1、CVDHalf 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 are the result
2、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 stuffDefinitionAtherosclerosis:A disease of large and medium-sized arteries that results in prog
3、ressive 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.LDLLDLOxidized LDL Induces leukocyte“homing”EndotheliumVessel LumenM
4、onocyteOxidized LDLMacrophageAdhesionMoleculesCytokinesIntimaLDLLDLEndotheliumVessel LumenMonocyteMacrophageAdhesionMoleculesMacrophages take up modified LDLFoam CellOxidized LDL Taken up by MacrophageIntimaNecrosis freesthe modified LDLFoam cells and macrophagesEtiologyWhat is the trigger for initi
5、ation of the disease?Hemodynamic stress Bacterial infection,particularly periodontal disease High lipid cocentrationsEtiologyFatty streaks are typically found in teenagers,so the disease begins early.Occurrence increases with obesity diabetes high lipid/cholesterol diets increasing age high blood pr
6、essureGenetic factors are prevalent(like in familial hypercholesterolemia)Familial HypercholesterolemiaIncidence:1 in 500The most common known form of genetic diseaseResults in 2X to 6X increase in serum cholesterol Severe and early atherosclerosis and myocardial infarction Diagnosed on the above tw
7、o items,and a family historyEtiology Mutations in the gene coding for LDL receptorsProtein synthesis,expost and importWays to get proteins into organelles or membranesCo-translational import Put proteins into organelles or membranes during the actual process of translation Examples:extracellular pro
8、teins,cell membranes,lysosomal enzymesPost-translational import Make proteins in the cytoplasm,and subsequently import them into the organelle of choice Examples:the nucleus,the mitochondrionEach is directed by“signals”embedded in the amino acid sequence of the newly synthesized proteinCo-translatio
9、nal import of proteinsStop-transfer or“topogenic”sequencesSequences of 20 hydrophobic amino acids bind inside the poreMove laterally out of the pore and into the membrane to build a transmembrane protein.There can be multiple topogenic sequences in a single polypeptide chainProtein traffickingIn the
10、 absence of any signal or targeting sequence,proteins are made and remain in the cytoplasmCo-translational import The default destination is export from the cell or to the cell membrane Targeting sequences can direct them elsewhere Post-translational import Nuclear localization sequences(NLS)target
11、proteins for import into the nucleus after translation.Transit sequences similarly target proteins for import into the mitochondrionPost-translational import into the nucleusNuclear proteins contain a nuclear localization signal(NLS)These proteins are made by free ribosomes(not ER-bound)Importin bin
12、ds to the NLSThe nuclear porerecognizes andtransportsimportinand theproteinPost-translational modificatications in the RERNewly synthesized polypeptides in the membrane and lumen of the ER undergo five principal modificationsFormation of disulfide bondsProper foldingSpecific proteolytic cleavagesAss
13、embly into multimeric proteins1.Addition and processing of carbohydrates(glycosylation)N-and O-linked oligosaccharidesOligosaccharidesOligo:fewO-linked Sugars linked to hydroxyl oxygen on serine or threonine Tend to be short N-linked Sugars linked to amide nitrogen on asparagine Tend to be long and
14、highly branchedABO blood type is determined by two glycosyltransferasesEndocytosis,and membrane cyclingHow a vesicle forms:the clathrin-coated pitStructure of a clathrin-coated vesicleClathrin Forms triskelions Consists of three heavy chains and three light chains.Coats also contain adaptor proteins
15、 that link membrane receptors to the clathrin coat.Assembly causes the budding of a coated vesicle,completely enclosed by clathrinThis is often called“receptor-mediated endocytosis”Three types of coated vesiclesClathrin Cell membrane and Golgi to endosomesCoatomers COP I Retrograde through golgi sta
16、ck Golgi to Rough ER COP II Rough ER to GolgiProtein targeting:lysozomal enzymesLysosomal hydrolases are tagged with mannose-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 pitLipop
17、roteinsConsist ofCholesterol esters with fatty acids,or triacylglycerolssurrounded by a phospholipid monolayercontaining cholesteroland one or moreapoprotein“handles”Intestine:chylomicrons form.These are spheres of cholesterol and triglycerides surrounded by phospholipid and apoproteins,for which va
18、rious tissues have receptors.The liver forms very low density lipoproteins(VLDL)for transport of triglycerides to adipose tissue and muscleOnce 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 qu
19、ickly,but reside in the blood for extended periods.They normally deliver cholesterol to peripheral 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&AQ:Do you need cholesterol for anyth
20、ing?A:Yes for steroid hormones and membranesQ:Can you make your own cholesterol?A: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 synthesisFamilial HypercholesterolemiaMutation
21、s in the LDL receptor may causeFailure to express receptors,orPoor apoprotein B binding,and thereforePoor internalization through receptor mediated endocytosisNo internalization no feedback to prevent cholesterol synthesisNo feedback excess synthesis of cholesterolExcess cholesterol Rapid lipid accu
22、mulationBut how do they become oxidized?The where,when,and why 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 mitocho
23、ndria,all the time,as a normal byproductSuperoxide(O2-)and peroxide(O2-2)in respirationROS are made deliberately by white cellsA“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
24、 to bacteria.Myeloperoxidase is greenHow you mitigate their effectsO2O2-H2O22H2O+O2Enzyme scavengersGlutathione(GSH),an“antioxidant”SuperoxidedismutaseSODCatalase2GSSG+2H2O2GSHGSH PeroxidaseOH no!The Fenton reaction Generates a hydroxyl radical through the oxidation of ferrous iron by peroxideThe Ha
25、ber-Weiss reaction Generates a hydroxyl radical through a reaction of superoxide with peroxideFe2+H2O2OHOH Fe3+H2O2OHOH O O O2+OH?So what?A free radical chain reaction can be initiatedIn this diagram,L represents a fatty acid chain(lipid)How do you stop it?OHH2OLHLLOOLHLOOHLOO2Fe2+Antioxidants found
26、 in LDL-tocopherol and-tocopherol 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 vegetablesOther carotenoids-carotene Lycopene(red pigment in vegetables)Crptoxanthin/Cantaxanthin Lute
27、inUbiquinol The only fat-soluble antioxidant your cells makeTreatments for FHCLow fat diet,no smoking,etcDrug 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 women Cholesterol synthesis inhibitorsLiver transplantThe liver contains 70%of the bodys LDL receptors
