspiraciónde etano Dímero D Complejo plasmina- v Disfunción Endotelial antiplasmina Factor de von Willibrand Fragmento 1+2 protrombina v Respuesta Inflamatoria P-Selectina Activación Plaquetaria Proteína C reactiva sICAM-1 IL-6 sVCAM-2 Lp-PLA2 Nitrato/Nitrito
- 12. Formación de la placa de ateroma Disfunción endotelial y los mediadores inflamatorios
- 13. Disfunción del endotelio Permeabilidad Adhesión Migración NO E-selectina Prostaciclinas LDL oxidada P-selectina PDGF MCP-1 ICAM-1 angiotensina II IL-8 endotelina MC-CSF PDGF
- 14. Formación de la estría grasa Migración del Activación Adherencia, músculo liso linfocitos T agregación plaquetaria y PDGF TNF-α migración de Formación de TNF-β IL-2 células espumosas leucocitos FGF-2 GC-CSF LDL-ox. P-selectina, E-selectina M-CSF ICAM-1, LDL-ox, MCP-1 IL-1 IL-8, MC-CSF, PDGF TNF-α
- 15. Formación de una lesión aterosclerótica Acumulación de Formación de Formación de una macrófagos core necrótico cubierta fibrosas M-CSF PDGF Apoptosis MCP-1 TNF-α Necrosis LDL-ox. TGF-β Acumulación lípidos IL-1 Actividad protolítica
- 16. Placa fibrosa inestable en aterosclerosis Ruptura de Adelgazamiento de la Hemorragia a partir de la placa cubierta fibrosa vasos de la placa Metaloproteinasas y otras enzimas proteolíticas
Notas del editor
- Role of LDL in inflammation LDL readily enters the artery wall by crossing the endothelial membrane. Once in the arterial wall, if LDL accumulates, it is subject to a variety of modifications. The best known of these is oxidation, both of the lipids and of the apo B. LDL is also subject to aggregation, and its phospholipids are subject to hydrolysis by phospholipases to form lysophosphatidylcholine. Several other chemical modifications have also been reported. The net effect of these changes is the production of a variety of modified LDL particles, and the evidence is now very strong that these modified LDL particles are proinflammatory. Reference: Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-924.
- Modified LDL stimulate expression of MCP-1 in endothelial cells Modified LDL is involved in many stages of the inflammatory process that leads to the development of atherosclerosis. Modified LDL activates endothelial cells to express monocyte chemotactic protein 1 (MCP-1), which attracts monocytes from the vessel lumen and into the subendothelial space, in what is one of the very early stages in the inflammatory process leading to the development of atherosclerosis.
- Differentiation of monocytes into macrophages The modified LDL plays an important role in promoting the differentiation of monocytes into macrophages, a key step in the inflammatory process on the way to the development of atherosclerosis. Reference: Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-924.
- Modified LDL induces macrophages to release cytokines that stimulate adhesion molecule expression in endothelial cells After modified LDL promotes the differentiation of monocytes into macrophages, the macrophages release a variety of chemicals, including cytokines. Of these cytokines, tumor necrosis factor α (TNF-α) and interleukin-1 (IL-1) activate endothelial cells to express adhesion molecules that bind monocytes, making them available for recruitment into the subendothelial space by MCP-1. Reference: Nathan CF. Secretory products of macrophages. J Clin Invest 1987;79:319-326.
- Macrophages express receptors that take up modified LDL The activated macrophages also express a variety of scavenger receptors, several of which recognize the different forms of modified LDL. The macrophages take up the LDL through these scavenger receptors, accumulate the lipid, and are converted into the lipid-rich foam cells that are the hallmark of atherosclerosis. Reference: Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-924.
- The remnants of VLDL and chylomicrons are also pro-inflammatory VLDL remnants and chylomicron remnants behave in much the same way as LDL. They enter the subendothelial space, where they become modified, and the modified remnants stimulate MCP-1, promote the differentiation of monocytes into macrophages, and are taken up by the macrophages to form foam cells. Like LDL, the remnant lipoproteins are proinflammatory and proatherogenic. References: Doi H, Kugiyama K, Oka H, Sugiyama S, Ogata N, Koide SI, Nakamura SI, Yasue H. Remnant lipoproteins induce proatherothrombogenic molecules in endothelial cells through a redox-sensitive mechanism. Circulation 2000;102:670-676.
- HDL prevent formation of foam cells Perhaps the best-known function of HDL is the promotion of cholesterol efflux from cells. Efflux of cholesterol from foam cells leads to a reduction in foam cell formation; although the macrophages may accumulate, they are not converted into foam cells. As a result, the inflammatory process is arrested to a certain extent. Therefore, HDL is anti-inflammatory and also protects against the development of atherosclerosis.
- HDL inhibit the oxidative modification of LDL HDL has protective effects in addition to promoting cholesterol efflux. One of the best known of these is the ability to inhibit the oxidation of LDL. To the extent that LDL oxidation is an important step in the development of the inflammatory process, this property of HDL is clearly anti-inflammatory.
- Inhibition of adhesion molecules The cytokine-induced expression of adhesion molecules in endothelial cells has been shown in vitro and more recently in vivo to be inhibited by HDL, in a process that potentially blocks a very early inflammatory stage in the development of atherosclerosis.