1. 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.

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

4. Atherosclerosis Universal Progressive Deleterious Irreversible (?)

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

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

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

8. 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.

9. 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.

10. 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.

11. 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

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

13. 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

14. 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 EndothelinsEDRF, NO Vascular integrity (cell proliferation and migration, wall remodeling) and injury repair through local growth factors are impaired VEGFCytokines 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

15. Regulation of coronary blood flow: Vasodilation O 2 CO 2 Vagal Stimulation Vasoconstriction Angiotension II Sympathetic stimulation

17. High homocysteinemia, Protein C

20. 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

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

22. Lipids and Apolipoproteins Categories –Chylomicrons and VLDL High triglycerides –IDL and LDL High cholesterol –HDL High proteins High phospholipid

24. Role of Lipids (Lipoproteins) in Metabolism TriglyceridesMajor energy source for cells CholesterolCell growth, cell division, membrane repair, steroid hormone production LipidsTransport of fat soluble vitamins

25. Positive and Negative risk Factors in Atherosclerosis PositiveNegative Age: Males > 45 yearsElevated HDL cholesterol Females > 55 yearsLow LDL cholesterol Family history of early CHDGood genes Elevated LDL cholesterol (>130 mg/dl)Female gender (estrogen) Diabetes mellitusExcerise Hypertension Obesity Smoking CHD, coronary heart disease

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

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

28. Lipoprotein Synthesis Intestine –CM –Nascent HDL Liver –VLDL –IDL –LDL –Nascent HDL

29. 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

30. Major Apolipoproteins and Their Function ApoLipo OriginFunction ApoA-IHDL Liver, intestineActivate LCAT, Cholesterol efflux via ABCA1 transporter ApoB-100VLDL, LiverLigand LDL receptor, TG LDLtransport from cells **Apo(a)Lp(a) LiverInhibits thrombolysis** ApoCIIHDL, VLDL LiverActivates lipoprotein lipase ApoEVLDL, IDL Liver, intestineLigand, LDL receptor, LRP receptor LCAT: lecithin:cholesterol acyltransferase ABCA1: ATP binding cassette protein A1 LRP: LDL receptor related protein

31. 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

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

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

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

36. Receptors Macrophage Scavenger (SR-A1) –Recognizes oxidized LDL –Role in atherogenesis

37. 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.

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

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

40. 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

41. 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.

42. 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.

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

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

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