Atherosclerosis Flashcards

(39 cards)

1
Q

stimulating endothelial cells with TNFa does what?

A

leads to a robust induction of genes involved in the recruitment of leukocytes to the vessel wall, such as E-selectin, VCAM-1 and IL-8

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2
Q

what does conditioning with high-shear laminal flow do to ECs exposed to TNFa?

A

TNFa leads to a robust induction of genes involved in the recruitment of leukocytes to the vessel wall, such as E-selectin, VCAM-1 and IL-8 , but conditioning the cells with high shear laminar flow leads to nearly complete suppression of this response.

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3
Q

what are the effects of shear laminar flow on inflammation?

A

aminar flow suppresses proinflammatory gene expression but sustains cytoprotective responses in response to TNFa.

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4
Q

Macrophage uptake of LDL

A
  • Physiological uptake of LDL via LDL receptor controlled by receptor down-regulation
  • Uptake of oxidised LDL by scavenger receptors is not regulated and results in “foam cell” formation.
  • Cholesterol-laden macrophages die by apoptosis or necrosis and release proinflammatory cytokines and growth factors.
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5
Q

VSCM role in atherosclerosis

A

– Migration and proliferation
– Collagen synthesis
– Remodelling and fibrous cap formation

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6
Q

Monocyte-macrophage role in atherosclerosis

A

– Foam cell formation
– Cytokine and growth factor release
– Major source of free radicals
– Metalloproteinases

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7
Q

Endothelial cells role in atherosclerosis

A
Barrief function ( ag to lipoproteins)
leukocyte recruitment
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8
Q

what do T lymphocytes do in atherosclerosis?

A

recruit macrophages

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9
Q

Intra-plaque haemorrhage causes and consequences

A
  • poorly formed vessels with inadequate pericyte and basement membrane support
  • density of microvessels correlates with density of activated macrophages: secreted growth and angiogenic factors
  • intraplaque haemorrhage linked to acute clinical events – due to physical disruption
  • extravasated erythrocytes provides a dual metabolic challenge –lipid from erythrocyte membranes and iron from heme
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10
Q

mouse models to study athero

A
•	ApoE-/-
–	34kd component of VLDL
	and chylomicrons
–	ligand for LDL receptor
•	LDL receptor -/-
–	Mutations in familial hypercholesterolaemia

the hypercholesrerolaemia is associated with atherosclerosis – a disease that simply does not exist in a wild-type mouse.

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11
Q

Accelerator molecules in atherosclerosis:

A
Adhesion molecules
•	P-selectin
•	E-selectin
•	ICAM-1
•	VCAM-1
Chemokines & receptors
•	MCP-1
•	CCR2
•	CXCR2
•	CX3CR1
Cytokines
•	IL-1
•	TNFa
•	IL-4    ● IL-6
•	IL-12  ●  IL-18
•	IFNg
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12
Q

decelerators in atherosclerosis

A

DECELERATORS:
• IL1RA
• TGFb
• IL-10

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13
Q

What is antigenic about oxidised LDL ?

A
  • large complex and unstable antigen with many possible epitopes including
  • modified apoB peptides (eg with MDA, 4-HNE adducts)
  • modified phospholipids (eg exposed phosphorylcholine headgroup)

these epitopes can be recognised by different systems: complement, antibodies…

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14
Q

Overview of atherosclerosis in relation to immune system

A
  • Atherosclerosis can be viewed as a dynamic chronic autoinflammatory disease of arteries
  • The innate immune system regulates the safe disposal of lipoproteins and other debris from the arterial wall and is intrinsically protective
  • Overdrive of the innate immune system leads to irreversible remodelling, and this may be accelerated by adaptive immune mechanisms
  • The interplay between proinflammatory and wound healing pathways governs plaque development
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15
Q

Inflammatory/hoemeostatic drivers:

A
  • Lipoprotein deposition and oxidation
  • Mechanical stress
  • Angiogenesis with micro-haemorrhage
  • Thrombosis
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16
Q

Tissue handling of oxidised LDL

A
  • Scavenger receptor-mediated phagocytosis and intracellular digestion
  • Extracellular digestion (cathepsin D, lysosomal acid lipase)
  • Humoral immunity (antibodies, comllement, CRP)
17
Q

briefly describe the complement system and its actions

A

Complement is an enzyme system that works in infection and inflammation.
Can be activated by three different pathways.
C3 and C5 will activate leukocytes.

Under homeostatic conditions, the system of inhibitors (DAF, CD59) does not allow the system to progress beyond C3.

In opsonising debris, complement may label it for take up and removal elsewhere. Also inhibits excessive uptake by macrophages. Also shields arterial wall.

18
Q

potential activators of complement in athero?

A
Apoptotic cells
Cholesterol crystals
Denatured LDL
Microparticles
Endotoxin
Immune-complexes
19
Q

IgM role in athero

A

Natural IgM antibodies
•germline encoded
•secreted largely by B1 cells
•scavenger functions (bacteria, oxLDL, apoptotic cells)
•Bind ubiquitous epitopes
(eg phosphorylcholine)
•can be explored directly using secretory IgM-/- mice, generated by mutation of the Cm gene

IgM

IgM deficiency accelerates atherosclerosis (experiment in mice that also are Ldlr-/-)

20
Q

key macrophage functions:

A
  • Death via apoptosis (generate lipid necrotic core with debris)
  • Expression of matrix metalloproteinases (lyses collagen in fibrous cap)
  • Expression of pro-apoptotic mediators (kills VSMCs which lay down collagen to strengthen fibrous cap)
  • Expression of pro-coagulant factors (tissue factor, F7)
  • Recruitment of further macrophages (vicious cycle)
  • Removal of plaque lipid (self-limiting)
21
Q

how do macrophages get into plaque?

A
  • Recruited as monocytes (MCP-1)
  • Monocytes adhere to endothelium (VCAM-1)
  • Monocytes transmigrate through endothelium
  • Monocytes differentiate to macrophages
22
Q

macrophages have oxidative enzymes:

A

NADPH Oxidase
• superoxide O2- •
• Other (ROS) derived from superoxide
•  hydrogen peroxide H2O2
Inducible nitric oxide synthase (iNOS)
• High concentrations of free radical NO nitric oxide
Myeloperoxidase
• HOCl hypochlorous acid (bleach) from ROS + Cl-
• HONOO Peroxynitrite (NO-adduct) from ROS + NO

23
Q

macrophages - tissue repair and growth factors

A
  • Platelet derived growth factor
  • Vascular smooth muscle cell survival and cell division
  • Fibroblast growth factor
  • Smooth muscle cells survival, cell division
  • Transforming growth factor beta
  • Increased collagen synthesis
  • Vascular endothelial growth factor
  • New capillary formation
24
Q

macrophage induced VSMC apoptosis

A
  • VSMC apoptosis is increased in atherosclerotic plaques
  • Fewer VSMCs in ruptured than unruptured plaques
  • VSMCs are the main cell type that synthesise collagen in plaques
  • TNF-a, IFN-g, IL-1 in synergistic combination induce VSMC apoptosis
  • Do macrophages directly induce VSMC apoptosis via FasL
25
macrophages and collagen/ fibrous cap
• Matrix metalloproteases • MMP-1 • MMP-2 • MMP-9 • MMP-14 • MMP-1, MMP-2, MMP-9 cleave collagen • Inhibited by TIMPs • TIMP-1 overexpression reduces atherosclerotic tissue weakening • Catalytic site contains Zn • Activate each other by proteolysis • MT-MMPs are transmembrane proteins that activate other MMPs Evidence for role of MMPs: • It is possible to delete single genes from mice to examine their function in disease in vivo (knockout mice) • Atherosclerosis-prone mouse Ldlr and Apoe models have more collagen in plaques (stronger and less rupture-prone) if also knockout for: • Mmp14 • Mmp13 • Mmp9 • Timp1 overexpressing mice – also more collagen in plaques (stronger and less rupture-prone)
26
summarise macrophages in athero
1. macrophages in atherosclerotic plaques are from monocytes via endothelium 2. macrophages in atherosclerotic plaques lyse matrix via MMPs, secrete free radicals, oxidise LDL, are activated by oxidised LDL, phagocytose, release growth factors, express tissue factor and kill other cells 3. unstable atherosclerotic plaques are rupture-prone and contain increased macrophages
27
Features and causes of vulnerable plaque
They have demonstrated that the extracellular matrix is actively destroyed by MMPs which are locally overexpressed by the macrophages.11 1. In the weakened plaque the number of macrophages producing MMP is increased and the number of smooth muscle cells repairing the extracellular matrix is decreased. 2. This imbalance between extracellular matrix synthesis and degradation is a solid basis for plaque rupture. 3. Activated T lymphocytes produce interferon (which decreases the synthesis of collagen I and III by smooth muscle cells12). 4. The T lymphocytes also influence the degradation of the ECM by stimulating macrophage production of MMP involving CD40 ligation.13 5. MMP expression is also induced by oxidised lipids contained in the lipid core. Oxidised LDL contributes to the plaque weakening by decreasing the natural inhibitor of MMP (TIMP-1) expressed by the macrophages, and by inducing apoptosis of the smooth muscle cells. 6. In contrast, high density lipoprotein (HDL) has a protective effect. Paraoxonase and lecithine–cholesterol acyltransferase (LCAT) are HDL associated enzymes; paraoxonase protects LDL and HDL from oxidation, and LCAT prevents the formation of oxidised lipids in LDL.
28
cellular participants of atheromatous plaque formation
At the cellular level, the principal players are the endothelial cells, smooth muscle cells, macrophages, T lymphocytes, and neutrophils, and their mutual interactions will result in plaque rupture.
29
role of endothelial cells in athermoatous plawue formation
Endothelial cells play a pivotal role since they represent the major barrier against thrombosis, and their dysfunction results in attracting inflammatory cells (dysfunctional endothelial cells allow T lymphocyte recruitment via over-expression of the cell adhesion molecules) within the plaque where they can induce spasm, and participate in the thrombogenesis.
30
features of a stable plaque
thick fibrous cap smaller lipid pools few inflammatory cells dense extracellular matrix ntact and thick fibrous cap that is made up of smooth muscle cells in a matrix rich in type I and III collagen.
31
strategies to stabilise the plaques
lower LDL increase HDL Decrease Ang II, Oxidative stress, blood pressure
32
The current paradigm designating TCFAs as a prelude to ruptures is primarily supported by....
autopsy findings, where definitive proof does not exist because of a lack of prospective animal or human data confirming a cause-and-effect relationship
33
what are the critical features distinguishing the TCFAs
Clearly, fibrous cap thickness, necrotic core size, and positive remodeling are critical morphological features that distinguish TCFAs and ruptures from earlier progressive lesions, defined as pathological intimal thickening or fibroatheromas.
34
what is the evidence that TCFA increase the susceptibility of rupture?
vulnerable plaques were commonly observed in patients dying a sudden coronary death and were more common in plaque ruptures than in stable plaques.27 The number of vulnerable plaques correlated with both high total cholesterol and the total cholesterol/high-density lipoprotein cholesterol ratio.27 In subjects dying of plaque rupture, additional lesion sites remote from the culprit plaque typically show TCFAs in 70% of cases. On the other hand, TCFAs are less frequent (30%) in cases where death is attributed to fibrocalcific plaques with flow-limiting stenosis, regardless of MI status, or plaque erosion
35
what is the major limitation in our knowledge and research into plaques?
our inability to accurately detect vulnerable plaques in humans in vivo and because of the lack of an animal model. Therefore, a major limitation today exists partly because the precise mechanisms of progression from an asymptomatic stable to high-risk plaque (TCFA or vulnerable plaque) that lead to rupture and thrombosis are incompletely understood.
36
factors affecting the structure and maintenance of the firbbous cap
High importance of collagen synthesis and breakdown in the maintenance of the integrity of the fibrous cap. VSCMs synthesize essential ECM proteins (eg collagen and elastin). This process may be inhibited by interferon-γ (IFN-γ) secreted by activated T cells, thereby disrupting collagen synthesis. Importantly, the expression of CD40 ligand on T cells may promote tissue proteolysis through the release and activation of matrix-degrading enzymes produced by vascular smooth muscle cells and inflammatory macrophages. Activated macrophages within the fibrous cap can secrete tissue proteases that support the breakdown of collagen and elastin to peptides and amino acids. The loss of structural molecules provided by the extracellular matrix can thin and weaken the fibrous cap, rendering it particularly susceptible to rupture and acute coronary syndromes. Additional factors involved in the activation of macrophages include tumor necrosis factor-α (TNF-α), macrophage colony-stimulating factor (M-CSF), and macrophage chemoattractant protein-1 (MCP-1),among others
37
vulnerable plaques re cap thickness - measurement
those lesions with intact fibrous caps of <65 μm observed at other (oftentimes multiple) sites in the coronary vasculature, in patients dying of acute plaque rupture, that are designated vulnerable plaques or TCFAs. Therefore, the current definition of vulnerability is exclusive to plaque rupture.
38
AMPK-ARF1-Mhem macrophages:
* Intraplaque hemorrhage directs an atheroprotective macrophage phenotype M-hem: antioxidative enzymes * Probably a generic response to hemorrhage • Novel ATF1-pathway, mediated by AMPK (ATF-1 is required for this protective response induced by heam) Physical binding of ATF1 to HO-1 and LXR genes induced by heme in blood-derived macrophages
39
what are the AMPK-ARF1-Mhem macrophage pathway and molecules. their effects?
Physical binding of ATF1 to HO-1 and LXR genes induced by heme in blood-derived macrophages * Novel ATF1-pathway (ATF-1 is required for this protective response induced by heam; Mediated by AMPK and reproduced by metformin ) * HO-1 antioxidant / anti-inflammatory * LXR – foam cell protection * Reciprocal storage of iron and lipid * LXR * Nuclear receptors for cholesterol overload * Activate cholesterol efflux to HDL * ATF1 * Closest homolog of CREB1 (which transcriptional effects of cAMP) * Survival factor