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.
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
Atherosclerosis
UniversalProgressiveDeleterious
Irreversible (?)
Progressiveness of Atherosclerosis• Onset at young age
• Progression through adulthood
• Culmination in old age with overt disease manifestation
• Consequences leading to severe disability & death
Fig. 16-3: Natural history of atherosclerosis. Pathogenesis of human atherosclerotic lesions and their clinical manifestations.
Table 16-8: Theories of Atherosclerosis
• Lipid accumulation• Myoclonal
• Thrombogenic• Inflammation• Free Radicals
**See page 299**
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.
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.
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.
Table 16-5: General Characteristics of Atherosclerotic Lesions
Early onset -- progressiveFocal lesionsEarly lesionsAdvance lesions
Damage, Repair, RegressionProgression of localized lesions influenced by:
Local factors: vessel structure and metabolism, blood turbulenceSystemic factors: diabetes, hypertension, stress, genetic predisposition
Table 16-4: Localized Factors Contributing to Atherosclerosis
Marginal vascularization of arterial wallRelative ischemiaLimited metabolic exchangeBlood turbulence and mechanical stress
• 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
Significance of Age Changes in the Vascular Endothelium*Table 16-2, page 293*Endothelial cells undergo significant changes indicative of abnormal functionThe imbalance of vascular tone is manifested by increased vasoconstriction
Endothelins EDRF, NOVascular integrity (cell proliferation and migration, wall remodeling) and injury repair through local growth factors are impaired
VEGF CytokinesMaintenance of blood fluidity is disrupted with increased cell adherence, blood coagulation, and thrombogenic properties
CytokinesThese alterations by themselves may induce pathology or may predispose with other factors to atherosclerosis
Regulation of coronary blood flow:
Vasodilation O2 CO2
Vagal Stimulation
VasoconstrictionAngiotension IISympathetic stimulation
Table 16-10 Symptoms of Angina Pectoris andAcute Myocardial Infarction in the Elderly
Angina Pectoris
Pain, less marked than in adult;may present as headache or epigastric distress
Myocardial Infarction
Variable presentation with chest pain,including breathlessness, confusion, fainting,
GI symptoms, sweating, hypotension, etc.
Table 16-11 Major Risk Factors inCoronary Heart Disease
AgeGenetic predispostion
HypertensionDiabetes mellitus
HypercholesterolemiaCigarette smoking
Also:Obesity
Poor physical fitness and lack of exercisePersonality type (?)
High homocysteinemia, Protein C
Table 16-12 Major Types ofCoronary Heart Disease Treatment
Medical treatmentDietExerciseNo smokingPharmacologic agents
Surgical treatmentAortocoronary bypass graft
Percutaneous coronary angioplasty withstreptokinase/ tissue plasminogen activator (TPA)anticoagulant therapy
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
Lipids and Apolipoproteins
• Major Categories
• Risk Factors in Atherosclerosis
• Lipoprotein Synthesis
• Apolipoproteins
• Lipolytic Enzymes
• Receptors
Lipids and Apolipoproteins
• Categories– Chylomicrons and VLDL
• High triglycerides
– IDL and LDL• High cholesterol
– HDL• High proteins• High phospholipid
Role of Lipids (Lipoproteins) in Metabolism
Triglycerides Major energy source for cells
Cholesterol Cell growth, cell division, membranerepair, steroid hormone production
Lipids Transport of fat soluble vitamins
Positive and Negative risk Factors in Atherosclerosis
Positive Negative
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
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
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
Lipoprotein Synthesis
• Intestine– CM– Nascent HDL
• Liver– VLDL– IDL– LDL– Nascent HDL
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
Major Apolipoproteins and Their Function
Apo Lipo Origin Function
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 acyltransferaseABCA1: ATP binding cassette protein A1LRP: LDL receptor related protein
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
Structure of Lp(a)
LDL
NC
S S
C
apo(a)
apoB-100
4
4
4
4
5
Kringle
N
Receptors
• LDL– Responsible for internalization of LDL– Also known as apoB-E receptor– Regulates cholesterol synthesis
LDL-Receptors
Endosome Lysosome
Aminoacids
CholesterolLDL
Cholesteryl ester(storage)LDL
Receptors
HMG-CoAreductase
LDL
LDL Receptor (apoB-E receptor)
ACAT
Regulates cholesterol synthesis and plasma cholesterol levels
Receptors
• Macrophage Scavenger (SR-A1)– Recognizes oxidized LDL– Role in atherogenesis
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.
Modification of LDL
LDL
Apo B-100
Derivatization:AldehydesGlucosylationeg. diabetes
Oxidation:Degradation of B-100 by reactiveoxygen species
Derivatized LDL
Oxidized LDL
The Scavenger Receptor:Clearance of modified LDL by macrophages
Oxidized LDLScavengerreceptor
Macrophage Macrophage Foam Cell
Fatty streaks
Lipid droplets
(SR-A1)
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
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.
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.
Reverse Cholesterol TransportDelivery of peripheral tissue cholesterol to the liver for catabolism
Requires HDL, apoA-I and LCAT
Peripheral Cell UC HDL
HDLCE
HDLUC
ABCA1
LiverVLDLor LDL apoB LDLr
SR-B1
UC
PL
CE
TG
diffusion
LCAT
LCAT
CE
CE
apoA-I
UC = unesterified cholesterolCE = esterified cholesterolPL = phospholipidLDLr = LDL receptor
NascentHDL
Bile to gut
Macrophage/ Foam cell
LDL and AtherosclerosisFitting the pieces together
Elevated LDL: Increased residence time in plasma Increased modification/oxidation of LDL
Artery wall
Monocyte
Endothelialcells
oxLDL
oxLDL (stimulates cytokine secretion)
Macrophage
Macrophage foam cell
Cytokines
Cytokines
Smooth muscle cellproliferation
HDL Protective RoleFitting the pieces together
oxLDL = oxidized LDLUC = unesterified cholesterol
ABCA1apoA-I
Endothelialcells
HDL
HDL
UC
PL
UC
Nascent HDL
HDL + UC
Macrophage foam cell
oxLDL
Monocyte
Arterywall