高血压英文ppt精品课件cardiovascular disease （cvd）

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 are the result of atherosclerosis.,Intima - endothelial cells and the internal elastic lamina Media - consists of smooth muscle cells and more elastic layers Adventitia - consists of connective tissue, fat cells, nerves and other stuff,Definition,Atherosclerosis: A disease of large and medium-sized arteries that results in progressive accumulation of smooth muscle cells and lipids within the intima. Typically kills by inducing myocardial infarction Different from arteriosclerosis (hardening of the arteries), which is due to calcification of the arterial wall.,Pathogenesis,Fatty streak Intimal thickening 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 ,LDL,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,Necrosis 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. 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 increase 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 import 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 mitochondrion 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 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 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 into 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 polypeptides in the membrane and lumen of the ER undergo five principal modifications Formation 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: few O-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 highly branched,ABO blood type is determined by two glycosyltransferases,Endocytosis, and membrane cycling,How a vesicle forms: the clathrin-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 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 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 pit“,Lipoproteins,Consist of Cholesterol esters with fatty acids, or triacylglycerols surrounded by a phospholipid monolayer containing 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 triglycerides 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 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 & A,Q: Do you need cholesterol for anything? A: Yes for steroid hormones and membranes Q: 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 synthesis,Familial Hypercholesterolemia,Mutations in the LDL receptor may cause Failure to express receptors, or Poor apoprotein 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 why of reactive oxygen species (ROS),By numerous cells, during many disease processes, as an unfortunate cause or side-effect In almost all cells, all the time, for cell signaling By white blood cells, during inflammation, to fight infection In mitochondria, all the time, as a normal byproduct,Superoxide (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 oxidase Neutrophils use H2O2 and Cl- to make hypochlorous acid (HOCl). HOCl is deadly to bacteria. Myeloperoxidase is green,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 reaction Generates a hydroxyl radical through the oxidation of ferrous iron by peroxide The Haber-Weiss reaction Generates a hydroxyl radical through a reaction of superoxide with peroxide,OH? So what?,A free radical chain reaction can b