Atherosclerosis (471)

CHD is the occlusion of blood flow through ____________ ______________
coronary arteries
Ischemia = ____________
lack of OXYGEN
Ischemia will develop if artery lumen diameter is reduced by _______
> 50%
What 3 vascular diseases can be due to increased LDL levels?
CARDIOvascular
CEREBROvascular
PERIPHERAL vascular
Severe hypertriglyceridaemia can also be associated with ______________
risk of PANCREATITIS
What is the definition of atherosclerosis?
The process of accumulation of lipid leading to thickening of arterial blood vessels
What are 3 fixed(non-modifiable) risk factors of atherosclerosis?
1) Age
2)Gender (Male > females; but catches up after menopause)
3) Dyslipoproteinemias (genetic defect)
What are 5 modifiable risk factors for atherosclerosis?
1) Hyperlipidemia
2) Hypertension
3) Diabetes
4) Obesity
5) Smoking
What enzyme is involved in cholesterol production?
HMG-CoA reductase
What is the main factor for clearance of plasma LDL ?
Hepatic LDL receptors
The rate of synthesis of LDL receptors is reduced due to what?
Adequate uptake of CHOLESTEROL into hepatocytes by LDL-R (via down regulation of gene transcription)
HMG CoA reductase activity is inhibited by what in the body?
Cholesterol
What is the main metabolite of cholesterol?
Bile acids
Approximately ______% of cholesterol and _____% of bile acids are reabsorbed from intestines
50%
97%
What are lipoproteins?
Soluble complex macrmolecules that transfer cholesterol and triglycerides through out the body
What are the 5 major types of lipoprotein?
1) Chylomicrons
2) VLDL
3) IDL
4) LDL
5) HDL
What do chylomicrons carry?
– EXOgenous dietary cholesterol
– triglycerides
What % of chylomicron is triglycerides?
80-90%
What do VLDLs carry? where are they synthesized?
– ENDOgenous cholesterol
– triglycerides
(synthesized in liver and peripheral tissue)
LDL carries cholesterol to where?
peripheral tissues
What is the function of HDL in regards to cholesterol transport?
– removes cholesterol from cells and plagues
– returns them to the liver for excretion in bile
What does extracellular lipoprotein lipase (LPL) do in adipose, skeletal and heart capilariy tissues?
Degrades triglycerides, so free fatty acids can be used for energy, or re-synthesis of triglycerides to be stored in adipose tissue and liver
What does LPL do to VLDL?
Degrades the triglycerides in them, and turn them into IDL and LDL
What happens after LDL is endocytosed via hepatic LDL receptors?
– Endocytosed vesicle fuses with lysomes
– Lysomal enzymes degrade LDL
– LDL receptors are recycled
What 3 types of cells have LDL receptors?
hepatocytes
adrenal cells
adipocytes
What part of the blood vessel wall is weakened (thickened, loss of elasticity) due to lipid accumulation?
arterial intima
Atherosclerosis begins with development of _______ _________ in the vessel wall
fatty streaks
Fatty streaks leads to atherosclerotic plaques that can _________, __________________________, and ______________________________
rupture,
set up thrombosis,
occlude the lumen
Atherosclerosis in the coronary arteries leads to ___________ and _____
angina,
MI
Atherosclerosis in the central nervous system leas to __________________ and _________
transient cerebral ischemia,
stroke
Atherosclerosis in the peripheral circulation elicits ________ and ___________
PVD,
gangrene
What is the artery intima made of?
– endothelial cells
– extracellular matrix
What is the artery adventitia made up of?
– Loose connective tissue
– small blood vessels
– nerve fibers
What does the artery media consist of?
smooth muscle cells
In the “response to injury” hypothesis of lesion formation, what are 3 possible sources of injury?
1) Mechanical
2) Infection (bacteria, virus)
3) Toxins
In the “response to injury” hypothesis, what do endothelial cells express after they are damaged?
cell adhesion molecules:
– P-selectin
– VCAM-1
What adheres to the injured endothelin via the adhesion molecules?
Monocytes
What happens after monocytes adheres?
monocytes migrate into the intima (aka. monocyte transmigration)
What causes LDL infiltration into the intima?
trapping – rapid LDL transport into subendothelium, but slow transport out
What happens to the LDL once they are trapped in the subendothelium?
oxidative modification into Ox-LDL
(by endothelial reactive oxygen species)
Ox-LDL can lead to what?
recruitment of additional circulating monocytes into the intima
What 3 ways do Ox-LDL cause more monocytes to infiltrate?
1) cause cells to express monocyte chemoattractant protein (MCP-1)
2) promote differentiation of monocytes into macrophages, which release cytokines (TNF-a, IL-1), which activate endothelial cells to express more adhesion molecules
3) Initiate generation of Macrophage-Colony Stimulating Factor (M-CSF), which cause macrophages to express savenger receptors
Ox-LDL is taken up by _______________to form ________________?
macrophages,
foam cells
Foam cells are the ______________ of atherosclerosis
hallmark
Engorgment of foam cells eventually causes ____________________
cell death (necrotic core)
Release of cytokines and growth factors from macrophages cause what to happen?
smooth muscles cells to migrate from artery media to the intima, proliferate, and secrete collage and extracellular matrix
The change in smooth muscle cells from contractile cells to synthetic cells causes the formation of what?
fibrous cap
What can be the result of the expanding intima due to migration of smooth muscle cells?
rupture of the endothelial wall -> leads thrombus formation
What are 3 roles of HDL that help prevents atherosclerosis?
1) Inhibit oxidation of LDL
2) Promote cholesterol efflux from foam cells
3) Inhibit adhesion molecule expression