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Medical Biochemistry and Pathophysiology > Week 6A: Atherosclerosis, Aneurysm, Cholesterol > Flashcards

Week 6A: Atherosclerosis, Aneurysm, Cholesterol Flashcards

HC 30, 31, 32

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1
Q

What structures are made extra in atherosclerosis to support new tissue?

A

Capillaries

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2
Q

Lethal infarctions in atherosclerosis

A

Myocardial or brain infraction

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3
Q

Important role endothelial cells

A

Barrier function, determine what does to the tissues

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4
Q

What do endothelial cells have on their cell surface to recognize etc

A

Proteins

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5
Q

Smoking risk factor for atherosclerosis

A

Smoking induces ROS formation in the blood
> Inflammation and activation monocytes in blood

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6
Q

How does LDL induce subendothelial inflammation in atherosclerosis? Explain all the steps

A

There is too much LDL in the low stressed vessel inner curvatures
> Too much ROS formation
> LDL goes into vessel wall and becomes minimally modified LDL (mLDL)
> Activation monocytes and extravasation to become activated macrophages
> Macrophages import mLDL with scavenger receptors
> Macrophages make cytokines and growth factors

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7
Q

Why do macrophages absorb mLDL with scavenger receptors instead of LDLR

A

LDLR does not recognize mLDL

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8
Q

Activated macrophages make products. Name them with their effects.

A

-Cytokines: attract more immune cells like monocytes and T-cells
-Growth factors: induce smooth muscle cell (SMC) migration and proliferation

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9
Q

Foam cell formation

A

Too much mLDL is taken up by macrophages
> Become immobile
> All lipids dissolve
> Cholesterol accumulates
> Very big cells: mechanically trapped in vessel wall: keep producing cytokines and growth factors

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10
Q

Atherosclerosis is a multi-factorial disease. Name the environmental factors, risk factors (molecular) and genetic components

A

Environment
> Smoking
> Diet
> Lack of exercise
Risk factors
> High cholesterol (LDL)
> Hypertension
> Diabetes
Genetic components
> Familiar Hypercholesterolemia (FH)
> Tangiers Disease
> others

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11
Q

Name treatment for the risk factors diabetes and high LDL and for environmental factors

A

Environmental > prevention
Diabetes > Insulin
High cholesterol/LDL > statins

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12
Q

Why do statins decrease cholesterol (LDL)

A

Promote the LDLR mostly

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13
Q

FH is caused by a mutation in the gene for:

A

LDL receptor

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14
Q

Acute myocardial infarction is caused by which process?

A

Blood coagulation

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15
Q

What does the plaque consist of in atherosclerosis

A

Cells > immune cells, SMCs, ECs (endothelial cells)

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16
Q

Risk factor for acute infarction

A

Exercise
> more blood flow > higher risk for rupture of the plaques
> ECs damaged > coagulation
> thrombus in the narrow vessel lumen: infarction

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17
Q

Which sex has the higher risk to get atherosclerosis?

A

Men

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18
Q

Symptoms myocardial infarct in women

A

Pain, shortness breath, fatigue, dizziness, restless feeling, fear, vomiting

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19
Q

Important with myocardial infarct symtoms men and women in atherosclerosis

A

Different symptoms!

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20
Q

Cell types in atherosclerotic plaque

A

-Endothelial cells (ECs)
-Monocytes/macrophages
-Smooth muscle cells (SMCs)
- T-cells

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21
Q

Stent treatment in atherosclerosis

A

Bring in stent around a balloon
> inflate balloon: stent sets out and widens vessel lumen
> deflate and remove balloon, stent remains in place

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22
Q

Explain why 1/3 of patients with stent treatment in atherosclerosis comes back with symptoms after light exercise after a while

A

SMC proliferation in the stent
> In-stent restenosis

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23
Q

In-stent restenosis is a pathology of the … cells

A

smooth muscle cells

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24
Q

Drug-eluting stent

A

Stent with a drug on the outside of the stent
> low dose: to prevent overgrowth of SMCs in the stent

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25
Q

Drug eluting stent with Taxol

A

Taxol disrupts microtubules and therefore proliferation of cells

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26
Q

Drug eluting stent with rapamycin

A

Rapamycin promotes mTOR enhanced expression of p27-kip1

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27
Q

Disadvantages of drug-eluting stents with taxol or rapamycin

A

Both drugs inhibit the growth of all cells, thus both SMC and EC growth
> No endothelial recovery after placing stent and thereby damaging the tissue: risk for thrombosis

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28
Q

One could prescribe double anti-platelet therapy (DAPT) when using a drug-eluting stent with rapamycin or taxol. What is the risk?

A

Risk for bleeding (and no hemostasis) at another surgury

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29
Q

What is the characteristic needed for a drug on a drug-eluting stent, which genes are targeted?

A

Only inhibit SMC growth
> target genes regulated in activation SMCs

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30
Q

Forms of SMCs

A

Contractile SMC <=> Activated SMC

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31
Q

Which gene is upregulated in activated SMCs, and how is this determined

A

Nur77
> Culture human SMCs, activate cells, harvest RNA over time, screening differential gene expression

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32
Q

What kind of protein is Nur77?

A

A nuclear hormone receptor
(like ER, estrogen receptor)

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33
Q

How are nuclear hormone receptors activated (like Nur77), take ER as an example

A
  • Inactive: the ligand binding domain is unbound, the C-terminal helix-12 is exposed and binds the co-repressor, DNA binding domain not active
  • Active: Ligand binds ligand binding domain, helix-12 folds in, co activator binds, DNA binding domain binds the response element.
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34
Q

Effect Nur77 on SMC growth? Why was this unexpected? What kind of gene/protein is Nur77 for the SMC?

A

Nur77 inhibits SMC growth
> Unexpected: expression in activated SMCs
> Nur77 is an endogenous protective factor.

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35
Q

Effects Nur77, that make it a good drug in atherosclerosis and in-stent restenosis

A

-Inhibits SMC growth
-Promotes EC survival
-Reduces inflammatory response macrophages

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36
Q

Which drug is put on a stent to target Nur77 and promote its activity?

A

6-Mercaptopurine (6-MP)
-Inhibits SMC growth
-Promotes EC survival
-Reduces inflammatory response macrophages

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37
Q

How is a drug-eluting stent with 6-MP made?

A

Stent made with biodegradable coating: releasing 6-MP.

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38
Q

Why are stented blood vessles embedded in plastic and not paraffin?

A

Paraffin can be ruptured by the metal of the stent

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39
Q

How are the holes in the sections of arteries with in-stent restenosis called and how is the phenomenon recognized?

A

Struts, and between and over the struts, there is a lot of SMC restenosis (SMC growth)

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40
Q

6-MP inhibits the neointima and there is endothelial coverage of the lesion at day 7, what is the disadvantage

A

Low dose insufficiently activate Nur77 and promote the survival, and loading of higher dose hard to do in porcine coronary arteries in research. Drugs needed to activate Nur77 at lower dose.
> find more specific/sensitive Nur77 acivator

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41
Q

SNPs in genes involved in in-stent restenosis and so SMC proliferation? And how is this studied?

A

Study: bare metal stent > patient follow up (1/3 restenosis) > DNA
- p27-kip1 involved: cell cycle inhibitor

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42
Q

Effect p27-kip1in SMC growth

A

Inhibit SMC growth
> cell cycle inhibitor in transition G0/G1 -> S

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43
Q

SNPs in p27-kip1 in in-stent restenosis

A

-838 C/A
> in promotor sequence

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44
Q

Which genotype of the -838 SNP of p27-kip1 leads to increased expression thus lower SMC growth?

A

AA > low risk in-stent restenosis. More activity of the promotor
AC/CC > higher risk, shorter time of problem free

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45
Q

Which allele of the SNP in -838 in p27-kip1 is beneficial to prevent in-stent restenosis? But which phenomenon has an increased risk in these allele? Why is the discovery of the SNP still useful?

A

AA
> but increased risk of acute myocardial infarct > EC growth also inhibited after placing stent.
> Thinner cap, easy rupture
But useful to predict patients at risk for in-stent restenosis.

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46
Q

Stents are a method for …

A

Angioplasty: creating more space in artery where a plaque has built up

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47
Q

HC31: Name the layers of the arteries

A

Adventitia:
> Fibroblasts
> Collagen
> Capillaries
Media
> multiple layers SMCs
Intima
> Single layer ECs

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48
Q

How are SMCs interconnected with their environment in arteries?

A

Via cytoskeleton and ECM connected to membrane

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49
Q

Cascade SMC contraction

A

-Stimulus at alpha-adrenergic receptor
-Gq> PLC-gamma> PI3K activation > Ca2+ release via IP3 > Ca/CaM > MLCK activation
-MLCK phosphorylates myosin light chain: contraction
-MLC-phosphatase is phosphorylated by PKG-Ia to reset myosin light chain

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50
Q

How is the SMC relaxation initiated?

A

Nitrogen oxide (NO) as primary signal (gas,diffusion in cell) for guanylate cyclase
- GTP to cGMP
- cGMP activates PKG-Ia
- PKG-Ia activates the phosphatase for myosin light chain

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51
Q

Where do aneurysms take place typically?

A

-Abdominal aorta: AAA
-Thoracic aorta:
-Ascending aorta: aortic root aneurysm
> also cerebral aneurysm

52
Q

In atherosclerosis: the lumen is …

A

narrowed

53
Q

Cerebral aneurysm location

A

At T-junction where much pressure is
> bulging aneurysm (sphere outward)

54
Q

Aneurysm: what happens

A

Widening of the artery

55
Q

Risk factors AAA (abdominal aortic aneurysms)

A

-Age: 50+
-Gender (male, women more after menopause)
-Blood pressure
-Smoking (++)
-Family history
-Atherosclerosis

56
Q

Type 2 diabetes risk factor for aneurysm?

A

Negative risk factor (surprisingly)
> hyperglycemia and much insulin in blood (potential effect of glucose or insulin)
> Metformin users had less AAA growth

57
Q

Which layers of the arteries are most (they are all, but which most) affected in aneurysms and atherosclerosis

A

Aneurysm: adventia and media
Atherosclerosis: intima

58
Q

Wall stress profiles and aneurysms and atherosclerosis

A

Aneurysm: outer curvature: more flow: risk aneurysm (rupture)/dissection
Atherosclerosis: inner curvature: low flow, more accumulation LDL
> The ECs sense the flow

59
Q

There is high mortality when aneurysms ….

A

rupture

60
Q

Risk of thrombus in aneurysm?

A

Not the largest problem, large lumen aorta

61
Q

When do you experience pain in aneurysm?

A

When rupture and leaking of blood

62
Q

Treatments for aneurysms are only done when…

A

> 5 cm diameter, then the risk of the surgery is less than that of spontaneous rupture of aneurysm.

63
Q

Treatments aneurysm

A
  • Endovascular repair (placement stent tube which becomes the new ‘vessel’. brought in through iliac vessel) > less invasive, but not always enough if aneurysm grows and blood goes around.
  • Conventional: open repair, make large prosthesis but aorta is made open in surgery.
    > no specific drugs against aneurysms!!
64
Q

When a section is viewed in aneurysm vessel wall, and there are holes in the media, what happened?

A

Atherosclerosis: holes are cholesterol crystals, SMCs lost and normal tissue disappeared.

65
Q

Why do aneursym vessel walls have dense nuclei at the adventitial side?

A

Local inflammation, local lymph node follicles made in aorta to communicate more (there is so much going on)
> T and B-cells and macrophages to communicate in aorta: dense nuclei

66
Q

ECM structure in media and adventitia

A

Delicate network in media and thick collagen cables in adventitia.
> so that diameter of vessel has maximum

67
Q

ECM in aneurysm vessel wall

A

ECM of adventitia is disrupted
> matrix changed, cells change behaviour since they use them as communication and interaction with environment

68
Q

Which enzymes are targeted to inhibit aneurysm

A

Proteases in inflammatory cells which degrade aorta

69
Q

Angiotensin II in aneurysm

A

Results
-Pump up blood pressure
-Release inflammatory cells (inducing)
-Activation Ras system through alpha-adrenergic receptor cascade

70
Q

Result ApoE and LDLR deficiency in mice

A

Pro-atherosclerosis.

71
Q

ACE inhibitors

A

Prevent AngII formation out of AngI done by ACE (enzyme)
> prevents both signalling routes of AngII

72
Q

ARBs and Losartan functions

A

(Prevent differentiation): prevent AT1R signalling only

73
Q

AngII receptors and routes

A

AT1R > increases blood pressure
AT2R > decreases blood pressure

74
Q

Possible reason chronic high blood pressure

A

Ras system activated (via AngII)

75
Q

Why is there faster rupture of the aorta in aneurysm than in humans?

A

Thinner wall of aorta (less layers SMCs in media) which is degraded

76
Q

In atherosclerosis, a new … is formed

A

Intima

77
Q

Which type of SMC is the healthy one

A

The contractile SMC

78
Q

Which transmembrane proteins connect to the ECM in SMCs?

A

Integrins

79
Q

Which feature do activated SMCs have which contractile SMCs do not?

A

Cortical actin filaments

80
Q

Macrophages in aneurysm

A

In the vessel wall (in media and adventitia, rather than under intima at atherosclerosis) > degradation of aorta > rupture

81
Q

Angiotensin II supplement to mice

A

ECM collagen gets degraded, inflammation in vessel wall (degradation SMCs)

82
Q

Decrease inflammation with doxycycline. Why? Why not used?

A

Smaller diameter lumen aorta in mice
> aneurysms grew faster in humans
> Mitochondria inhibited (endosymbiosis theory)
> cell die with long-term antibiotics
-The difference: prevention in stead of curing (difference)
-Inflammatory cells very active: toned down after antibiotics. > done in mice without inflammatory response, tone down inflammatory cells
> successful in prevention in mice, not in intervention for curing in humans

83
Q

Doxycycline is an …

A

antibiotic

84
Q

Human vs mouse AAA, the top affected pathways are the same: always disturbed in AAA. They are:

A

-Oxidative phosphorylation
-Mitochondrial dysfunction
-Sirtruin signalling pathway (also has to do with feeling healthy)

85
Q

Important: inflammation has same/different roles in atherosclerosis and aneurysm

A

different

86
Q

Key players in genetic aneurysm diseases

A

-MLCK (contraction SMC, MYLK gene)
-Myosin filaments (MYH11)
-PRKG (relaxation SMC, codes for PKG-1)
-Actin filaments (ACTA2 gene)
> contractile apparatus involved in AAA
-Fibrillin-1
-Fibrillin-4
-Collagens 1, 3 and 5
-TGFbeta-signalling (in scarring)
> ECM and mechanosensing of environment involved

87
Q

Marfan syndrome

A

Rare disease
> FBN1 gene mutated > Fibrillin-1
> Distributed over whole gene
Fibrillin-1 forms fibers like collagen
Marfan: bone, lung, heart defects
> aortic defects: aortic root very large: rupture and death.

88
Q

MFS treatment (Margan syndrome)

A

Surgery when >5cm aneurysm
-Beta-blockers to reduce blood pressure when needed
-AngII-receptor blocker losartan prevents aneurysms better than beta-blockers in MFS mice

89
Q

Which drugs protected patients from aneurysm rupture: choose 2 out of beta-blockers, ARBs, ACE inhibitors, Calcium-channel blockers (all blood pressure lowering drugs). Explain why some do not help.

A

Beta-blockers and ARBs
> Why
> Calcium channel blocker: contraction disrupted, dangerous

90
Q

High odds ratio for calcium channel blockers for aortic dissection: so

A

higher risk

91
Q

Gene expression profile in MFS mice: which pathways disrupted?

A

Oxidative phosphorylation and mitochondrial dysfunction (Again, important)
> metabolic changes in aortic aneurysm

92
Q

Mitochondrial dysfunction hypothesis to aneurysm

A

Mitochondrial dysfunction
> KLF4 induction
> SMC phenotypic switch
> Loss of contractile SMC phenotype
> Aneurysm formation

93
Q

Stimulate mitochondrial function how?

A

-Sports
-Sports mimetics
-Mitochondrial repair

94
Q

HC32: Name the good of the cholesterol (functions)

A

-Biosynthesis: precursor for bile salts, vitamin D, steroid hormones like testosterone and estrogen
-For membranes

95
Q

Gall stone formation and treatment

A

Cholesterol crystals in bile bladder: too much cholesterol
> removed through surgery

96
Q

Depositions cholesterol in retina visually

A

Yellow depositions

97
Q

Problem cholesterol in mammals

A

Cannot be broken down
> no energy content

98
Q

Cholesterol transport: how, where

A

Cholesterol is insoluble
> Transport in lipoproteins: chylomicrons, VLDL/IDL/LDL, HDL
> Cholesteryl esters in lipoprotein core
> Distinct functions of the classes of lipoproteins

99
Q

There are a lot of genes involved in cholesterol metabolism. What if one if them is mutated?

A

All disease related mutations

100
Q

Cellular level regulation of cholesterol

A

Balance SREBP and LXR transcription factors

101
Q

Why is a low cholesterol diet not too efficient (not as efficient as you might think)? Where cholesterol biosynthesis?

A

When you eat less, you make more, and vice versa.
> synthesis in liver

102
Q

Which TFs rule in the cell when high/low cholesterol

A

High: LXR rules: efflux upregulated
Low: SREBPs rule: uptake and synthesis upregulated

103
Q

What proteins are upregulated by SREBPs

A

-Genes and enzymes which are all needed to make cholesterol
- Increase levels of LDLR by promoting the transcription and synthesis

104
Q

What is the actual rate limiting step of cholesterol synthesis: not HMG-CoA reductase step

A

Squelene epoxidase
> Squalene to lanosterol

105
Q

Approximately how many cholesterol is taken up by one LDLR

A

1500

106
Q

What happens with the endosome after receptor mediated endocytosis of LDL after binding to LDLR?

A

Fusing with lysosome
> release cholesterol
> recycling LDLR

107
Q

How long does a cycle of LDL receptor mediated endocytosis and recycling take and what is the half-life of cholesterol

A

every 10 minutes
> half-life: 24h
> much cholesterol uptake
> regulation is important: because of huge effect!

108
Q

Familial hypercholesterolemia (FH) caused by defect in …

A

LDLR

109
Q

Monogenic form FH

A

Heterozygous: one LDLR gene functional

110
Q

Homozygous FH

A

Both alleles LDLR affected, very bad, few treatment options

111
Q

Effects statins

A

-More LDLR made!
(and competitive inhibition HMG-CoA reductase)

112
Q

The secretory proprotein NARC-1 is converted to the active form….

A

PCSK9

113
Q

Effect PSCK9

A

Binds to LDLR
> prevents recycling LDLR
> LDLR+PCSK9 binds LDL > sent to lysosome and degradation including LDLR

114
Q

Mutations in PCSK9

A

-Some cause autosomal dominant hypercholesterolemia
-Others inhibit hypercholesterolemia

115
Q

Loss-of-function mutation PCSK9

A

PCSK9 broken down > LDLR works better > more LDL cholesterol clearance from blood > inhibits hypercholesterolemia

116
Q

Gain-of-function mutation PCSK9

A

More functional PCSK9 > less functional LDLR > less cholesterol uptake from blood from LDL > hypercholesterolemia

117
Q

Treat upregulated PCSK9

A

Antibody-based targeting: inhibit PCSK9 to lower LDL cholesterol in blood
> only use when statins don’t work

118
Q

Which TF promotes PSCK9 synthesis

A

SREBP: regulate LDL intake, not too much

119
Q

Name ligands for LXR

A

Cholesterol derivates: oxysterols
> oxidized cholesterol

120
Q

Where is LXR positioned?

A

Always on the DNA, but repressed by corepressors. Always bound to RXR.
> Bind oxysterol ligands: corepressors replaced by coactivators

121
Q

LXR effects

A

-Promote reverse cholesterol efflux by promoting ABCA1
-Inhibit LDLR
-Promote SREBP1c in liver: TAG to blood in VLDL
-Promote bile acid formation by CYP enzyme in liver

122
Q

What happens to LXR-null mice

A

Cannot deal with excess dietary cholesterol: liver can’t sense and respond to high cholesterol

123
Q

LXR effect on the IDOL gene. And result?

A

LXR upreglates IDOL
> IDOL breaks down LDLR by polyubiquitinating it
> IDOL is an E3 ubiquitin ligase
> Uptake LDL cholesterol goes down
> LXR expression goes down: negative feedback because of less cholesterol in cell

124
Q

Normally, less uptake of LDL is caused in cells when feeding them LDL and LXR ligands. What happens if IDOL is deficient?

A

Not less LDL uptake because LXR expression does not result in a functional IDOL which breaks down LDLR

125
Q

Role LXR in immunity: what if deficient

A

Immunity works not great

126
Q

Effect cholesterol in cell on SREBP2 expression

A

Inhibited, cannot move from ER to Golgi membrane

Medical Biochemistry and Pathophysiology (16 decks)

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