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MBB334 - Biochemical Basis of Human Disease > Chamberlain - Atherosclerosis > Flashcards

Chamberlain - Atherosclerosis Flashcards

1
Q

What kind of disease is atherosclerosis?

A
  • chronic inflam disease influenced by many factors, involving vast array of inflam cells and cytokines
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2
Q

What is the structure of an artery wall?

A
  • lumen = where blood flows
  • 3 layers = endothelial (1 cell thick), tunica intima (usually same thing as endothelial, but can become thicker in disease), tunica media (thick layer of smooth muscle), tunica externa (or adventitia)
  • layer of elastic tissue separates each layer = external/internal elastic lamina (EEL/IEL)
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3
Q

When is inflam good?

A
  • pathogens, parasites, tumours, wound healing
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4
Q

When is inflam bad?

A
  • myocardial reperfusion injury, atherosclerosis, ischaemic heart disease, rheumatoid arthritis, asthma etc.
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5
Q

What can atherosclerosis cause?

A
  • principal cause of heart attack, stroke and gangrene of extremities
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6
Q

What is the main problem in atherosclerosis?

A
  • when plaque ruptures leading to thrombus formation and ultimately death
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7
Q

What can influence pathogenesis?

A
  • multitude of lifestyle choices, medical conditions and haemodynamics of blood flow itself
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8
Q

When can atherosclerosis begin, and how does this dev?

A
  • most get at v young age and dev through life, but most dont have serious problems
  • can begin before birth (maternal hypercholesterolaemia)
  • can take years/decades to dev
  • often remain symptomless for majority of life
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9
Q

What does atherosclerosis always begin w/?

A
  • initial damage to endo cells of artery wall
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10
Q

What medical risk factors are there?

A
  • raised lipoprotein
  • high LDL
  • low HDL
  • dyslipidemia
  • hypertension
  • overweight
  • TIID
  • fam history
  • infection (eg. chlamydia, pneumonia)
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11
Q

What behavioral risk factors are there?

A
  • diet
  • smoking (nicotine damages endo cells)
  • physical inactivity
  • alcohol consumption
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12
Q

What is the diff between medical and behavioral risk factors?

A
  • medical can’t really change, many assoc w/ lipids
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13
Q

What is the biggest risk factor?

A
  • age
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14
Q

What diff risk factors cause endothelial dysfunction?

A
  • dyslipidemia, TIID and smoking
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15
Q

How are plaques distrib?

A
  • found in peripheral and coronary arteries –> coronary is what causes heart attacks
  • focal distrib along artery length
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16
Q

What may govern reg of plaques?

A
  • haemodynamic factors –> changes in flow/turbulence, eg. tends to dev at bifurcation of artery or at bend (as blood bounces off wall etc.), alters gene expression
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17
Q

What does an atherosclerotic plaque consist of?

A
  • complex lesion consisting of: lipid, necrotic core, connective tissue, fibrous “cap” (separates everything from blood and stabilises plaque)
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18
Q

When do plaques become a big problem, and why?

A
  • when blocks blood flow

- angina, heart attack, thrombosis if ruptures and rupture often what causes heart attack

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19
Q

Eventually what will the plaque do as it grows?

A
  • obstruct lumen resulting in restriction of blood flow (angina) or may rupture (thrombus formation → death)
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20
Q

What is the responses to injury hypothesis?

A
  • endothelial cells being damages leads to endo dysfunction
  • -> healthy endothelium prod NO and other mediators, protect against atheroma
  • -> alt NO biosynthesis: affects BP control, regional blood flow, predisposes to atherosclerosis
  • signals sent to inflam cells, accum and migrate into vessel wall
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21
Q

How can adhesion act as a stimulus?

A
  • chemoattractants (= chemicals that attract leucocytes) are released from site of injury (damaged ECs) and conc grad is prod
  • damaged ECs also express adhesion mols
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22
Q

What is the adhesion cascade and how is it a part of extravasation?

A
  • usually leucocytes flowing through blood not interacting
  • but if chemoattractants then start to express selectins/integrins (adhesion molecules)
  • leucocytes bind to these, rolling slows down, until eventually stop, then can start to migrate through gaps in endothelial wall
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23
Q

How can LDL act as a stimulus, leading to atherosclerosis?

A
  • LDL can pass in and out of arterial wall in excess, accum in arterial wall
  • problem when in excess
  • ECs and macrophages gen free radicals
  • LDL ox by free radicals (oxLDL)
  • oxLDL engulfed by macrophages, via scavenger receptors (CD36) to form foam cells
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24
Q

What are foam cells and what do they release?

A
  • big cell prod lipid –> release more pro-inflam cytokines
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25
Q

What cytokines in plaques are important?

A
  • IL-1 v important

- also IL-6, IL-8, IFN-γ, TGF-β, MCP-1, PDGF

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26
Q

What is the earliest lesion and how do they form?

A
  • fatty streaks
  • appear at v early age (<10 yrs)
  • form by accum of lipid-laden macrophages (foam cells) and T lymphocytes w/in intimal layer of vessel wall (below endothelium)
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27
Q

What is the next stage of progression after fatty streaks, and what is happening at this stage?

A
  • intermediate lesions
  • foam cells degrade LDL w/in them, releases cholesterol they contain and this can cause crystals, which causes foam cell to apoptose and cholesterol crystals released into ec area
  • lumen still big at this stage and not really affected, as grows outward 1st
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28
Q

What are intermediate lesions composed of?

A
  • composed of layers of foam cells, vascular smooth muscle cells, T lymphocytes, adhesion and aggreg of platelets to vessel wall, iso pools of ec lipid
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29
Q

What protective mechs exist so stays at stage of intermediate lesions?

A
  • reverse cholesterol transport
  • HDL contains apo-A1 particles that interact w/ foam cells to collect cholesterol from LDL, so out of vessel wall
  • mature HDL then travels to liver to release cholesterol (then processed for excretion)
  • HDL then recirculates back to heart to repeat process
  • result is not enough LDL to make enough diff for plaque to keep growing
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30
Q

What are the diff stages of progression?

A
  • fatty streaks
  • intermediate lesions
  • protective mech at this stage
  • fibrous plaques or advanced lesions
  • plaque rupture
31
Q

What happens as progress to fibrous plaques or advanced lesions?

A
  • thought to need an added impetus –> another risk factor or area of disturbed flow
  • cytokine release by cells causes SMC (smooth muscle cell) prolif and dep of connective tissue
  • leads to dense, fibrous cap made up of connective tissue overlying lipid-rich core
  • cap and core = atheromatous plaque, may be calcified
  • if grows big enough, starts to impede blood flow = symptomatic
  • prone to rupture
32
Q

What is the cap in fibrous plaques made up of?

A
  • ec matric prots inc collagen (strength) and elastin (flexibility)
33
Q

What is the lipid core in fibrous plaques made up of?

A
  • necrotic and apoptotic debris, SMCs, foam cells, macrophages and T lymphocytes
34
Q

Can drugs be used to stop progression at the stage of fibrous plaques?

A
  • if not too bad, but if too big then too late for this
35
Q

How does the cycle of vascular formation and LDL result in the formation of a necrotic core?

A
  • LDL enters vessel walls
  • macrophages enter, engulf LDL, become foam cells
  • LDL lysed, cholesterol released, crystallises
  • crystals in foam cells induce apoptosis
  • ec lipid pool w/in arterial wall
  • further attraction of macrophages
36
Q

What makes the cap more stable?

A
  • the thicker it is the more stable
37
Q

What leads to plaque rupture?

A
  • plaques constantly growing and receding
  • fibrous cap has to be reabsorbed and redeposited in order to be maintained
  • large no. of VSMC (vascular smooth muscle cells) and matric prots stab plaque
  • large no. of macrophages predisposes plaque to rupture, increased matrix metalloproteinases and gelatinase –> cap becomes weak
38
Q

What does plaque rupture result in?

A
  • provides substrate for thrombus formation and vessel occlusion
39
Q

How are plaque rupture and erosion similar?

A
  • both induced by cholesterol cystallisation
40
Q

How are plaque rupture and erosion diff?

A
  • ruptured plaque: thin fibrous, collagen poor cap, large necrotic core, many macrophages, fibrin rich thrombus
  • eroded plaque: proteoglycan and glycosaminoglycan rich, little or no lipic core, neutrophils and NETs, many SMCs, platelet rich thrombus
41
Q

How can plaques be disrupted?

A
  • torn cap projects into lumen of the artery and thrombus contained w/in plaque core
42
Q

Should we target plaque erosion too?

A
  • more and more drugs that can slow progression (aimed at targeting intervention of plaque rupture, turn thick plaque into thin plaque)
  • so instances of plaque rupture decreasing, but erosion is still an issue (current research)
  • erosion mostly affects endothelial cells
43
Q

Why are lipids packaged into lipoproteins for transport around body?

A
  • as v hydrophobic
44
Q

What is the general structure of lipoproteins?

A
  • central core of hydrophobic lipid (triglycerides, cholesterol) surrounded by hydrophilic coat (phospholipids, free cholesterol, apolipoproteins)
45
Q

What are lipoproteins classified according to?

A
  • density

- only differ in size and apolipoprotein they express

46
Q

What are the 5 diff lipoproteins?

A
  • HDL = most dense
  • LDL
  • IDL (intermed)
  • VLDL (v low)
  • chylomicrons
    (decreasing in amount of core lipid_
47
Q

What are the 3 pathways of lipoprotein transport?

A
  • exogenous (dietary)
  • endogenous (liver to tissues)
  • reverse cholesterol (tissues back to liver)
48
Q

What is the exogenous pathway of lipoprotein metabolism?

A
  • lipids digested
  • chylomicrons assembled w/ apolipoprotein B-48
  • chylomicrons move into liver and subsequently into bloodstream, where HDL donates apolipoprotein C-II and E, forming mature chylomicron –> ApoC can only bind to receptors on adipose tissue, while ApoE can only bind receptors on hepatocytes
  • mature chylomicrons activate lipoprotein lipase (LPL), an enz on surface of cells –> LPL catalyses hydrolysis reaction, releasing glycerol and FAs from chylomicrons, which can be reabsorbed by tissue
  • remnants endocytosed and hydrolysed w/in lysosomes –> also release glycerol and FAs in cell
  • cholesterol stored, secreted in bile, ox to bile acids or converted into VLDL
49
Q

What is the endogenous pathway of lipoprotein metabolism?

A
  • in liver triacylglycerol and cholesterol assembled into apolipoprotein B-100 to form VLDL
  • HDL donates apolipoprotein C-II and E
  • apolipoprotein C-II activates LPL, causing hydrolysis of VLDL particle and release of glycerol and FAs → absorbed by adipose tissue and muscle, hydrolysed VLDL particles now called IDL
  • IDLs return to liver and further hydrolysed by hepatic lipase, releases glycerol and FAs, leaving behind IDL remnants (= LDL), after LDLs bind to target tissues they’re endocytosed, internalised LDL particles hydrolysed w/ lysosomes, releasing mainly cholesterol
50
Q

What is the reverse cholesterol pathway of lipoprotein metabolism?

A
  • removes cholesterol from peripheral tissues and returns to liver
  • ApoA1 of HDL binds to transport prots ABC-A1 or ABC-G1 in macrophages/foam cells and adsorbs cholesterol
  • HDL then transports cholesterol to liver via either:
  • -> indirect pathway: cholesterol esters transfer to VLDL and LDL particles via cholesterol ester transport prot (CETP), LDL binds to LDLR on liver
  • -> direct pathway: ApoA1 of HDL binds SRB1 receptor on liver, cholesterol transferred to liver, HDL recirculates
51
Q

What is dyslipidemia?

A
  • abnormal amount of lipids in blood

- mostly hyper = elevation of lipids in blood

52
Q

How can dyslipidemia be a 1° disease?

A
  • due to combo of diet and genetics
  • usually polygenic, but can be monogenic
  • classified according to which lipoprot is abnormal
  • targeted directly w/ drugs
  • type II: familial hypercholesterolaemia gives greatest risk
53
Q

How can dyslipidemia be a 2° disease?

A
  • consequence of other conditions, eg. diabetes, chronic renal failure, liver disease, certain drugs
  • treated where poss by correcting underlying cause
54
Q

What is Familial Hypercholesterolemia (FH)?

A
  • genetic disorder causing v high levels LDL in blood and early cardiovascular disease (CVD)
55
Q

What mutations lead to FH?

A
  • usually mutation in either:
  • -> LDLR gene (encodes LDL receptor prot, which removes LDL from circulation)
  • -> Apolipoprotein B (ApoB), which is part of LDL that binds w/ receptor
  • mutations in other genes rare, but exist
56
Q

Is FH polygenic or monogenic?

A
  • now thought to be polygenic (40% monogenic)
57
Q

Is FH homo or heterozygous, and how does this affect treatment?

A
  • homozygous (rare)
  • heterozygous (1:500)
  • heterozygous normally treated w/ statins, bile acid sequestrants, or other lipid lowering agents (to lower cholesterol)
  • homozygous often doesn’t respond to medical therapy and may req other treatments, inc LDL apheresis (removal of LDL in method similar to dialysis) and occasionally liver transplantation
58
Q

How can dyslipidaemia/atherosclerosis be treated?

A
  • main treatment aimed at decreasing levels of LDL
  • drug therapy (1 of 3 drugs or a combo) used alongside dietary changes
  • main drugs:
  • -> statins (prodrugs) = HMG-CoA reductase inhibitors
  • -> inhibitors of cholesterol absorption
  • -> PCSK9 inhibitor
  • when drugs not enough: PCI (stent, angioplasty) or CABG (= coronary artery bypass graft)
59
Q

How do statins target cholesterol synthesis?

A
  • main reg step (rate limiting step) = conversion of HMG-CoA to mevalonate, catalysed by HMG-CoA reductase (–> controls excessive cholesterol formation by feedback mechanism)
  • inhibit HMG-CoA reductase
  • in hypercholesterolaemia cholesterol continues to be prod despite excess cholesterol in blood (lack of uptake by LDL receptor)
  • statins given orally are absorbed and extracted by liver (site of action)
  • subject to extensive presystemic metabolism via cytochrome P450 and/or glucuronidation pathways
60
Q

Why are diff statins given dep on person?

A
  • diff statins processed diff in liver
61
Q

What is the mech of action of statins?

A
  • decreased cholesterol synthesis in liver causes increased LDL receptor synthesis (to take more cholesterol from circulation)
  • increased LDLR causes increased LDL clearance from plasma into liver
  • thus reduce plasma LDL
  • also reduce plasma triglyceride and increase HDL
62
Q

How do statins cause pleiotropic effects?

A
  • products of mevalonate pathway involved w/ lipidation (ie. react w/ prot to add hydrophobic group)
  • fatty groups serve as anchors to localise prots in organelles
  • several important mem-bound enzs (eg. endothelial NO synthase) mod in this way
  • thus by inhib mevalonate pathway statins also affect lipidation
63
Q

What pleiotropic effects can statins cause?

A
  • improved endothelial function
  • reduced vascular inflam
  • reduced platelet aggregability
  • increased neovascularisation of ischaemic tissue
  • increased circulating endothelial progenitor cells
  • stab of atherosclerotic plaque
  • antithrombotic actions
  • enhanced fibrinolysis
  • inhib of germ cell migration during dev
  • immune suppression
  • protection against sepsis
64
Q

What is an eg. of a drug acting by cholesterol absorption?

A
  • Ezetimibe, a azetidinone cholesterol absorption inhibitor
65
Q

What is the action of Ezetimibe?

A
  • blocks intestinal absorption of cholesterol (and plant stanols) by blocking transport prot in brush border of enterocytes
  • doesn’t affect absorption of fat soluble vits, triglycerides or bile acids
  • high potency comp to resins
66
Q

How do sterols/stanols work?

A
  • inhibitors of cholesterol absorption
  • structurally similar to cholesterol –> incorp into mixed micelles replacing cholesterol
  • so less cholesterol absorbed into bloodstream = reduced serum total and LDL cholesterol concs
  • may also activate transporter prots w/in enterocytes –> increases movement of cholesterol from enterocytes back into intestinal lumen to be excreted
67
Q

What would the optimal efficacy of sterols/stanols be?

A
  • plant stanols taken as part of meal –> virtually unabsorbed by body, retain efficacy LT
68
Q

How does Evolocumab work?

A
  • PCSK9 inhibitor
  • binds PCSK9, prevents it binding LDLR, so no degrad, so LDL binds LDLR, internalises, LDL released, LDLR recycles back to liver cell surface, increases no of LDLRs available to clear LDL from blood
  • lowers circulating LDL levels
69
Q

What kind of drug is Evolocumab?

A
  • human monoclonal Ab (biologic)
70
Q

What is the role of PCSK9?

A
  • binds LDLR, complex internalises, receptor undergoes lysosomal degrad, LDL continues to circulate
71
Q

Why are we targeting lipids in atherosclerosis?

A
  • understand much better than inflam
72
Q

Overall what do HMG-CoA reductase inhibitors do?

A
  • decrease cholesterol synthesis
  • increase exp of LDL receptors on hepatocytes
  • increase LDL cholesterol (LDL-C) uptake
  • reduce cardiovascular events and prolong life in people at risk
73
Q

What is the most freq class of drugs used to target atherosclerosis?

A
  • HMG-CoA reductase inhibitors (statins, eg. simvastatin)

MBB334 - Biochemical Basis of Human Disease (7 decks)

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