1. Discussion March 12th, 2007 Ryan Klimczak Lectures 19-21

2. Functions of the CV system Transports O 2 & nutrients to the tissues & returns C0 2 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

3. 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.

4. Atherosclerosis can cause: Gangrene-a death of body tissue that usually occurs when there has been an interruption of blood supply, followed by bacterial invasion Aneurysm-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

5. Gangrene of the fingers and toes

6. Aneurysm - notice ballooning of the blood vessel Stroke

10. Theories of Atherosclerosis: -Lipid accumulation -Myoclonal (muscle contraction irregularities) -Thrombogenic (blood clots) -Inflammation -ROS/Free Radicals

13. 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 animalssterolsteroidalcohollipidcell membranesbodybloodanimals Lipids - Lipids are a class of hydrocarbon-containing organic compoundshydrocarbonorganic compounds

14. 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.lipoprotein particlesnmsmall intestinelipidsadiposelipoprotein 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.lipoproteinbloodapolipoproteins 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.lipoproteinsnmcholesterolliver]atheromalivercardiovascular diseases 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.amphipathichydrophobic

16. 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.enzymehydrolyzeslipidslipoproteinschylomicronsvery low density lipoproteinsfatty acidsglycerol 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.enzyme cholesterollipoproteinHDL 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.endocytosisLDLapoprotein 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.

17. 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 cholesterol Triglyceride 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

18. Lipoprotein Lipase (LPL) LPL Excess Surface Material HDL assembly Fatty Acids and Glycerol Energy apoC-II CM VLDL apoE apoA-I cholesterol phospholipid Endothelial Cell CM VLDL apoE Liver Lipolytic products Bile acids muscle “Remnant” TG TG = triglyceride LDL

19. 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 Chol Bile acids

20. 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