1、CVD,Half of all Americans die from cardiovascular disease (CVD) Ischemic (Coronary) Heart Disease Hypertensive Disease Rheumatic Fever / Rheumatic Heart Disease Cerebrovascular Disease (Stroke) Estimated 2001 CVD cost = $300 billion ($180 billion in direct health care costs) 3/4 of all CVD deaths ar
2、e the result of atherosclerosis.,Intima - endothelial cells and the internal elastic laminaMedia - consists of smooth muscle cells and more elastic layersAdventitia - consists of connective tissue, fat cells, nerves and other stuff,Definition,Atherosclerosis: A disease of large and medium-sized arte
3、ries that results in progressive accumulation of smooth muscle cells and lipids within the intima. Typically kills by inducing myocardial infarctionDifferent from arteriosclerosis (hardening of the arteries), which is due to calcification of the arterial wall.,Pathogenesis,Fatty streak Intimal thick
4、ening Plaque Thrombosis or aneurysm,http:/www.iir.suite.dk/,Low Density Lipoproteins in fatty steaks,Hydrophobic core of triglycerides and “cholesterol esters”,apoB protein,Surface monolayer of phospholipids and cholesterol,This and the following seven slides were modified from images at http:/,LDL,
5、LDL,Oxidized LDL Induces leukocyte “homing”,Endothelium,Vessel Lumen,Monocyte,Oxidized LDL,Macrophage,Adhesion Molecules,Cytokines,Intima,LDL,LDL,Endothelium,Vessel Lumen,Monocyte,Macrophage,Adhesion Molecules,Macrophages take up modified LDL,Foam Cell,Oxidized LDL Taken up by Macrophage,Intima,Necr
6、osis frees the modified LDL,Foam cells and macrophages,Etiology,What is the “trigger“ for initiation of the disease? Hemodynamic stress Bacterial infection, particularly periodontal disease High lipid cocentrations,Etiology,Fatty streaks are typically found in teenagers, so the disease begins early.
7、 Occurrence increases with obesity diabetes high lipid/cholesterol diets increasing age high blood pressure Genetic factors are prevalent (like in familial hypercholesterolemia),Familial Hypercholesterolemia,Incidence: 1 in 500 The most common known form of genetic disease Results in 2X to 6X increa
8、se in serum cholesterol Severe and early atherosclerosis and myocardial infarction Diagnosed on the above two items, and a family history Etiology Mutations in the gene coding for LDL receptors,Protein synthesis, expost and import,Ways to get proteins into organelles or membranes,Co-translational im
9、port Put proteins into organelles or membranes during the actual process of translation Examples: extracellular proteins, cell membranes, lysosomal enzymes Post-translational import Make proteins in the cytoplasm, and subsequently import them into the organelle of choice Examples: the nucleus, the m
10、itochondrion Each is directed by “signals” embedded in the amino acid sequence of the newly synthesized protein,Co-translational import of proteins,Stop-transfer or “topogenic” sequences,Sequences of 20 hydrophobic amino acids bind inside the pore Move laterally out of the pore and into the membrane
11、 to build a transmembrane protein. There can be multiple topogenic sequences in a single polypeptide chain,Protein trafficking,In the absence of any signal or targeting sequence, proteins are made and remain in the cytoplasm Co-translational import The default destination is export from the cell or
12、to the cell membrane Targeting sequences can direct them elsewhere Post-translational import Nuclear localization sequences (NLS) target proteins for import into the nucleus after translation. Transit sequences similarly target proteins for import into the mitochondrion,Post-translational import int
13、o the nucleus,Nuclear proteins contain a nuclear localization signal (NLS) These proteins are made by free ribosomes (not ER-bound) Importin binds to the NLS The nuclear pore recognizes and transports importin and the protein,Post-translational modificatications in the RER,Newly synthesized polypept
14、ides in the membrane and lumen of the ER undergo five principal modificationsFormation of disulfide bonds Proper folding Specific proteolytic cleavages Assembly into multimeric proteins Addition and processing of carbohydrates (glycosylation),N- and O-linked oligosaccharides,Oligosaccharides Oligo:
15、few O-linked Sugars linked to hydroxyl oxygen on serine or threonine Tend to be shortN-linked Sugars linked to amide nitrogen on asparagine Tend to be long and highly branched,ABO blood type is determined by two glycosyltransferases,Endocytosis, and membrane cycling,How a vesicle forms: the clathrin
16、-coated pit,Structure of a clathrin-coated vesicle,Clathrin Forms triskelions Consists of three heavy chains and three light chains. Coats also contain adaptor proteins that link membrane receptors to the clathrin coat. Assembly causes the budding of a coated vesicle, completely enclosed by clathrin
17、 This is often called “receptor-mediated endocytosis”,Three types of coated vesicles,Clathrin Cell membrane and Golgi to endosomes Coatomers COP I Retrograde through golgi stack Golgi to Rough ER COP II Rough ER to Golgi,Protein targeting: lysozomal enzymes,Lysosomal hydrolases are tagged with manno
18、se-6-phosphate. The enzyme that does this recognizes a signal patch on the folded hydrolase. Mannose-6 phosphate binds to a M6P receptor that concentrates it into a “coated pit“,Lipoproteins,Consist of Cholesterol esters with fatty acids, or triacylglycerols surrounded by a phospholipid monolayer co
19、ntaining cholesterol and one or more apoprotein “handles”,Intestine: chylomicrons form. These are spheres of cholesterol and triglycerides surrounded by phospholipid and apoproteins, for which various tissues have receptors. The liver forms very low density lipoproteins (VLDL) for transport of trigl
20、ycerides to adipose tissue and muscle Once the triglycerides are taken up, an apoprotein may be lost resulting in low density lipoprotein (LDL) with a single apoprotein b (Apo-B).,LDLs are not taken up quickly, but reside in the blood for extended periods. They normally deliver cholesterol to periph
21、eral tissues.The liver secretes high density lipoproteins (HDL) which are low in cholesterol. These take up cholesterol from peripheral tissues, and return it to the liver.,Q & A,Q: Do you need cholesterol for anything? A: Yes for steroid hormones and membranesQ: Can you make your own cholesterol? A
22、: Yes, you can. Primarily in the liver, in the smooth endoplasmic reticulum.Q: How does your body regulate the amount of cholesterol that is made?,feedback control of cholesterol synthesis,Familial Hypercholesterolemia,Mutations in the LDL receptor may cause Failure to express receptors, or Poor apo
23、protein B binding, and therefore Poor internalization through receptor mediated endocytosis No internalization no feedback to prevent cholesterol synthesis No feedback excess synthesis of cholesterol Excess cholesterol Rapid lipid accumulation But how do they become oxidized?,The where, when, and wh
24、y of reactive oxygen species (ROS),By numerous cells, during many disease processes, as an unfortunate cause or side-effectIn almost all cells, all the time, for cell signalingBy white blood cells, during inflammation, to fight infectionIn mitochondria, all the time, as a normal byproduct,Superoxide
25、 (O2-)and peroxide (O2-2) in respiration,ROS are made deliberately by white cells,A “respiratory burst” generating large quantities of O2- (superoxide) O2- is antibacterial NADPH oxidaseNeutrophils use H2O2 and Cl- to make hypochlorous acid (HOCl). HOCl is deadly to bacteria. Myeloperoxidase is gree
26、n,How you mitigate their effects,O2,O2-,H2O2,2H2O + O2,Enzyme scavengers Glutathione (GSH), an “antioxidant”,Superoxide dismutase SOD,Catalase,2,GSSG + 2H2O,2GSH,GSH Peroxidase,OH no!,The Fenton reactionGenerates a hydroxyl radical through the oxidation of ferrous iron by peroxide The Haber-Weiss re
27、actionGenerates a hydroxyl radical through a reaction of superoxide with peroxide,OH? So what?,A free radical chain reaction can be initiated In this diagram, L represents a fatty acid chain (lipid)How do you stop it?,OH,H2O,LH,L,LOO,LH,LOOH,LO,O2,Fe2+,Antioxidants found in LDL,-tocopherol and -toco
28、pherol Forms of vitamin E highest concentration of antioxidants in LDL depleted first -carotene A carotenoid precursor of vitamin A abundant in brightly colored fruits and vegetables Other carotenoids -carotene Lycopene (red pigment in vegetables) Crptoxanthin / Cantaxanthin Lutein Ubiquinol The onl
29、y fat-soluble antioxidant your cells make,Treatments for FHC,Low fat diet, no smoking, etc Drug treatment Dietary ion-exchange resins to bind bile acids, and helps prevent cholesterol absorption in the intestine Nicotinic acid (niacin, B3), which enhances LDL uptake Estrogen replacement in post-menopausal womenCholesterol synthesis inhibitors Liver transplant The liver contains 70% of the bodys LDL receptors,
