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Today March 13, 2006

Today March 13, 2006. -Aging of Cardiovascular System -Atherosclerosis -Dr. Forte’s lecture NOTE: I highly recommend reading the chapters on aging and the CV system.

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Today March 13, 2006

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  1. TodayMarch 13, 2006 -Aging of Cardiovascular System -Atherosclerosis -Dr. Forte’s lecture NOTE: I highly recommend reading the chapters on aging and the CV system.

  2. Arteriosclerosis: Sclerosis: hardening of the arterial wall and narrowing of the arterial lumenAtherosclerosis:Same as arteriosclerosis PLUS presence of artheroma (yellowish plaque containing lipids and cholesterol) on the arterial wall

  3. AtherosclerosisUniversalProgressiveDeleteriousIrreversible (?)

  4. Progressiveness of Atherosclerosis • Onset at young age • Progression through adulthood • Culmination in old age with overt disease manifestation • Consequences leading to severe disability & death

  5. Fig. 16-3: Natural history of atherosclerosis. Pathogenesis of human atherosclerotic lesions and their clinical manifestations.

  6. Table 16-8: Theories of Atherosclerosis • Lipid accumulation • Myoclonal • Thrombogenic • Inflammation • Free Radicals **See page 299**

  7. Extracellular cholesterol and cholesterol-filled macrophages (foam cells) accumulate in subendothelial space. Subsequent structural modifications of LDL particles render them more atherogenic. Oxidation of subendothelial LDL attracts monocytes, which enter subendothelium and change into macrophages. Macrophages may take up oxidized LDL to form foam cells.

  8. Fibrous plaque larger than fatty streak and occupies more of the arterial lumen. Thickened cap synthesized by modified smooth muscle cells. Central core consists of extracellular cholesterol. Foam cells surrounding core derived primarily from smooth muscle cells. Fatty streaks may continue to form at periphery of plaque.

  9. Total or partial occlusion of coronary artery due to plaque rupture and thrombosis can cause angina or frank myocardial infarction. Plaques likely to rupture termed unstable. Rupture usually occurs in lipid-rich and foam cell-rich peripheral margins and may result in thrombosis and arterial occlusion.

  10. Table 16-5: General Characteristics of Atherosclerotic Lesions • Early onset -- progressive • Focal lesions • Early lesions • Advance lesions • Damage, Repair, Regression • Progression of localized lesions influenced by: • Local factors: vessel structure and metabolism, blood turbulence • Systemic factors: diabetes, hypertension, stress, genetic predisposition

  11. Table 16-4: Localized Factors Contributing to Atherosclerosis Marginal vascularization of arterial wall Relative ischemia Limited metabolic exchange Blood turbulence and mechanical stress

  12. Endothelium-derived relaxing factor (EDRF)/nitric oxide (NO) induce vasal dilation • Endothelins induce vasal constriction • Vascular endothelial growth factor (VEGF) induces mitogenesis and promotes angiogenesis and wound healing • Cytokines participate in repair of vascular wall; promote cell adhesion and stimulate thrombotic activity

  13. Significance of Age Changes in the Vascular Endothelium*Table 16-2, page 293* • Endothelial cells undergo significant changes indicative of abnormal function • The imbalance of vascular tone is manifested by increased vasoconstriction • Endothelins EDRF, NO • Vascular integrity (cell proliferation and migration, wall remodeling) and injury repair through local growth factors are impaired • VEGF Cytokines • Maintenance of blood fluidity is disrupted with increased cell adherence, blood coagulation, and thrombogenic properties • Cytokines • These alterations by themselves may induce pathology or may predispose with other factors to atherosclerosis

  14. Regulation of coronary blood flow: Vasodilation O2 CO2 Vagal Stimulation Vasoconstriction Angiotension II Sympathetic stimulation

  15. High homocysteinemia, Protein C

  16. Lipids, Lipoproteins and Aging Objectives of the lecture -The main point of this lecture is to understand what lipids and apolipoproteins are -Know what LCAT, Lp(a), LPL, HDL,LDL, ABC1a are -Understand the basics of lipid circulation in the body -Know what metabolic syndrome is

  17. Lipids and Apolipoproteins • Major Categories • Risk Factors in Atherosclerosis • Lipoprotein Synthesis • Apolipoproteins • Lipolytic Enzymes • Receptors

  18. Lipids and Apolipoproteins • Categories • Chylomicrons and VLDL • High triglycerides • IDL and LDL • High cholesterol • HDL • High proteins • High phospholipid

  19. Role of Lipids (Lipoproteins) in Metabolism Triglycerides Major energy source for cells Cholesterol Cell growth, cell division, membrane repair, steroid hormone production Lipids Transport of fat soluble vitamins

  20. Positive and Negative risk Factors in Atherosclerosis PositiveNegative Age: Males > 45 years Elevated HDL cholesterol Females > 55 years Low LDL cholesterol Family history of early CHD Good genes Elevated LDL cholesterol (>130 mg/dl) Female gender (estrogen) Diabetes mellitus Excerise Hypertension Obesity Smoking CHD, coronary heart disease

  21. Normal Plasma Lipid Levels (mg/dl) Triglyceride Total Chol. HDL-Chol TC/HDLC Adult female 80 190 55 3.5 Adult male 120 200 43 4.7 Neonate 35 70 35 2.0

  22. Disease of the modern age Cluster of risk factors Contributing factors LDL elevated Triglyceride elevated HDL low Glucose elevated Blood pressure elevated Prothrombic marker (PAI-1) elevated Pro-inflammatory marker (CRP) elevated Advancing age Obesity Abdominal fat Physical inactivity Endocrine dysfunction Racial/ethnic contributions Metabolic Syndrome

  23. Lipoprotein Synthesis • Intestine • CM • Nascent HDL • Liver • VLDL • IDL • LDL • Nascent HDL

  24. Apolipoproteins • Definition: • Markers on lipid cell surface that determines metabolic fate of lipids • Roles in Metabolism • apoA-I • HDL • Reverse Cholesterol Transport • apoB-100 • VLDL, IDL, LDL • Sole protein on LDL • Necessary for assembly and secretion in liver • Ligand for LDL receptor apoA-I is important in reverse cholesterol transport (review figure 17.3) • Process whereby lipid free apoA-I and subclasses of HDL mediate the removal of excess cholesterol

  25. Major Apolipoproteins and Their Function ApoLipo OriginFunction ApoA-I HDL Liver, intestine Activate LCAT, Cholesterol efflux via ABCA1 transporter ApoB-100 VLDL, Liver Ligand LDL receptor, TG LDL transport from cells **Apo(a) Lp(a) Liver Inhibits thrombolysis** ApoCII HDL, VLDL Liver Activates lipoprotein lipase ApoE VLDL, IDL Liver, intestine Ligand, LDL receptor, LRP receptor LCAT: lecithin:cholesterol acyltransferase ABCA1: ATP binding cassette protein A1 LRP: LDL receptor related protein

  26. Key Enzymes in Lipoprotein Metabolism • Lipoprotein lipase (LPL): hydrolysis of triglyceride rich particles • Lecithin:cholesterol acyltransferase (LCAT): participates in removal of excess cholesterol from peripheral cells, helps HDL mature

  27. apo(a) Kringle Structure of Lp(a) apoB-100 LDL C 5 S S N 4 C 4 4 4 N

  28. Receptors • LDL • Responsible for internalization of LDL • Also known as apoB-E receptor • Regulates cholesterol synthesis

  29. LDL LDL LDL Receptor (apoB-E receptor) Regulates cholesterol synthesis and plasma cholesterol levels HMG-CoA reductase Cholesteryl ester (storage) LDL Receptors LDL-Receptors ACAT Cholesterol Amino acids Lysosome Endosome

  30. Receptors • Macrophage Scavenger (SR-A1) • Recognizes oxidized LDL • Role in atherogenesis

  31. The Scavenger Receptor (SR-A1 receptor) How macrophages deal with oxidized or modified LDL The scavenger receptor recognizes modified and/or oxidized LDL and internalizes the modified LDL. Accumulation of these modified LDL in the cell leads to the accumulation of cholesterol droplets in the macrophage and the formation of foam cells.

  32. Modification of LDL LDL Apo B-100 Oxidation: Degradation of B-100 by reactive oxygen species Derivatization: Aldehydes Glucosylation eg. diabetes Oxidized LDL Derivatized LDL

  33. The Scavenger Receptor:Clearance of modified LDL by macrophages Macrophage Macrophage Foam Cell Lipid droplets Oxidized LDL Scavenger receptor (SR-A1) Fatty streaks

  34. Alzheimer’s disease and Lipoproteins Late onset AD involves chr 19: • apo E gene on chr 19 • association of AD with apo E4 allele • 80% of familial AD have at least one apo E4 allele • apo E4 a major risk factor in AD

  35. ABCA1 Transporter/Receptor Large plasma membrane spanning ATP dependent protein. Essential for moving excess intracellular cholesterol and phospholipid to the plasma membrane. Acts as a flipase, flipping cholesterol and phospholipid from inner leaflet of plasma membrane to outer leaflet. Necessary for removing excess cholesterol from foam cells and preventing early steps in atherosclerosis. ApoA-I is required for capturing the cholesterol released from the foam cell.

  36. Reverse Cholesterol Transport (RCT) The process whereby excess cholesterol in peripheral cells, especially foam cells, is returned to the liver for degradation and excretion. RCT involves apoA-I, ABCA1 and LCAT as well as receptors on the liver for uptake of the excess cholesterol.

  37. Reverse Cholesterol TransportDelivery of peripheral tissue cholesterol to the liver for catabolismRequires HDL, apoA-I and LCAT Peripheral Cell diffusion HDL UC UC HDL Macrophage/ Foam cell UC ABCA1 LCAT PL LCAT Nascent HDL HDL CE CE CE apoA-I SR-B1 UC = unesterified cholesterol CE = esterified cholesterol PL = phospholipid LDLr = LDL receptor TG CE Liver VLDL or LDL apoB LDLr Bile to gut

  38. LDL and AtherosclerosisFitting the pieces together Elevated LDL: Increased residence time in plasma Increased modification/oxidation of LDL Monocyte Endothelial cells Cytokines oxLDL Artery wall oxLDL (stimulates cytokine secretion) Cytokines Macrophage Smooth muscle cell proliferation Macrophage foam cell

  39. HDL Protective RoleFitting the pieces together HDL Monocyte Endothelial cells oxLDL HDL Artery wall UC HDL + UC ABCA1 apoA-I PL UC oxLDL = oxidized LDL UC = unesterified cholesterol Macrophage foam cell Nascent HDL

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