Atherosclerose
De vaatwand is een heleboel lage van gladde spiercellen, waarop een laag epitheel zit. Bij
atherosclerose zie je dat het lumen van het vat dicht gegroeid zit, zoals je ziet bij benen.
Ook wel slagaderverkalking. It is the underlying pathology of myocardial and cerebral
infarction.
- It is a multifactorial disease. Environment are smoking, diet and lack of exercise.
Risk factors are high LDL, low HDL, hypertension and diabetes. Genetic components
are mutations in genes of LDL receptor - Tangier disease and FH. So many genes
are involved in this process, see dia 11.
If there is a high level of LDL in circulation, there is also more LDL in the tissue which is
oxidized, this cannot be taken up by regular LDL receptors. oxLDL activates endothelial
cells. This activation leads to expression of receptors on endothelial cells to which
monocytes can bind and grow into the vessel wall. Now they are macrophages. These
macrophages have scavenger-receptors which can take up oxidized LDL, which they keep
on doing and eventually cannot leave the vessel wall. These cells are foam cells. When
rupturing, they attract more immune cells due to their cytokines.
Acute myocardial fraction can happen due to acute constriction of coronary vessels in
women. As soon as menopause kicks in, the protection of MI in women is lost due to the
decrease in estrogen. In acute myocardial function, there is a rupture in a plaque. This will
lead to thrombus formation and the vessel is blocked.
Cells involved in atherosclerosis are monocytes/macrophages, T-cells, endothelial- and
smooth muscle cells.
Treatment of atherosclerosis → get a balloon and blow the plaque away, dotteren, was not
very effective. A stent is a tiny tube with holes in and a balloon inside. You enter the artery
through the arm and when you are at the plaque, you inflate the balloon and push the stent
in the vessel wall. In 1-3 patients you get in-stent restenosis, something grows inside stent.
It is predominantly smooth-muscle cells. Now there is a drug which prevent in-stent
restenosis on the stent → drug-elutin stents. But the endothelial cells are also affected by
this drug, after insertion of drug-elutin stents, the endothelial cells need to grow back.
- No endothelial recovery → risk for thrombosis.
- Double anti-platelet therapy → Risk for bleeding at other surgery.
Drugs used are like …..
When culturing human SMCs, activate the cells and harvest RNA at different time points and
perform screen differential gene expression, activated SMC show higher levels of Nur77.
Nur77 is a nuclear hormone receptor of the family NR4 subfamily A. These are TF, with a
N- transcription activation domain, DNA-binding domain and ligand binding domain, - C.
Nur77 ligand was unknown. When overexpressing Nur77, cells grew slower which was
counterintuitive as it turns out to be a endogenous protective factor. In mice when
overexpressing Nur77, there was less SMC growth. Other group found Nur77 also promotes
EC survival and it reduces inflammatory response in macrophages. Now docent thought that
6-MP, which activates Nur77, was a nice drug for a stent. It was found that 6-MP moderately
inhibits restenosis, but promotes endothelial coverage of the lesion.
,Also they looked to try find a DNA motive which correlates with the obtaining in-stent
restinosis; p27kip1 SNP; -838A/C. AA is beneficial in in-stent restenosis. As if you have an
A, there is more p27kip1 expression and p27kip1 inhibits SMC cell growth.
Aortic aneurysm formation
You have adventitia layer, mostly of fibroblast, the media which is muscle cells and the
intima. Muscle cells like to contract, actin filaments are bound integrins and also ECM is
bound to integrin. Mechanosensing is about this as the cells are bound to the ECM and there
contraction and relaction also. When contracting you pull on ECM and cells around.
SMC contraction goes through a 7TM membrane, and through PI3K Ca2+ release activating
MLCK through CaM which can phosphorylate myosin light chain. When relaxed GTP ->
cGMP and activates PKG-;alfa which can dephosphorylate and inactivate myosin light chain
through phosphorylation of myosin light chain phosphatase.
In aneurysm disease, you get SMC death and cannot regenerate the vessel wall. Aneurysms
formation is mostly at a few locations like at the abdomen or ascending aorta, where the
genetic aneurysm formate. Atherosclerosis is mostly in smaller arteries. Aneurysm is in the
aorta, which is a very big vessel.
- Risk factor is aging, mostly males, smoking++, family history (though most often not)
and atherosclerosis. Type 2 diabetes is a negative risk factor, surprising. In the US
they did a study counting how many people got aneurysm and how many people take
metformin. It seems that metformin intake slows AAA formation. But this is just a
association.
Mortality after aneurysm rupture: 70%. Two types of surgery for aneurysm. Conventional,
open repair which is quite invasive or endovascular repair. When looking at tissue from
aneurysm in open repair, they see that lymph node structures are made in the aorta,
meaning that there is a lot wrong as there is a huge immune response. So inflammation
plays a role. Also there are lesions in the micro aortas vessels. Also cells are dying whic is
replaced with scar tissue.
AngII which is a peptide hormone that can drive up blood pressure and promotes
inflammation. ApoE or LDLR deficient = pro-atherogenic mice which are male with osmotic
minipump with AngII. The macrophages in the aortic vessel are eating away the aorta. It was
shown that aneurysm formation was decreased by giving immunosuppressant, but only in
preventive studies, not treatment studies. Azathioprine inhibits proliferation, so these
immune suppressants also do not help for the aorta to regenerate.
Mitochondria are orgginaly bacterial. Some antibiotics interfere with mammalian cells due to
this reason. Doxycycline does interfere with the mammalian cells. In the mouse
experiments is worked well so a clinical trial started and assesed at halfway, 1.5 year. They
saw that the AAA grew. Then mouse and human samples were compared, oxidative
phosphorylation, mitochondrial dysfunction and sirtuin signalling pathway were all
most affected in AAA. Metformin induced mitochondrial genesis.
Marfan syndrome, mutation in Firbrilin-1 which can form networks or put elastin on it and
get elastin filaments. Most people with Marfan die from aortic rupture. Marfan patients have
, problems with forming ECM. In humans it seemed that rupture of aorta can be avoided bu
ARB’s. Calcium channel blockers should not be given. In aorta are different subpopulations
of cells. In Marfan, there are more osteogenic SMC.
The good, the bad and the ugly - cholesterol
High cholesterol is the basis of atherosclerosis. Cholesterol is needed in live, membrane,
bile salts, sexhormones and vitamin D. It is also the most decorated molecule. When having
high cholesterol you can get cholesterol deposits in the joints and retina, gal stones,
one of the most common places is near the eye. We can't break cholesterol down, but we
can use it in synthesis and deposit it through bile salts in feces. Also we are made of water,
but rely on cholesterol which is a lipid. This brings though modes of transportation. LDL
transport cholesterol in the forward pathway. A lot of energy is needed in the processes in
handling of cholesterol through all the lipoproteins.
Homeostasis of cholesterol is through cholesterol uptake and - synthesis and lose it through
efflux. All cells can make cholesterol, but some do not do it, and just take it up. effluc through
LXR, and SREBP which does synthesis and uptake. SREBP activates the entire pathway for
cholesterol synthesis and upregulates LDLR. With one LDL particle you get 1500 cholesterol
molecules. The LDLR is a cyclic receptor, with a cycle of 10 minutes and a halflife of a day,
so you need to regulate this. 1 in 200 people in Netherlands has a heterogenic LDLR allele
mutation.
- You need 25 enzymes, molecular oxygen, co-enzymes. A lot of energy needed for
cholesterol.
Statins work through HMG-CoA reductase. Once liver cells cannot make cholesterol, now
more LDLR is expressed by liver and liver takes LDL out of circulation.
What does NARC-1 have to do with the LDLR. NARC-1 is also the genes that encodes for
PCSK-9, this secreted protein binds LDLR on outside of the cell and prevents the LDLR from
finishing its cycle by sending this receptor to a lysosome to be degraded, the receptor itself.
Mutations in PCSK-9 can cause hyper cholesteremia. Another paper found that mutations in
PCKS=9 cause low LDL cholesterol. So mutations can cause high and low levels. Both can
be right as PCKS-9 can have a gain or- loss of functions. Within a few years, there were
antibodies against PCSK9, this lower the functional amount and increases LDLR thus
lowering high LDL.
When high cholesterol LXR are activated as cholesterol leads to production of oxysterols
which are co-activators (?) of LXR. LXR will stop synthesis, make products and turn of efflux.
So LXR promotes reverse cholesterol efflux through HDL.
- LXR null mice cannot deal with excess dietary cholesterol. But cholesterol is
important for every part in the body. No LXR → alzheimers.
LDLR → cholesterol uptake ^ → LXR ^ → IDOL ^ and IDOL will ubiquinate LDLR and lower
LDLR.
De vaatwand is een heleboel lage van gladde spiercellen, waarop een laag epitheel zit. Bij
atherosclerose zie je dat het lumen van het vat dicht gegroeid zit, zoals je ziet bij benen.
Ook wel slagaderverkalking. It is the underlying pathology of myocardial and cerebral
infarction.
- It is a multifactorial disease. Environment are smoking, diet and lack of exercise.
Risk factors are high LDL, low HDL, hypertension and diabetes. Genetic components
are mutations in genes of LDL receptor - Tangier disease and FH. So many genes
are involved in this process, see dia 11.
If there is a high level of LDL in circulation, there is also more LDL in the tissue which is
oxidized, this cannot be taken up by regular LDL receptors. oxLDL activates endothelial
cells. This activation leads to expression of receptors on endothelial cells to which
monocytes can bind and grow into the vessel wall. Now they are macrophages. These
macrophages have scavenger-receptors which can take up oxidized LDL, which they keep
on doing and eventually cannot leave the vessel wall. These cells are foam cells. When
rupturing, they attract more immune cells due to their cytokines.
Acute myocardial fraction can happen due to acute constriction of coronary vessels in
women. As soon as menopause kicks in, the protection of MI in women is lost due to the
decrease in estrogen. In acute myocardial function, there is a rupture in a plaque. This will
lead to thrombus formation and the vessel is blocked.
Cells involved in atherosclerosis are monocytes/macrophages, T-cells, endothelial- and
smooth muscle cells.
Treatment of atherosclerosis → get a balloon and blow the plaque away, dotteren, was not
very effective. A stent is a tiny tube with holes in and a balloon inside. You enter the artery
through the arm and when you are at the plaque, you inflate the balloon and push the stent
in the vessel wall. In 1-3 patients you get in-stent restenosis, something grows inside stent.
It is predominantly smooth-muscle cells. Now there is a drug which prevent in-stent
restenosis on the stent → drug-elutin stents. But the endothelial cells are also affected by
this drug, after insertion of drug-elutin stents, the endothelial cells need to grow back.
- No endothelial recovery → risk for thrombosis.
- Double anti-platelet therapy → Risk for bleeding at other surgery.
Drugs used are like …..
When culturing human SMCs, activate the cells and harvest RNA at different time points and
perform screen differential gene expression, activated SMC show higher levels of Nur77.
Nur77 is a nuclear hormone receptor of the family NR4 subfamily A. These are TF, with a
N- transcription activation domain, DNA-binding domain and ligand binding domain, - C.
Nur77 ligand was unknown. When overexpressing Nur77, cells grew slower which was
counterintuitive as it turns out to be a endogenous protective factor. In mice when
overexpressing Nur77, there was less SMC growth. Other group found Nur77 also promotes
EC survival and it reduces inflammatory response in macrophages. Now docent thought that
6-MP, which activates Nur77, was a nice drug for a stent. It was found that 6-MP moderately
inhibits restenosis, but promotes endothelial coverage of the lesion.
,Also they looked to try find a DNA motive which correlates with the obtaining in-stent
restinosis; p27kip1 SNP; -838A/C. AA is beneficial in in-stent restenosis. As if you have an
A, there is more p27kip1 expression and p27kip1 inhibits SMC cell growth.
Aortic aneurysm formation
You have adventitia layer, mostly of fibroblast, the media which is muscle cells and the
intima. Muscle cells like to contract, actin filaments are bound integrins and also ECM is
bound to integrin. Mechanosensing is about this as the cells are bound to the ECM and there
contraction and relaction also. When contracting you pull on ECM and cells around.
SMC contraction goes through a 7TM membrane, and through PI3K Ca2+ release activating
MLCK through CaM which can phosphorylate myosin light chain. When relaxed GTP ->
cGMP and activates PKG-;alfa which can dephosphorylate and inactivate myosin light chain
through phosphorylation of myosin light chain phosphatase.
In aneurysm disease, you get SMC death and cannot regenerate the vessel wall. Aneurysms
formation is mostly at a few locations like at the abdomen or ascending aorta, where the
genetic aneurysm formate. Atherosclerosis is mostly in smaller arteries. Aneurysm is in the
aorta, which is a very big vessel.
- Risk factor is aging, mostly males, smoking++, family history (though most often not)
and atherosclerosis. Type 2 diabetes is a negative risk factor, surprising. In the US
they did a study counting how many people got aneurysm and how many people take
metformin. It seems that metformin intake slows AAA formation. But this is just a
association.
Mortality after aneurysm rupture: 70%. Two types of surgery for aneurysm. Conventional,
open repair which is quite invasive or endovascular repair. When looking at tissue from
aneurysm in open repair, they see that lymph node structures are made in the aorta,
meaning that there is a lot wrong as there is a huge immune response. So inflammation
plays a role. Also there are lesions in the micro aortas vessels. Also cells are dying whic is
replaced with scar tissue.
AngII which is a peptide hormone that can drive up blood pressure and promotes
inflammation. ApoE or LDLR deficient = pro-atherogenic mice which are male with osmotic
minipump with AngII. The macrophages in the aortic vessel are eating away the aorta. It was
shown that aneurysm formation was decreased by giving immunosuppressant, but only in
preventive studies, not treatment studies. Azathioprine inhibits proliferation, so these
immune suppressants also do not help for the aorta to regenerate.
Mitochondria are orgginaly bacterial. Some antibiotics interfere with mammalian cells due to
this reason. Doxycycline does interfere with the mammalian cells. In the mouse
experiments is worked well so a clinical trial started and assesed at halfway, 1.5 year. They
saw that the AAA grew. Then mouse and human samples were compared, oxidative
phosphorylation, mitochondrial dysfunction and sirtuin signalling pathway were all
most affected in AAA. Metformin induced mitochondrial genesis.
Marfan syndrome, mutation in Firbrilin-1 which can form networks or put elastin on it and
get elastin filaments. Most people with Marfan die from aortic rupture. Marfan patients have
, problems with forming ECM. In humans it seemed that rupture of aorta can be avoided bu
ARB’s. Calcium channel blockers should not be given. In aorta are different subpopulations
of cells. In Marfan, there are more osteogenic SMC.
The good, the bad and the ugly - cholesterol
High cholesterol is the basis of atherosclerosis. Cholesterol is needed in live, membrane,
bile salts, sexhormones and vitamin D. It is also the most decorated molecule. When having
high cholesterol you can get cholesterol deposits in the joints and retina, gal stones,
one of the most common places is near the eye. We can't break cholesterol down, but we
can use it in synthesis and deposit it through bile salts in feces. Also we are made of water,
but rely on cholesterol which is a lipid. This brings though modes of transportation. LDL
transport cholesterol in the forward pathway. A lot of energy is needed in the processes in
handling of cholesterol through all the lipoproteins.
Homeostasis of cholesterol is through cholesterol uptake and - synthesis and lose it through
efflux. All cells can make cholesterol, but some do not do it, and just take it up. effluc through
LXR, and SREBP which does synthesis and uptake. SREBP activates the entire pathway for
cholesterol synthesis and upregulates LDLR. With one LDL particle you get 1500 cholesterol
molecules. The LDLR is a cyclic receptor, with a cycle of 10 minutes and a halflife of a day,
so you need to regulate this. 1 in 200 people in Netherlands has a heterogenic LDLR allele
mutation.
- You need 25 enzymes, molecular oxygen, co-enzymes. A lot of energy needed for
cholesterol.
Statins work through HMG-CoA reductase. Once liver cells cannot make cholesterol, now
more LDLR is expressed by liver and liver takes LDL out of circulation.
What does NARC-1 have to do with the LDLR. NARC-1 is also the genes that encodes for
PCSK-9, this secreted protein binds LDLR on outside of the cell and prevents the LDLR from
finishing its cycle by sending this receptor to a lysosome to be degraded, the receptor itself.
Mutations in PCSK-9 can cause hyper cholesteremia. Another paper found that mutations in
PCKS=9 cause low LDL cholesterol. So mutations can cause high and low levels. Both can
be right as PCKS-9 can have a gain or- loss of functions. Within a few years, there were
antibodies against PCSK9, this lower the functional amount and increases LDLR thus
lowering high LDL.
When high cholesterol LXR are activated as cholesterol leads to production of oxysterols
which are co-activators (?) of LXR. LXR will stop synthesis, make products and turn of efflux.
So LXR promotes reverse cholesterol efflux through HDL.
- LXR null mice cannot deal with excess dietary cholesterol. But cholesterol is
important for every part in the body. No LXR → alzheimers.
LDLR → cholesterol uptake ^ → LXR ^ → IDOL ^ and IDOL will ubiquinate LDLR and lower
LDLR.
