Presentation on theme: "Pathogenesis of Atherosclerosis Judith Berliner, Ph.D. Departments of Pathology and Medicine Division of Cardiology David Geffen School of Medicine at."— Presentation transcript:
Pathogenesis of Atherosclerosis Judith Berliner, Ph.D. Departments of Pathology and Medicine Division of Cardiology David Geffen School of Medicine at UCLA
Alterations in Endothelial Cells and Monocytes in Fatty Streak Lesions 1.Endothelial cells display increased adhesion molecules and chemotactic factors. VCAM-1, MCP-1, IL-8. 2.In fat feeding there is an increase in the number of monocytes in the blood and a change in the ratio of subtypes. 3. Monocytes become more adhesive for endothelium.Only specific monocyte subtypes enter the vessel wall: GR1/ly6C hi
Effects of Leukocyte Trafficking Genes on Atherosclerosis In Knockout Mouse Models Defect Response M-CSF less MCP-1, CCR2 less P, E selectin less VCAM-1 less
Foam Cell Formation 1.Normal LDL does not cause foam cell formation 2.Aggregated LDL-taken up by the LDL receptor 3.Oxidized LDL-taken up by scavenger receptors CD 36, SRA-1, LOX-1 4.Sphingomyelinase modified LDL-taken up by scavenger receptors 5.Foam cell formation is inhibited by HDL 6.Foam cells accumulate near the EC
Effect of genes related to foam cell formation on fatty streak formation Gene CD36 SRA-1 LOX-1 Apo A1 ABC-A1 Effect Less More
Fibrous Plaque 1.Cytokines produced by macrophages lead to SMC migration and proliferation 2.SMC proteases digest elastic lamina to aid migration of SMC into the intima 3.SMC synthesize collagen and specific proteoglycans 4.SMC take up lipid forming foam cells 5.SMC and monocytes die by apoptosis or necrosis liberating cell contents. 6.Lymphocytes enter the lesion.
Role of Lymphocytes in Atherosclerosis 1.T cells, mainly of Th-1 subtype,enter the vessel. They produce high levels of gamma interferon.Knockout of gamma in mice decrease atherosclerosis. 2.B1b cells are increased. B1b are innate immune cells that make antibodies to oxidized lipids which also react with bacteria. They may serve a protective function.
Characteristics of the complex plaque 1.Accelerated cell death and growth of necrotic core 2.Angiogenesis 3.Formation of small thrombi on lumenal surface 4.Hemorrhage from newly formed vessels 5.Incorporation of thrombi and clots into vessel wall
Effectors of Thrombus formation 1. Endothelium Promoters of thrombosis Promoters of thrombolysis 2. Macrophages Produce tissue factor Necrotic core contains tissue factor 3. Platelets Show increased reactivity in atherosclerosis
Initiators of Atherogenesis: Lipoproteins: LDL and VLDL Oxidative Stress: Lipid oxidation, activation of inflammation Hypertension: Angiotensin and alteration in NO Diabetes: Hypertension and glycosylated proteins Smoking and pollutants: Oxidative stress
Evidence that oxidative stress is important in atherosclerosis 1.Levels of ROS increased in atherosclerotic vessels 2.Feeding of cholesterol stimulates ROS formation 3.Lipid oxidation products stimulate inflammation in vitro and in vivo
4. Risk factors such as glucose, AII and smoking increase ROS 5. Accumulation of oxidized lipids in lipoproteins is prognostic 6. Exposure of platelets to oxidized lipids causes activation 7. Antioxidant enzymes are protective
1. CD 36 2. Paraoxonase 3. Platelet Activating Factor Acetyl Hydrolase 4. HO-1 5. Glutathione Transferase 6. Glutathione Synthase Atherogenic gene polymorphisms in humans associated with oxidation
Therapeutic Approaches A.Decrease plasma cholesterol levels – Statins B.Increase HDL protein or its mimetics C.Increase reverse cholesterol transport by activating LXR D.Decrease the levels of angiotensin E.Inhibit inflammation: NFkB inhibitor, MCP-1 inhibitor, PPAR gamma agonist. F.Identify proatherogenic polymorphisms