Discussion March 12th, 2007Ryan KlimczakLectures 19-21

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Functions of the CV system• Transports O2 & nutrients to the tissues

& returns C02 to the lungs and other products of metabolism to the kidney

• Regulates body temperature

• Distributes hormones and other agents that regulate cell function

Components:

Heart

Pump that circulates the blood throughout the body

Vascular System

Transports blood to the body tissues

Central Nervous System (CNS)

Particularly the centers in the medulla that regulate the function of the heart and blood vessels

Key words:

Arteriosclerosis: a chronic disease characterized by abnormal thickening and hardening of the arterial walls with a resultant loss of elasticity

Atherosclerosis: A form of arteriosclerosis characterized by the deposition of atheromatous plaques containing cholesterol and lipids on the innermost layer of the walls of large and medium-sized arteries.

Atherosclerosis can cause:Gangrene-a death of body tissue that usually occurs when there has

been an interruption of blood supply, followed by bacterial invasionAneurysm-Weakness or injury to the wall of a blood vessel causing

dilatation or ballooning and, in severe cases, threatening the integrity of the circulatory system resulting in hemorrhage or stroke. A weakened point of an artery, vein or the heart.

Stroke-Also called a "brain attack" and happens when brain cells die because of inadequate blood flow. 20% of cases are a hemorrhage in the brain caused by a rupture or leakage from a blood vessel. 80% of cases are also know as a "schemic stroke", or the formation of a blood clot in a vessel supplying blood to the brain

Myocardial infarction-destruction of heart tissue resulting from obstruction of the blood supply to the heart muscle

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Gangrene of the fingers and toes

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Aneurysm - notice ballooning of the blood vessel

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Stroke

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Theories of Atherosclerosis:

-Lipid accumulation

-Myoclonal (muscle contraction irregularities)

-Thrombogenic (blood clots)

-Inflammation

-ROS/Free Radicals

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 (?)

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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

Key terms:

Triglycerides - The storage form of fat consisting of three fatty acids and glycerol

Cholesterol - Cholesterol is a sterol (a combination steroid and alcohol) and a lipid found in the cell membranes of all body tissues, and transported in the blood plasma of all animals

Lipids - Lipids are a class of hydrocarbon-containing organic compounds

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Chylomicron - large lipoprotein particles (having a diameter of 75 to 1,200nm) that are created by the absorptive cells of the small intestine. Chylomicrons transport exogenous lipids to liver, adipose, cardiac and skeletal tissue where they are broken down by lipoprotein lipase.

Low density lipoprotein - a class of lipoprotein particles that varies in size (18-25 nm in diameter) and contents (while carrying fatty acid molecules in blood and around the body). The LDL contains the apolipoproteins B-100 and Apo E.It is commonly referred to as bad cholesterol as high LDL levels can lead to cardiovascular disease.

High density lipoprotein-class of lipoproteins, varying somewhat in their size (8-11 nm in diameter), that carry cholesterol from the body's tissues to the liver.]It is hypothesised that HDL can remove cholesterol from atheroma within arteries, and transport it back to the liver for excretion or re-utilization; the main reason why HDL-bound cholesterol is sometimes called "good cholesterol", or HDL-C. A high level of HDL-C seems to protect against cardiovascular diseases, and low HDL

cholesterol levels [less than 40 mg/dL] increase the risk for heart disease. Apolipoprotein-ipid-binding proteins which are the constituents of the plasma

lipoproteins. The amphipathic (detergent-like) properties of apolipoproteins solubilize the hydrophobic lipid constituents of lipoproteins, but apolipoproteins also serve as enzyme co-factors, receptor ligands, and lipid transfer carriers that regulate the intravascular metabolism of lipoproteins and their ultimate tissue uptake.

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Key components involved:Lipoprotein lipase (LPL) -enzyme which hydrolyzes lipids in lipoproteins, like those found in chylomicrons and very low density lipoproteins (VLDL), into three fatty acids and one glycerol molecule.

Lecithin cholesterol acyltransferase (LCAT)- enzyme which converts free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol) which is then sequestered into the core of a lipoprotein particle

eventually making the newly synthesized HDL spherical. LDL receptor-mosaic protein that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognises the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles.

ABCA1 transporter- 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.

Scavenger receptor A1 (SR-A1) - The scavenger receptor recognizes modified and/or oxidized LDL and internalizes the modified LDL.

Key pharmacological therapies:

Statins (atorvastatin, etc.) - target the liver, inhibits cholesterol biosynthesis, increases LDL receptors

Bile Acid Sequestrants (colestipol, etc.)-bind and remove bile in intestine, increases cholesterol conversion to bile, increases LDL clearance, lowers plasma cholesterolTriglyceride Reducers (gemfibrozil, etc.)- Reduces synthesis of VLDL in liver, increases catabolism of VLDL, lowers plasma TG, increases HDL

Cholesterol Absorption Inhibitor (ezetimibe)- Blocks uptake of dietary cholesterol in small intestine, inhibits ABC transporter receptors on surface of intestinal absorptive cells, lowers plasma cholesterol

Lipoprotein Lipase (LPL)

LPL

Excess SurfaceMaterial

HDL assembly

Fatty Acidsand

Glycerol

Energy

apoC-II

CM

VLDLapoE

apoA-Icholesterol

phospholipid

Endothelial Cell

CM

VLDLapoE

Liver

Lipolyticproducts

Bile acids

muscle

“Remnant”

TG

TG = triglyceride

LDL

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

Chol

Bile acids

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