Atherosclerosis Flashcards
(39 cards)
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 • CXCR2 • CX3CR1
Cytokines • IL-1 • TNFa • IL-4 ● IL-6 • IL-12 ● IL-18 • IFNg
decelerators in atherosclerosis
DECELERATORS:
• IL1RA
• 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 Microparticles Endotoxin Immune-complexes
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
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
Myeloperoxidase
• 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