Inflammation in CVD Flashcards
How does intima inflammation increase atherosclerosis development?
Inflammation of the intima includes increased production of pro-inflammatory chemokines, including M-CSF (macrophage colony stimulating factor, AKA CSF-1), MCP-1 (monocyte chemotactic protein, AKA CCL2) lead to increased monocyte infiltration through upregulation of VCAM-1 expression and increasing vascular permeability.
Thus inflammation of the endothelium not only aids in the development of foam cells but also in the intima infiltration of lipoproteins and subsequent production of oxLDLs.
How was the importance of M-CSF shown in a mouse model?
LDLR -/- mice deficient in MCP-1 were shown to be far less prone to atherogenesis (Gu et al, 1998). The red stained plaques are notably absent in their vasculature.
The size of atheromas was similarly reduced in LRLR -/- mice by the op mutation; a null mutation in the M-CSF gene.
What is the effect of AT2 on athersclerosis?
Angiotensin 2 signalling through the AT1 receptor promotes inflammation and stimulates fibrous cap formation by triggering smooth muscle cell proliferation via the Smad, CTGF and TGF-β signalling pathways.
How does inflammation reduce plaque stability?
The inflammatory response leads to increased expression of collagen degrading enzymes including the SMC and macrophage secreted MMPs (especially MMP1, AKA interstitial collagenase).
Furthermore, inflammation increases SMC IFN-γ signalling leading to decreased collagen and fibronectin production.
What receptors are able to take up LDLs, and what is different about one of them?
There are seven or eight different lipoprotein receptors characterised, including VLDLRs and the highly unspecific CD36 (also able to take up FFAs). LDLR, SR-A and SR-B are largely responsible for LDL and oxLDL uptake respectively. Acetyl LDLRs are also able to take up acetylated LDLs.
The scavenger receptors lack the negative feedback mechanism that prevents LDLRs from causing foam cell formation. These are induced by inflammatory cytokines in macrophages and SMCs.
In what ways can inflammation dysregulate cholesterol homeostasis?
VSMC/LDL Pathway
Increased Cholesterol Synthesis
Inhibition of Cholesterol Efflux
What is the VSMC/LDL Pathway and what does it have to do with inflammation?
Recent research has shown that 45% of the foam cells in the lipid core did not originate as macrophages, but vascular SMCs that have significantly altered their phenotype.
These also take up the oxLDLs via the LDLR pathway which is possible because inflammatory signalling via TNF-α and IL-1β prevents the downregulation of LDLRs in cholesterol homeostasis.
How does inflammation increase cholesterol synthesis?
Inflammatory signalling, including through IL-1β, increases HMG CoA Reductase expression by interfering with SCAP-SREBP mediated downregulation.
How does inflammation inhibit cholesterol efflux?
Via Dysregulation of PPAR ABCA1 Upregulation.
PPARα and γ are responsible for activating the LXR-RXR transcription factors, via heterodimerisation with RXR, leading to increased ABCA1 transcription and thus efflux.
The PPAR nuclear receptors are stimulated by PUFAs, but are inhibited by assorted cytokines including IL-1β. This reduces ABCA1 expression and hence cholesterol efflux.
How can inflammatory inhibition of cholesterol efflux be targeted in therapy?
This is a therapy opportunity, with PPARα being activated by Bezafibrate and PPARγ being activated by Troglitazone, which have been shown to have beneficial effects on blood TG and HDL levels – although does affect insulin sensitivity.
What is the large scale effect on lipids of inflammation.
Lipids are Redistributed to an Intracellular Location in Inflammation.
How does inflammation redistribute lipids to an intracellular location?
Upregulation of LDLRs, SR-A, and CD36 inflammation increases LDL (and oxLDL) uptake.
By increasing HMG CoA Reductase expression, it increases cholesterol synthesis.
By downregulating ABCA1 expression cholesterol efflux is reduced.
What is the impact of lipid redistribution for therapy?
This can lead to confusing results of blood tests, which can show low plasma cholesterol in those with increased CVD risk due to the high level of inflammation.
This can even lead to an apparent negative correlation between blood cholesterol and CVD mortality in inflamed patients.
How can inflammation be used to monitor CVD risk?
C-Reactive Protein (CRP) is an important inflammation biomarker correlating with risk and associating with adverse events.
The reduction in CRP caused by statins is also beneficial to patients, but in patients with chronic inflammation, especially those with CKD, the dose must be much higher and longer-term.
3 with high risk and intermediates with moderate risk.
How can the effect of inflammation on CVD be exploited?
General anti-inflammatory and lipid lowering treatments have been shown to be effective as preventative treatments.
