Describe the three regions of the vasculature (tunica): describe which layer it is and what cells are present, and any extra that makes sense
- the initima: inner region; endothelial cells
- the media: middle region; smooth muscle cells (SMCs)
- the adventita: peripheral region; fibroblasts, adipocyotes, and ICs; the vaso vasorum is the network of small blood vessels that irrigate bigger blood vessels
How do Ly6Clow monocytes become this phenotype, what is the role of this monocyte, what chemokine directs its movement?
Ly6Chigh monocyte –> NR4A1-induced transition into a Ly6Clow monocyte –> CX3CL1 recruite this monocyte to the blood where they patrol the vasculature and clean up debris and dead endothelial cells –> if recruited to damaged tissues, they play reparative roles
For the following particles describe how much cholesterol they contain, how much TGA they contain, and their function: chylomicron, VLDL, LDL, and HDL (for LDL and HDL also describe their apoprotein)
chylomicron
- low cholersterol
- high TGA
- transport of dietary (exogenous) TGA from gut to periphery
VLDL
- low cholersterol
- high TGA
- transport of TGA synthesiszed in the liver (endogenous) to periphery
LDL
- high cholesterol
- low TGA
- transport of cholesterol and fat-soluble vitamins to periphery
- apoprotein: B100
HDL
- high cholesterol
- low TGA
- reverse transport of cholesterol from periphery to the liver
- apoprotein: A and E
What is athersclerosis?
a progressive thickening and hardening of the walls of medium-sized and large arteries as a result of fat deposits on their inner lining
Describe the sequence of atherscelorisis progression: nomenclature and main histology
- initial lesion: macrophage infiltration, isolated foam cells
- fatty streak: mainly intacellular lipid accumulation
- intermediate lesion: small extracellular lipid pools in initima
- atheroma: core of extracellular lipid
- fibroatheroma: single or multiple lipid cores
- complicated lesion: hemmorhage and thrombosis (i.e breaks)
Describe plaque states during atherosclereosis progression
earlth atheroma –> stabilized plaque (small lipid pool, thin fibrous cap) OR vulnerable plaque (thin fibrous cap, large lipid pool, many inflammatory cells)
vulnerable plaque –> stabalized cap OR thrombosis (ruptures plaque)
thrombosis –> healed reptured plaque (reabsorbed) OR blocks small arteries (in brain - stroke; in heart - myocardial infarction)
In athersclerosis, describe endothelial activation and monocyte recruitment (include comorbidities)
hypertension, dyslipidemia, smoking, diabetes –> high [LDL] –> LDL enters intima –> oxidation of LDL (oxLDL = DAMP) –> oxLDL activates LOX-1 activating endothelial cells (opening of tight junctions) –> activated endothelial cells secrete MCP-1 and CCL2 to recruit monocytes and increase monocyte adhesion molecules –> monocyte enters the intima where GM-CSF and M-CSF cause the monocyte to diffeerntiate into a macrophage
Describe how macrophages handle LDL and HDL
LDL
- uptake of LDL cholesterol occurs via the LDLR, pinocytosis and phagocytosis
- oxidation of LDL enhances internalization via a number of receptors, including CD36, SRAs, LOX, and TLRs (e.g. TLR4)
HDL
- cholesterol can be cleared using two main pathways: 1o = transport of cholesterol to the pm; 2o efflux of cholesterol to lipid-poor apolipoproteins or HDL
- 2o: the ApoA/ApoE disks and mature HDL cholesterol efflux via ABCA1, ABCG1, SR-B1 (CD36) or via diffusion –> exogenous lipid-free ApoA or endogenous ApoE interact with ABCA1 to stimulate the efflux of cholesterol to form nascent HDL particles (e.g. ApoA or ApoE containing phospholipid disks)
How is the control of cholesterol uptake and efflux deregulated in athersclerosis?
- expression of SRs increases –> increased uptake of oxLDL (enhanced cholesterol uptake)
- expression of cholesterol transporters ABCA1 and ABCG1 is suppressed –> diminished cholesterol efflux + promotes cholesterol deposition in macrophages (diminished cholesterol efflux)
What are foam cells?
macrophages all filled with lipids, especially cholesterol
Describe how plaques form in athersclerosis
- migration of SMCs, from the media to the intima, the proliferation of resident initial SMCs and media-derived SMCs, and the heightened synthesis of ECM macromolecules such as collagen, elastin, and proteoglycans –> lesions
- plaque macrophages and SMCs can die in advancing lesions
- extracellular lipid derived from dead and dying cells can accumulate in the central relgion of a plaque –> “lipid/nectroic core”
- advancing plaques also contain cholesterol crystals and microvessles
The balance of pro-inflammatory and anti-inflammatory processes controls the resolution of the lipid-driven inflammation in athersclerotic lesions. Describe what happened if the balance shifts towards pro-inflammatory state vs the anti-inflammatiory state.
pro-inflammatory
- resolving mechanisms fail
- pyroptosis (mediated by inflammasome activation) or necroptosis can ensue
- these pro-inflammatory forms of cell death further promote inflammation and generation of a nectrotic/lipid core
anti-inflammatory
- pro-resolving mediators, apoptosis, autophagy-associated cell death, and cholesterol efflux from the lesions are favoured
- efferocytosis of dead cells –> resolution
- these process promote the formation of a stable plaque with a small necrotic/lipid core
What promotes a vulnerable plaque to stabalize?
behaviour changes + low LDL drugs
Recall: what are the lipid-mediator class switch from inflammation to resolution effects? i.e. what lipid-mediated anti-inflammatory processes occur
- feedback on lipid mediator synthesis
- less oxidative stress
- more efferocytosis
- less oxLDL uptake
- more collage production
- fewer proteases
Describe pro-inflammatory feedback in atherscelerosis
- uptake of modified LDL partciles such as oxLDL through SRs –> intracellular accumulation of cholesterol crystals that can activate the inflammasome –> IL-1B secretion
- components of modified LDL can also ligate TLRs, triggering an intracellular signaling cascade that –> expression of a series of genes encoding pro-inflammaotry molecules (including cytokines, chemokines, eicosanoids, proteinases, oxidases, and co-stim molecules)
- ultimately, old foam cells die via apoptotic or non-apoptotic forms of regulated cell death
- pyropoptosis and necroptosis are pro-inflammaotry via release of pro-inflammaotry mediators
- unless foam cells and the macrophages that have consumed them return to the blood, all cholsteryl-ester-loaded cells contribute to the generation and growth of a pro-inflammatory necrotic lipid core (if no one cleans up the apoptotic debris –> bodies may repture –> inflammation)
Describe the conditions that would allow for deficient efferocytosis
increase of don’t-eat-me signals
- inappropriate expression of CD47 on apoptotic cells –> CD47-SIRPa interaction
decrease of eat me signals
- cleavage of MERTK by the protease ADAM17 on the macrophage
- decrease surface levels of calreticulin on apoptotic cells
What protein from oxLDL particles get taken in, processed and presented by APCs to T cells
ApoB100
Describe how plaque rupture occurs and what the outcomes of rupture are
increase plaque fragility can –> rupture and release of the necrotic core to the lumen of the vasculature –> quickly surrounded by platelets and coagulation factors forming a thrombus/clot
thrombus can become associated to the endothelium where it is assimilated –> narrowing of blood vessels
thrombus can be released to the blood stream where it can –> blockade of narrow (or narrowed) blood vessels –> MI or stroke
What is myocardial infarction?
ventricle of the heart becomes noxic –> cell death
describe cardiac remodelling vs adverse cardiac remodelling
cardiac remodelling –> scar formation, fibrosis (holds dead cells in place)
adverse cardiac remodelling –> ventricle becomes saggy –> heart failure
What type of macrophages promote repair and which cells do their pro-regenerative factors affect?
Gata6+ macrophage –> pro-regenerative factors –> cardiomyocytes, endothelial cells, SMCs, fibroblasts
what are the repair functions of cardiac macrophages?
- Treg induction
- fibrosis
- repair angiogenesis
Describe how MI can break tolerance of cardiac Ags
- there is a consititutive presentation of myocardial Ags in the context of MHC-II in s.s in myocardium
- resting/tolerogenic APCs prevent CD4+ T-cell activation and subsequent induction of autoimmunity in heart draining lymph nodes
- activation of APCs, for example, by PRR ligands released from injured myocardium or expression of pro-inflammatory cytokines –> increase co-stim molecules –> transitly breaks tolerance against myocardial Ags
What determined a good outcome of inflammation in the context of antherscelerosis?
- efficient efferocytosis
- switch to anti-inflammatory mediators
- efflux of cholesterol and inflammatory cells
- lack of autoreactive responses
- angiogenesis and moderative fibrosis
