What are some medium-sized or muscular arteries?
coronary arteries and renal arteries
What are the large or elastic arteries?
aorta and major branches, and pulmonary artery
What is the structure of small arteries and arterioles?
media essentially all smooth muscle cells
arterioles thin internal elastic membrane; terminal artiorles no elastic
What is the purpose of venules?
points where leukocytes emigrate in inflmmation
What is the response of endothelial cells in response to injury?
stimulation: rapid, reversible responses independent of new protein synthesis
activation: elaboration of gene products with biologic activity requires hours/day to develop
Where do vascular smooth muscle cells migrate to?
intima and proliferation occurs in normal vascular repair and pathologic processes
What are ht pro-growth factors associated with vascular smooth muscle cells?
pro-growth factors: PDGF, endothelin, thrombin, FGF, IFN-gamma, IL-1
What are the clinical significance of vascular disease?
responsible for more morbidity adn mortality;
two basic pathologies
-narrowing or obstruction-atherosclerosis and associated thrombosis
weakening of the vessel wall
-dilation adn rupture
How does intimal thickening occur?
stereotyped resposne to vascular injury of any kind
endothelium
-recruitment of smooth muscle cells or smooth muscle precursor cells to the intima
2. smooth muscle cell mitosis
3. elaboration of extracellular matrix
intimal smooth muscle cells cannot contract
healing response which may narrow or occlude the vessel
What is the arteriosclerosis?
hardening of artiers;
arteriolosclerosis?
small arteries and arterioles
-monckeberg medial calcific sclerosis
What is atherosclerosis
elastic arteries and large/medium muscular arteries
-most common: contributes to 50% ofall death
What is monckeberg arteriosclerosis?
calcific deposits in media of medium sized muscular arteries >50 yo no obstruction to the blood flow usually not clinically significant unrelated to atherosclerosis
What is atherosclerosis?
most prevalent and signifcant disease pattern
– progressive disease of elastic arteries and large to medium-sized muscular arteries
two basic types of damage
aneurysm formation and stenosis
What is the clinical syndrome associated with atherosclerosis in elastic arteries?
=aorta–aneurysm with rupture
- -carotid arteirs -occlusion causing stroke
- -iliac arteries - occlusion causing gangrene
What is the clinical syndorme associated with atherosclerosis in medium// large sized muscular arteries?
coronary arteries- occlusion leads to MI
popiteal arteries – cause gangrene
renal artery- narrowingocclusion causing secondary HTN
mesenteric arteries – narrowing/occlusion causing bowel infarction
What is the morphology of fatty streak?
multiple yellow, flat dots to streaks, usually in aorta and later in cornoaries; may be precursor to atheromas
What is lipid incorporation?
LDL cholesterol is transported into the vessel wall
endothelial cells and monocytes/macrophages generate free radical that oxidize LDL resulitng in lipid peroxidation
oxLDL is taken up by macrophages via scavenger receptors; resulting in activationa dn release of proinflammatory cytokines
What is the fibro-fatty plaque?
raised yellow-white plaque in intima with soft yellow core and white fibrous cap
- fibrous cap
- necrotic center
- media
What is the risk of advanced/vunerable plaques?
are at risk for: ruptured ulceration, erosion and hemorrhage -thrombosis, embolism -progressive luminal narrowing atheroembolism aneurysm formation
What are the signs of a vunerable plaque?
small fibrous cap, more inflammationa dn larger lipid cores
What is thrombosis?
partial or complete occlusion of vessel lumen: thrombus may be incorporated into the lesion, further narrowing it; likely happens repeatedly
What are factors contributing to thrombosis?
shear stress, high levels of LDL, smoking, through elevation of fibrinogen
What is the anuerysm formation?
atrophy of media, destruction of elastic fibers
leads to thinned weakend wall prone to rupture
What is atherosclerosis pathogenesis-1?
chronic inflammatory response of arterial wall to endothelial injury
What is atherosclerosis pathogenesis-2?
chronic endothelial injury/dysfunction; incrased permeability, enhanced leukocyte adhesion -specific cause unknown -strongly suspected causes: hemodynamic disturbance hypercholesterolemia
What is the atherosclerosis pathogenesis-3?
adhesion molecules attract leukocytes
monocytes adhesion, migration, and transformation to macrophages
-T lymphs: secretion of cytokines and fibrogenic mediators
What is the atherosclerosis pathogenesis-4?
infection: importance is unclear at present
-HSV, CMV, Chlamydia
smooth muscle cells: proliferation and migration into intima withproduction of matrix proteins
How does cholesterol cytotoxicity occur?
formation of cholesterol crystals
triggering of apoptotic pathways
formation of toxic oxysterols
disruption of membrane domains that are crucial for function of enzymes and signaling molecules
contributionto mechanisms that promote atherosclerosis
What are the four steps of cholesterol synthesis?
three acetate condense to form 6-c mevalonate
mevalonate converts to phosphorylated 5-C isoprene
six isoprenes polymerize to form 30-C linear squalene
squalene cyclizes to form teh fourrings that are modified to produce cholseterol
What is the step 1 formation of mevalonate from acetyl-CoA associated with?
2 Acetyl-CoAs-> acetyoacetyl-CoA acetyl-CoA+acetoacetyl-CoA-> Beta-hydroxyl-Beta-methylglutaryl- CoA catalyed by HMG-CoA synthase HMG-CoA+2NADPH->mevolanate catalyzed by HMG-CoA reductase
What is the rate limiting step of cholesterol?
Catalyzed by HMG-CoA reductase;
HMG-CoA+2 NADPH -> mevalonate
Step 2 occurs by what process?
3 Po43- transferred stepwise from ATP to mevalonate
decarboxylation and hydrolysis;
creates a diphosphorylated product isoprene
What are the two activated isoprene unit?
isopentyl pyrophosphate and dimethylallylpyrophosphate
What are the six activated isoprene units condense to form?
squalene
how does conversion of squalene to 4-ring cholesterol?
squalene monoxygenase adds one oxygen to end of squalene chain; diversion
cyclization product in animals is lanosterol converts to cholesterol
What are fates of cholesterol after synthesis?
in vertebrates most cholesterol synthesized in the liver and then exported
What are the adrenal gland-synthesized steroids?
mineralcorticoids
glucocorticoidds
What are the gonad syntehsized steroids?
progesterone, androgens and estrongens
What are cholesteryl esters are more non-polar than cholesterol?
contain a fatty acid esterfied to the oxygen; comes from fatty acyl-CoA
makes the cholesterol more hydrophobic
transported in lipoproteins to other tissues or stored in liver
What is cholesterol and other lipids are carried on lipoprotein particles?
lipids are carried through the plasma on spherical particles
surface is made of protein (called apolipoproteins) and a phopholipid monolayer
interior contains cholesterol, TG, CE
What is chylomicrons important apolipoproteins and other ?
apoB-48 + other apoLps, largest lipoprotein
What is the role of chylomicrons?
delivers cholesterol and Triglycerides from gut to tissues and liver
What are the apoliproteins and VLDL?
apoB-100 and other apoLps
Where is VLDL synthesized?
synnthesized in liver, delivers TG to tissues as fatty acids via lipoprotein lipases
What is the IDL?
short lived lipoprotein between VLDL and LDL
What is LDL?
apoB-100 only stays in circulation longer
What are the apolipoproteins associated with HDL?
apoA-I and apoA-II
What does Niemann-Pick C1-Like 1 protein do?
intestinal cholesterol and plant sterol absorption mediator
What does ABCG5/G8 do?
export plant sterols back nto intestinal lumen
What is the role of ApoB-48?
synthesized by intestinal epithelial cells; uniique to chylomicron
What is the role of apoC-II?
activates lipoprotein lipase on the vascular endothelium; facilitates relase of FA to adipose or muscle
What is a cofactor for LPL?
heparin
Where are chylomicron remnants removed from circulation?
removed by endocytosis at teh liver; through a process that rquires apoE as a ligand
What is the role of the LDL receptor-related protein?
important because it is the back up receptor responsible for the uptake of apoE enriched remnants of chylomicrons adn VLDL
An inherited absence of LDL-receptor related protein leads to what congenital disease?
type III hyperlipoproteinemia
What is the role of VLDL?
produced in liver when TG production is stimulated; increased FA intake or synthesis of FAs; contain apoB100, abpoCs; constituitively made in liver
After their synthesis in the ER TG is transferred by what to thesite of VLDL, apoB-100, site for formation?
MTP( microsomal triglyceride transfer protein)
A mutation of MTP(microsomal triglyceride transfer protein) causes what genetic disorder?
abetalipoproteinemia (vitamin deficiency, fat in stool, developmental delays)
What is the role of acyl-Coa: Cholesterol acytltransferase?
ACAT catalyzes esterfication of cellular sterols with fatty acids; and ACAT-2 regulates absorption of dietary cholesterol
What is the manipulation of hepatic receptor gene expression is the most effective way to modulate what?
plasma LDL-C
Muscle and adipose have LDL receptors that recognize wha?
apoB-100
What does a mutation result in the LDL receptor result in?
hypercholesterolemia
The regulation of LDL receptor expressio is mediated by what transcription factors?
sterol regulatory element binding proteins and SREBP cleavage activating protein (Scap)
What is the role of propprotein convertase subtilisin/kexin type 9
a serine protease that decreases the steady-state level of expression of the LDL receptor
Gain of function mutations in PCSK9 result in what?
reduced LDL receptors and increased susceptibility to coronar heart disease
A loss of function mutation in PCSK9 leads to what?
incraeased LDL receptor function; lower LDL cholesterol llevels
What is the clinical signifigance of Lipoprotein(a)?
LDL like particle, that is a cardiovascular risk factor
What is the structure of Lipoprotein(a)?
Apo(a) protein covalently linked to apoB100;
What is the variable of Apo(a) protein?
variable because of kringle repeats; inverse correlation between size of apo(a) protein and plasma concentration
What is the clinical significance of HDL?
anti-oxidant anti-thrombotic reduces vascular adhesion molecules on endothelium stimulates endothelial repair promotes endothelial function lowers inflammation stabilizes (atherosclerotic) plaqus
What is the function fo HDL?
carries out reverse cholesterol transport
What are the proteins of HDLs?
ApoA-I (most abudnant protein)
ApoA-II (2nd most abundant)
C-apolipoproteins
What is the function of apolipoprotein A-I?
primary protein component
synthesized in liver and intestine
required for HDL production
help activate LCAT
What is the role of ATP binding cassette transporter 1 with respect to HDL?
helps release free cholesterol; promotes efflux of cellular phospholpid and cholesterol to lipid-free apoA-I
What is tangier disease?
mutation of ABCA1; resulting in extremely low levels of HDL
What is lecithin-cholesterol acyl transferase function?
helps form cholesterol estter core of HDL
LCAT esterfies the HDL
What activates lecithin-cholesterol transferase (LCAT)?
apoA-I
What is the function of cholesteryl ester transfer protein (CETP)?
exchanges lipids between LDL and HDL; deficiency in humans associeated with increased HDL level
What is the role of phospholipid transfer protein?
catalyzes transfer of phospholipids between lipoprotein classes
Needed for maximal activity of LCAT
What are the role of hepatic lipase in HDL movement?
after CETP and pLTP mediated lipid exchange TG enriched HDL becomesa better substrate for hepatic lipase;
hydrolyzes TG and PL to generate smaller HDL particles
appears to play a pivotal role in regulating HDL-C levels
What oes endothelial lipase do?
hydrolyzes HDL phospholipids generating smaller HDL particles.
What is the receptor for HDL?
expressed in liver, ovaries, testes, adrenal glands
Scavenger receptor-BI
What converts cholesterol to bile acid?
cholesterol 7-alpha hydrozylase
How is cholesterol synthesis and transport regulated?
covalent modification of HMG-CoA reductase
transcritptional regulation of HMG-CoA
activation of ACAT which increases esterfication for storage
transcription reg of LDL receptro
