Coronary heart disease and atherosclerosis Flashcards

Question

What can happen to Arterial Ox-LDL deposits?

Answer 1

Inflammation: Activation of ‘bug-detector’ pathways (the immune system mistakes the Aterial Ox-LDL deposits for a pathogen and triggers an inflammatory response= bad) Homeostasis: Safe clearance+ reverse cholesterol transport (removed from the plaque and engage in emigration where the macrophages take the fat out of the plaque in a lymph node or interact with HDL to ‘suck’ the cholesterol out of the plaque into the HDL to the liver through reverse cholesterol transport.)

Answer 2

I. Generate free radicals that further oxidise lipoproteins: Macrophages have oxidative enzymes that can modify native LDL. a) NADPH Oxidase, for example superoxide O2-. b) Myeloperoxidase, for example, HOCl hypochlorous acid (bleach) from ROS + Cl-, HONOO Peroxynitrite. LDL gets oxidised, triggers macrophages which think it’s a bug and oxidise it further etc (positive feedback loop) O2-.: dot is a single unpaired electron, this is in NADPH Oxidase which oxidises anything in vicinity (usually LDL, which makes it more oxidised) HONOO is the same as HOCl but derived from hydrogen peroxide instead: both are free radicals and oxidise readily

Answer 3

II. Phagocytose modified lipoproteins, & become foam cells Macrophages accumulate modified LDLs to become enlarged foam cells.

Answer 4

IIIa. Express cytokine mediators that recruit monocytes Plaque macrophages express inflammatory factors that are involved in monocyte recruitment. 1) Cytokines – protein immune hormones that activate endothelial cell adhesion molecules Interleukin-1 upregulates vascular cell adhesion molecule 1 VCAM-1 VCAM-1 mediates tight monocyte binding (VCAM 1- vascular cell adhesion molecule 1, makes endothelial cells sticky, mediates tight monocyte binding (makes endothelial cells sticky from monocytes)) Atherosclerosis is reduced in mice without IL-1 or VCAM-1 2) Chemokines - small proteins chemoattractant to monocytes Monocyte chemotactic protein-1 (MCP-1) MCP-1 binds to a monocyte G-protein coupled receptor CCR2. Atherosclerosis is reduced in MCP-1 or CCR2 deficient mice. Both of these set up positive feedback loop / vicious cycle leading to self-perpetuating inflammation.

Answer 5

Express chemo-attractants & growth factors for VSMC “Wound healing” role of the macrophage in atherosclerosis - Macrophages release complementary protein growth factors that recruit VSMC and stimulate them to proliferate and deposit extracellular matrix 1) Platelet derived growth factor Vascular smooth muscle cell chemotaxis Vascular smooth muscle cell survival Vascular smooth muscle cell division (mitosis) 2) Transforming growth factor beta Increased collagen synthesis from smooth muscle cells Matrix deposition Normal medial vascular smooth muscle cells to Atherosclerotic: Normal= High Contractile filaments+ low matrix deposition genes Atherosclerotic= low contractile filaments+ high matrix deposition genes Conversion happens with PDGF + TGF-b Atheroscleoritc synthetic vascular smooth muscle cells are less good at contracting but better at making collagen than contractile cells

Answer 6

``` IIIc. Express Proteinases that degrade tissue Metalloproteinases (=MMPs): Family of ~28 homologous enzymes Activate each other by proteolysis. Degrade collagen. Catalytic mechanism based on Zn. ``` Effect of plaque erosion/rupture - Blood coagulation at the site of rupture may lead to an occlusive thrombus and cessation of blood flow. Where there are WBCs there isn’t collagen- macrophages eat a hole in the plaque and make it more rupture-prone At the site of plaque rupture, blood clots form because it’s full of pro-coagulant factors, very severe and rapid thrombus formation= complete blockage of blood flow= MI

Answer 7

``` Large soft eccentric lipid-rich necrotic core Increased VSMC apoptosis Reduced VSMC & collagen content Thin fibrous cap Infiltrate of activated macrophages expressing MMPs ```

Answer 8

OxLDL derived metabolites are toxic eg 7-keto-cholesterol is very toxic. Macrophage foam cells have protective systems that maintain survival in face of toxic lipid loading. Once overwhelmed, macrophages die via apoptosis. Release macrophage tissue factors and toxic lipids into the ‘central death zone’ called lipid necrotic core. Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood.

Answer 9

Transcription Factor Master regulator of inflammation Activated by numerous inflammatory stimuli: Scavenger receptors Toll-like receptors Cytokine receptors Switches on numerous inflammatory genes Matrix metalloproteinases Inducible nitric oxide synthase NF-kappa-B directs multiple genes in concert Multiple different inflammatory stimuli→ NF-κ-B→ Coregulation of multiple different inflammatory genes

Answer 10

Risk factors lead to activation of endothelial cells which become more leaky which lets LDL through and it binds to that specific place (see before), it gets readily oxidised and binds to the scavenger receptors that have mistaken it for a bug, which activates the macrophages and causes them to take up the oxidised LDL. This results in lipid accumulation in the macrophages as well as NFkB activation. Inflammation activation mode causes ROS (Reactive Oxgen Species) to be secreted which further oxidises LDL which causes the vicious cycle, cytokines which further activate the endothelial cells which make them sticky from monocytes which causes another vicious cycle, chemokines attract more monocytes which causes another vicious cycle, MMPs (matrix metal…. Proteins?) degrade the collage and make the fibrous cap thinner which makes it more likely to rupture Secretion of growth factors that regenerates more collagen that makes it thicker again (more stable and less rupture prone), can also redirect cholesterol through HDL back to the liver

Brainscape's Knowledge GenomeTM

Coronary heart disease and atherosclerosis Flashcards

Brainscape's Knowledge Genome^TM