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Pathogenesis of Atherosclerosis. Judith Berliner, Ph.D. Departments of Pathology and Medicine Division of Cardiology David Geffen School of Medicine at UCLA. Fatty Streak. Early Fibrous Plaque. Advanced Plaque. Thrombus. Ages of Progression Fatty Streak – 0-30 Fibrous Plaque – 30-50
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Pathogenesis of Atherosclerosis Judith Berliner, Ph.D. Departments of Pathology and Medicine Division of Cardiology David Geffen School of Medicine at UCLA
Ages of Progression Fatty Streak – 0-30 Fibrous Plaque – 30-50 Complicated Plaque – 40+ Thrombosis – 50+
Nitric Oxide Function (anti-inflammatory) • Causes smooth muscle cell relaxation (vasodilation) • Suppresses SMC proliferation and matrix synthesis • Reduces the expression of inflammatory genes • Inhibits platelet aggregation
Fatty Streak • Retention of LDL • Entry of monocytes • Foam cell formation
Fatty Streaks Form in the Fetus of Hypercholesterolemic Mothers
Localization of Macrophages in Fibrous Plaques Human coronary artery lesionImmunoperoxidase with Mab to macrophages (HAM-56)
Alterations in Endothelial Cells and Monocytes in Fatty Streak Lesions • Endothelial cells display increased adhesion molecules and chemotactic factors. VCAM-1, MCP-1, IL-8. • 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 Normal LDL does not cause foam cell formation Aggregated LDL-taken up by the LDL receptor Oxidized LDL-taken up by scavenger receptors CD 36, SRA-1, LOX-1 Sphingomyelinase modified LDL-taken up by scavenger receptors Foam cell formation is inhibited by HDL Foam cells accumulate near the EC
Gene CD36 SRA-1 LOX-1 Apo A1 ABC-A1 Effect Less Less Less More More Effect of genes related to foam cell formation on fatty streak formation
Fibrous Plaque • Cytokines produced by macrophages lead to SMC migration and proliferation • SMC proteases digest elastic lamina to aid migration of SMC into the intima • SMC synthesize collagen and specific proteoglycans • SMC take up lipid forming foam cells • SMC and monocytes die by apoptosis or necrosis liberating cell contents. • Lymphocytes enter the lesion.
Effect of genes related to SMC migration, proliferation, matrix synthesis and death of foam cells on plaque formation Gene PDGF IL-1beta FGF Effect on atherogenesis Less Less Less
Role of Lymphocytes in Atherosclerosis • 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 • Accelerated cell death and growth of necrotic core • Angiogenesis • Formation of small thrombi on lumenal surface • Hemorrhage from newly formed vessels • Incorporation of thrombi and clots into vessel wall
Genes associated with formation of the complex plaque • VEGF, angiogenesis • Regulators of thrombosis • Regulators of thrombolysis • Regulators of apoptosis