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Flashcards in Atherosclerosis Deck (39)
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stimulating endothelial cells with TNFa does what?

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


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

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.


what are the effects of shear laminar flow on inflammation?

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


Macrophage uptake of LDL

• 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.


VSCM role in atherosclerosis

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


Monocyte-macrophage role in atherosclerosis

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


Endothelial cells role in atherosclerosis

Barrief function ( ag to lipoproteins)
leukocyte recruitment


what do T lymphocytes do in atherosclerosis?

recruit macrophages


Intra-plaque haemorrhage causes and consequences

• 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


mouse models to study athero

• 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.


Accelerator molecules in atherosclerosis:

Adhesion molecules
• P-selectin
• E-selectin
• ICAM-1
• VCAM-1

Chemokines & receptors
• MCP-1
• CCR2
• CX3CR1

• IL-1
• TNFa
• IL-4 ● IL-6
• IL-12 ● IL-18
• IFNg


decelerators in atherosclerosis

• TGFb
• IL-10


What is antigenic about oxidised LDL ?

• 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...


Overview of atherosclerosis in relation to immune system

• 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


Inflammatory/hoemeostatic drivers:

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


Tissue handling of oxidised LDL

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


briefly describe the complement system and its actions

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.


potential activators of complement in athero?

Apoptotic cells
Cholesterol crystals
Denatured LDL


IgM role in athero

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


key macrophage functions:

• 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)


how do macrophages get into plaque?

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


macrophages have oxidative enzymes:

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
• HOCl hypochlorous acid (bleach) from ROS + Cl-
• HONOO Peroxynitrite (NO-adduct) from ROS + NO


macrophages - tissue repair and growth factors

• 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


macrophage induced VSMC apoptosis

• 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


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)


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


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.


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.


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.


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.