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
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