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

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