Atherosclerosis 1 Flashcards
7 pathophysiological “players” (cells and molecules) in the formation of atherosclerosis?
Endothelial cell dysfunction / inflammation.
Oxidized lipoproteins.
Macrophages (and monocytes, foam cells, T cells)
Paracrine signaling molecules
Smooth muscle cells -> matrix deposition.
Matrix proteases -> plaque rupture.
Platelets -> thrombosis formation.
6-7 main risk factors for atherosclerosis?
Age and gender Lipoprotein disorders Hypertension Diabetes Family history of premature CHD Smoking
Why do we think atherosclerosis preferentially affects some areas of the circulation?
It affects areas with large amounts of shear stress, which induces endothelial changes / turbulence that help monocytes/macrophages adhere.
What’s the first step in initiated atherosclerosis?
Endothelial dysfunction
What are 8 factors that contribute to endothelial dysfunction?
Shear stress (HTN!) Oxidant stress (smoking!) Diet and physical inactivity Excess and modified lipoproteins Glycation (diabetes) Adipocytokines Infection (HSV, CMV, chlamydia, gut flora?) Genetic susceptibility
What’s the first visible atherosclerotic lesion?
“fatty streaks”
What adhesion molecules are upregulated in endothelial dysfunction?
VCAM-1, ICAM-1, E-selectin
One notable chemokine for leukocytes (esp. macrophages) in endothelial dysfunction? (and its receptor?)
MCP-1 (which binds CCR2)
What cytokine activates monocytes recruited to dysfunctional endothelium?
M-CSF promotes maturation to macrophages.
Why do macrophages think pathogens are present in pre-atherosclerotic lesions?
Oxidized lipids resemble lipids found on some pathogenic bacteria…
Why do mostly only remnant particles like LDL, and Lp(a) get into pre-atherosclerotic lesions?
They’re the only particles that are small enough.
How do the lipids in the pre-atherosclerotic lesions get oxidized?
Macrophages produce lots of reactive oxygen species that oxidize the lipids.
What protein to macrophages use to internalize lipoproteins? Will they stop internalizing them if the patient has no functional LDLR?
They use “scavenger receptors” - which are also used for phagocytosis of bacteria.
They do have LDLR, but they take up acetylated/oxidized LDL with scavenger receptors.
Do T cells play a role in atherosclerosis?
Yeah. Th1 and Th17 are problematic. Th2 might be protective. Tregs are definitely protective.
(But, they aren’t strictly necessary for atherosclerosis.)
How do Th1 cells and macrophages have a positive feedback loop in atherosclerosis?
Th1 cells make IFN gamma to activate macrophages.
Macrophages make IL-12 to promote Th1 differentiation.
