Term
| What are the 5 leading causes of death in the US? |
|
Definition
1. heart disease
2. cancer
3. stroke
4. chronic lower resp. disease
5. accidents |
|
|
Term
| What is the relationship between atherosclerosis and the leading causes of death in the U.S. and the world? |
|
Definition
| atherosclerosis is responsible for the majority of deaths from cardiovascular disease which includes heart disease and stroke |
|
|
Term
| What is Artherosclerosis? |
|
Definition
| Artherosclerotic plaques are mushy deposits of cholesterol esters and hard deposits of calcium phosphate mineral |
|
|
Term
| How do atherosclerotic plaques kill? |
|
Definition
| site of fibrin clot formation -> block coronary or cerebral arteries |
|
|
Term
| What changes have occurred in the U.S. death rate over the 1999-2006 period for which CDC data are avaliable? |
|
Definition
| decline explained by 25% decline in death by cardiovascular disease (no other cause of death has declined) |
|
|
Term
| Why has motality due to cardiovascular diease in the US declined? |
|
Definition
1. Statins
2. reduced smoking
3. baby aspirin
4. longer life expectancy |
|
|
Term
|
Definition
| loss of bone density that can cause fractures |
|
|
Term
| what is the relationship between osteoporosis and cardiovascular mortality? |
|
Definition
| people with increased bone loss are more likely to die, and there is an increased cvd in people with rapid decrease in bone mineral density |
|
|
Term
| what are the major glycerophospholipids in the mammalian plasma membrane? |
|
Definition
| phosphatidyl(choline/ethanolamine/serine) *serine is the only one with a net - charge and in inner leaflet |
|
|
Term
| What is membrane fluidity, and how is it maintained in bacteria, plants, and animals? |
|
Definition
hydrophic tails of the 2FA of glycerophospholipid can be liq or crystal.
liq allows phospholipids and proteins to diffuse
crystal does not
Bacteria and plants: FA with C=C (veg oil)
Animals: little or no C=C (like lard) and prevent crystal state by incorporating cholesterol (ring hydrophobic prevent crystalization of sat FA) |
|
|
Term
| What human tissues synth cholesterol? |
|
Definition
| Most, but only liver synth excess of its own needs |
|
|
Term
| What is the commited step of metabolic pathways (cholesterol biosynth)? |
|
Definition
the step that converts a substrate (many uses) into product (one use)
HMG-CoA reductase converts substrate HMG-CoA (can also make ketones) -> product mevalonate (only used to make cholesterol) |
|
|
Term
| How is the synth of cholesterol regulated? |
|
Definition
| at the committed step: HMG-CoA reductase cellular levels |
|
|
Term
| What is the fxn of lipoproteins? |
|
Definition
| water-sol delivery of hydophobic-insol cholesterol and TAG (triacylglycerol) |
|
|
Term
| What is the structure of lipoproteins? |
|
Definition
spherical protein and lipid found in blood
hydrophobic interior: cholesterol esters and TAGs (triacyglycerols)
outer: phospholipids and free cholesterol with a polar region facing out and hydrophobic in
proteins on surface play role in met |
|
|
Term
| How is the density of a lipoprotein related to diameter? |
|
Definition
inc. D -> dec. p
because the larger diameter inc. mass of interior and the highest density is in the thick phospholipid |
|
|
Term
| Outline the role of lipoproteins in the transport of triacylglycerol (TAGs) and cholesterol in humans |
|
Definition
|
|
Term
| How does LDL differ from VLDL? |
|
Definition
liver secretes VLDL ->
TAGs are hyrolyzed by lipoprotein lipase and removed so
LDL has smaller diameter and higher density |
|
|
Term
| What is the fate of dietary cholesterol? |
|
Definition
| all dietary cholesteral appears first in liver |
|
|
Term
| Why is it difficult to reduce serum cholesterol by eating a low cholesterol diet? |
|
Definition
| liver synth more cholesterol when dietary levels are low |
|
|
Term
| What is the impact of lipoproteins on the amount of cholesterol in blood? |
|
Definition
| cholesterol in plasma is cholesterol and cholesteryl esters in plasma lipoproteins |
|
|
Term
| What is the metabolic fate of cholesterol in humans? |
|
Definition
| not met for energy -> excess is secreted |
|
|
Term
| How do statins lower serum cholesterol? |
|
Definition
| competitive inhibitors of HMG-CoA reductase (binds more tightly than HMG-CoA) -> reduces amount of cholesterol made in liver |
|
|
Term
| How could statins have side effects? |
|
Definition
| inhibition of HMG-CoA reductase in all tissues (not just liver) |
|
|
Term
| What is the major met fate of LDL? |
|
Definition
| extrahepatic cell endocytosis -> liberates cholesterol for use |
|
|
Term
| What is familial hypercholesterolemia? |
|
Definition
| recessive defect in LDL receptor -> failure to remove LDL from plasmid by endocytosis |
|
|
Term
| What is the effect of familial hypercholesterolemia on atherosclerosis? |
|
Definition
rapid formation of atheromas (atheromatous plaques) in vascular system
homozygous: heart attack by age 5
hetero: age 30
|
|
|
Term
| What is the role of a fibrin clot in cardiovascular mortality? |
|
Definition
| Fibrin clots cause heart attacks and stokes by blocking arteries. |
|
|
Term
| Define the term hemostasis |
|
Definition
complex process that stops bleeding (opp of hemorrhage)
3 steps:
1. vasoconstriction
2. platelet plug
3. blood coagulation (clot) |
|
|
Term
| Describe the important properties of platelets |
|
Definition
small blood cells req for coagulation
5-9 day lifetime in circulation
10^11 made each day
no DNA -> cant divide or synth protein |
|
|
Term
| What is the 1st event in sealing a leak in the vascular system? |
|
Definition
| platelet activiation due to contact with molecules that are usually shielded (ex collagen) -> Platelets aggregate -> plug for 6hrs -> help direct formaction of clot by secretion of growth factos -> repair hole |
|
|
Term
| diagram blood coagulation cascade. label contact activiation (intrinsic), tissue factor (extrinsic), and final common pathways |
|
Definition
|
|
Term
| How does thrombin cause fibrinogen to form a clot? |
|
Definition
| thrombin protease converts fibrinogen into fibrin -> aggregate to form insol fibers -> allign in a dense network -> clot |
|
|
Term
| What is factor XIIIa and how does it stabilize the fibrin clot? |
|
Definition
| XIIIa is a transglutaminase forms peptide bond linkage of lysine to fibrin and glutamine to another (same fiber or different) be able to show chem stucture of cross link |
|
|
Term
| What factors in the blood coagulation cascade have the calcium-binding amino acid Gla? |
|
Definition
| IX, VII, X, and prothrombin |
|
|
Term
| What vitamin is the cofactor for the enzyme that catalyzes the post-translational modification glutamic acid residues to form acid? |
|
Definition
| Vit K cofactor for modifcation of proteins that contain gamma-carboxyglutamic acid |
|
|
Term
| What is the role of calcium in the blood coagulation cascade? |
|
Definition
to coordinated the vitK-dependent coagulation factors to the activated platelet.
Be able to draw how Ca++ can link coagulation factors to the negatively charged plasma membrane of the activated platelet |
|
|
Term
| WHy is the blood coagulation called a cascade? |
|
Definition
cascade of proteolytic activations that cleaves a bond in the next protein activating the enzyme
wach of the steps is signal amplification, and very fast |
|
|
Term
| What activates the contact activation pathway? |
|
Definition
| proteins in the contact pathway recognise molecules that are only exposed with a leak , bind to it, and activate XII |
|
|
Term
| What activates the tissue factor pathway? |
|
Definition
Tissue factor (only member of system extrinsic o blood) is normally separated from blood (outer surface of subendothelial).
Tissue factor binds to VIIa inc. its rate of activiating X |
|
|
Term
| How does vitK deficiency affect blood coagulation? |
|
Definition
| req for the final common pathway of blood coagulation (Dam exp removing cholesterol from chicks) |
|
|
Term
| How does warfarin affect blood coagulation? |
|
Definition
| it is a vit K anatagonist so it inhibits blod clotting. very low doses reduce affinity to vit K to reduce freq of heart attacks |
|
|
Term
| What are the major causes of hemophilia? |
|
Definition
| sex-linked genetic defect in the gene for VIII or factor IX. |
|
|
Term
| WHy are the symptoms of hemophilia so much less severe than the symptoms of vitamin K-deficiency or warfarin poisoning? |
|
Definition
| VIII or IX only affects contact activation pathway, not the tissue factor pathway. vit K is req for the final common pathway |
|
|
Term
| WHat is the relationship bw the proteases involved in blood coagulation and in protein digestion in the SI? |
|
Definition
all have the same mechanism of zymogen activation and cataysis. all are serine proteases secreted as zymogens and activated by a single peptide bond.
the sequences show that the genes arose from a common ancestor that occured at vertebrate evolution |
|
|
Term
| What is the fxn of coagulation factors VIII and V? |
|
Definition
| function to form a prothrombinase/Xase complex to regenerate thrombin and Xa |
|
|
Term
| why is gamma-carboxyglutamic acid-containing region of factors IX, X, and VII retained in activation, but not for prothrombin and thrombin? |
|
Definition
| thrombin needs to be released from the platelet to efficiently clease fibrinogen and form the clot, so thrombin has no Gla (which would bind it to platelet like factors) |
|
|
Term
| How is the blood prepared for infusion into patients? |
|
Definition
| citrate is added to chelate Ca and prevent clotting. at infusion, citrate is removed by cells and clotting ability is restored |
|
|
Term
| How does the blood coagulation cascade illustrate the different roles that proteolytic cleavages can play in extracellular processes? |
|
Definition
| enzyme activation, binding protein activation, initiation of polymerization |
|
|
Term
| How is thrombin inactivated? |
|
Definition
| formation of a complex with anti thrombin III. antireversible and eventually cleared and destroyed |
|
|
Term
| What is heparin? What is its role in blood coagulation? |
|
Definition
Heparin is a polysaccharide with a high degree of sulfation and a very high - charge (GAG)
Antithrombin III binds to heparin and heparin sulfate -> increase binding of antithrombin (inhibiting thrombin)
heparin is secreted by mast cells in response to thrombin activity |
|
|
Term
| Describe how a clot is removed |
|
Definition
hydrolysis of peptide bonds in clot fibrin by plasmin protease resulting in peptides soluble in blood and removed by kidney filtration.
plasminogen is cleaved to plasmin at clot site by TPA.
TPA is secreted by endothelial cells after the leak has been repaired. (clot removal is the final step |
|
|
Term
| What is the evidence that a single clot is the cause of death by a heart attack or most strokes? |
|
Definition
| clot (thromus) found in blocked artery. in cases that death occurs the day after there are signs of gross necrosis downstream |
|
|
Term
| what causes the formation of the clot that causes death |
|
Definition
| rupture of a single atherosclerotic plaque. initiation of clotting is triggered by exposure at rupture and blood coagulation cascade |
|
|
Term
| can injection of tissue plasminogen factor (TPA) prevent death? |
|
Definition
| if injected soon after heart attack or stroke can remove clot and restore blood flow before downstream tissue becomes necrotic |
|
|
Term
| how can inhibitors of platelet activation reduce the odds that a life-terminating clot forms at the site of atherosclerotic plaque rupture? |
|
Definition
| inhibition of the platelet activation cascade. |
|
|
Term
| how does aspirin reduce the odds that a clot forms at the site of plaque rupture? |
|
Definition
aspirin partially inhibits the platelet acivation cascade (inhibits aggregation)
aspirin inhibits COX, thromboxin is the signaling molecule for the aggregation |
|
|
Term
| how does plavix reduce the odds that a clot forms at the site of plaque rupture |
|
Definition
plavix partially inhibits the platelet activation cascade to reduce the aggregation at the rupture.
specifically, plavix inactivates ADP which is the signaling molecule of active platelets to signal others |
|
|
Term
| is daily low dose aspirin effective in reducing cardiovascular mortality? |
|
Definition
| studies show that 81mg dose reduces cardiovascular mortality by 25% |
|
|
Term
| does coronary artery bypass surgery or stent implantation decrease mortality from heart attacks? |
|
Definition
| no, but it provides relief from symptoms from the reduced supply of oxygen to heart muscle |
|
|
Term
| why study bone to understand atherosclerosis? |
|
Definition
1. carbon apatite is the mineral phase of both
2. post-menopausal women with bone loss inc. mortality from cardiovascular disease
3. postmenopausal have inc mineral in arteries
4. artery calcification is the best preditor of heart disease mortality and heart attack |
|
|
Term
|
Definition
|
|
Term
| How does the structure of bone affect its mechanical properties? |
|
Definition
*collagen: tensile strength, no risistance to compression
*mineral: resist compression, no tensile stregth |
|
|
Term
| Briefly describe the effect of removing mineral or protein on the appearance and mechanical properties of bone |
|
Definition
| bone does not change shape (both form independent continuum structure) |
|
|
Term
| what two kinds of calcium phosphate mineral are normally found in a vertebrate? whaere are they each found, and what are their properties? |
|
Definition
*hydroxyapatite: tooth enamel, large needle-shaped crystals
*carbonate apatite: bone, tooth dentine, and atherosclerotic plaqyes; crystals are small and plate-like |
|
|
Term
| what is the effect of pH on the solubility of hydroxyapatite and carbonate apatite? |
|
Definition
high sol in acid, low in base
(osteoclasts and stomach secrete acid; arterial blood is more alkaline than venous) |
|
|
Term
| is plasma supersaturated with respect to carbonate apatite? |
|
Definition
| yes, so introduction of crystal means it will grow which explains why people become more calcified with age |
|
|
Term
| do crystals form spontaneously in solution with the same temp, pH, Ca, P as human plasma? |
|
Definition
No, you would need to increase these conc.
probably catalysts (nucleators) in plasma that lower activation barrier for crystal formation |
|
|
Term
| since apatite crystals can readyily grow at plasma Ca and P levels, what keeps humans from slowly turning into a "pillar of salt"? |
|
Definition
| mechanisms inhibit growth of ectopic mineral crystals in soft tissues (many tissues do not calcify) |
|
|
Term
| what is type 1 collagen and where is it found? |
|
Definition
| most abundant protein, extracellular matrix of bone, tendon, artery adventitia, sclera, artery intima, most soft tissues |
|
|
Term
| what is a collagen molecule? |
|
Definition
subunits of collagen fibers
3 polypeptide chains
-2 alpha1, 1 alpha2 chains
-each chain has 1000aa with gly every 3rd (gly-pro-Y)n
triple helix |
|
|
Term
| how do collagen molecules aggregate to form a collagen fibril? |
|
Definition
| cells that make collagen fbers secrete inactive procollagen molecules with N- and C- terminal polypeptide segments that inhibit fiber formation. proteases remove sequences and fibers spontaneously form |
|
|
Term
| where is the water within the collagen fibril? |
|
Definition
| bw each collagen molecule (70% of fibril), increases diameter not length |
|
|
Term
| where is the mineral depositied during the mineralization of bone? |
|
Definition
| water is replaced by the mineral (doesnt change length or diameter) and crystals grow until meet other crystals |
|
|
Term
| how is collagen mineralized during bone formation? |
|
Definition
1. nucleator makes apatite crystals in solution (can diffuse in)
2. calification inhibitos prevent growth outside fibril (cant diffuse in) |
|
|
Term
| what is the normal level of calcium in serum? |
|
Definition
60% of calcium is bound to serum proteins
ionic/free calcium (biologically active) |
|
|
Term
| what is serum calcium homeostasis, and why is it important? |
|
Definition
mechanisms to maintain ionic calcium levels to 1.2mM
1. 2nd messenger signaling pathways (channels)
2. normal bone mineralization
3. soft tissue calcification |
|
|
Term
| how is serum calcium regulated? |
|
Definition
calitonin inc osteoblasts (form bone)
PTH inc osteoclasts (remove Ca from bone) |
|
|
Term
| what is the evidence that bone has a strength sensor? |
|
Definition
bone loss with weightlessness/bed rest
inc bone strengh with resis training |
|
|
Term
| why is a strength sensor needed? |
|
Definition
| to make sure the bone weakening for maintaining calcium levels happens evenly (prevent breakage) |
|
|
Term
| what are the major types of bone in the human skeleton? |
|
Definition
cortical: (compact) in middle of long bones
trabecular: (spongy) lattice of trabeculae at ends of long bones |
|
|
Term
| how is trabecular bone turned over? |
|
Definition
| BMU (trabecular bone multicellular unit) moves along surface of a trabeculae |
|
|
Term
| How is a trabecular BMU created? |
|
Definition
| bone lining cell resparated bone lining and marrow. lining cells lift from surface creating liq space, and vascular connections are formed and brings osteoclast/blast precursors |
|
|
Term
| what is the fate of a single trabecular BMU? |
|
Definition
| osteoclasts die, osteoblasts continue until cavity is refilled and then die |
|
|
Term
| How is cortical bone turned over? |
|
Definition
cortical BMU (bone multicellular unit) deep within
osteoclasts create "cutting cone"
osteoblasts create "closing cone"
BMU removes and repaces cylinder of cortical bone (unit of bone created=osteon) |
|
|
Term
|
Definition
1. remove microfractures
2. tap calcium locked in bone |
|
|
Term
| which of the two bone types is turned over more rapidly? |
|
Definition
trabecular 25%
cortical 2% |
|
|
Term
| what is the definition of osteoporosis? |
|
Definition
| bone mineral density that is 2.5 stdev below peak for a person of same size/gender (usually asymptomatic) |
|
|
Term
|
Definition
| defect in BMU osteoblasts do not fully replace bone. defect is not known |
|
|
Term
| what bones are most affected by osteoporosis? |
|
Definition
| trabecular bone diameter and number of connections |
|
|
Term
| what are the most common types of fractures seen in patients with osteoporosis? |
|
Definition
a. vertebral fractures (crush): shorten
b. hip:
c. wrist |
|
|
Term
| how is osteoporosis treated? what is the rationale for each treatment? |
|
Definition
a. calcium and vitD supp to reduce the need to remove Ca from bone
vit D promotes adsorption of Ca (some side effects of vitD)
b. bisphosphonate: inhibits osteoclast, does not promote osteoblast and reduces bone turnover
c. estrogen: bone loss accelerates with menopause
d. exercise
e. drug increases osteoblast in BMU (goal solves defect) |
|
|
Term
| diagram the anatomy of the artery wall |
|
Definition
|
|
Term
| what is the structure and fxn of the intima? |
|
Definition
thin monolayer of vascular endothelial cells with tight junctions in contact with blood
prevents diffusion of blood inter artery wall |
|
|
Term
| what is the structure and fxn of the media? |
|
Definition
alternating layers of elastin (in sheets called lanellae) and vascular smooth muscle cells (VSMCs)
alasticity of artery helps propogate the force of heart beat |
|
|
Term
| what is the stucture and fxn of adventitia? |
|
Definition
dense sheet of type1 collagen
limits stretch |
|
|
Term
| what kinds of artery calcification are found in patients? |
|
Definition
a. medial artery calcification: calcification foci within elastic lamellae and moves to kill vascular cell muscles bw (urema and diabetes)
b. intimal artery calcification: crystals associated with lipid deposits, artherosclerotic plaque developes |
|
|
Term
| four stages in the history of the plaque that kills (and draw) |
|
Definition
1. fatty streak: in intima and macrophages, foam cells, foci
2. mature plaque with a dense cap of fibrous tissue: intima thicker with hard mineral plate, large cholesterol ester deposit, protease removing fibrous cap
3. a mature plaqu with a increasingly thinner fibrous cap: little collagen remaining
4. rupture: platelets activates, fibrin clot |
|
|
Term
| what is the concentration of LDL in intima compared with other tissues? |
|
Definition
| same as serum and higher than other tissues because intima has no lymphatic ducts |
|
|
Term
| what is the lifetime of LDLs in intima? |
|
Definition
longer than other tissues (wks-months)
become damaged (oxidation)
only enter/exit through endotheial cell layer |
|
|
Term
| what are foam cells, and how are they formed? |
|
Definition
macrophages containing cholesterol esters (damaged LDLs)
eventually get to big and die and esters are released into intima -> deposit in plaque |
|
|
Term
| where is the origin of the macrophages found in the intima of atherosclerotic plaques? |
|
Definition
monocytes in blood
intima cells secrete pro-inflammatory factors -> endothelial cells express adhesion molecules -> bind to monocytes -> differentiate into macrophages in intima |
|
|
Term
| what is the link bw postmenopausal osteoporosis and artery calcification? |
|
Definition
a. higher rate of bone loss have most artery calification
b. bone loss due to BMU defect
c. BMU defect enters circulatory system
d. might be an agent from BMU that promotes calcification
e. or systemic condition that drives both processes |
|
|
Term
| how could bone loss generate small crystals in the BMU? |
|
Definition
| elevated osteoclast activity inc Ca and P levels in fluid generates spon crystal formation |
|
|
Term
| what are the molecular mechanisms responsible for the development of an atherosclerotic plaque? |
|
Definition
not known, plausible mech:\
1. mineral foci in early fatty streak
2. foci attract macrophages which dissove them
3. macrophages engulf oxidized LDL -> no mech to disove -> foam cell
4. macrophages die and deposite cholesterol esters that accumulate on fatty streak
5. big foci (too big for macrophage) fue to form hard plate
flaw: how do foci continue to appear in intima
5.
4. |
|
|
Term
| what are the universal features of atheroclerotic plaque? |
|
Definition
a. located in intima
b. contain cholesterol esters (mush) and hard mineral
c. numerous macrophages and foam cells |
|
|
Term
| what are the univeral features of fatty streaks? |
|
Definition
a. found in arteries before atherosclerotic plaque
b. in intima with cholesterol esters, mineral, macrophafes, and foam cells
c. do not increase width of imtima (untile plaque)
d. progress to atherosclerotic plaque |
|
|
Term
| why do postmenopausal women with highet rate of bone loss have the highest risk for myocardial infarction (heart attack) and ischemic strokes? |
|
Definition
| both caused by fibrin clots that arise at the site of ruptured atherosclerotic plaque, and bone loss can be a mechanism that could account for the appearance of small mineral foci in intima |
|
|
Term
| is bone loss the basis for all atherosclerosis? |
|
Definition
| no. it contributes but some people have it that dont have bone loss, so there has to be another mech for foci in intima |
|
|
