Atherosclerosis 1 Flashcards
(38 cards)
What is atherosclerosis?
-arterial intimal disease of large-medium arteries characterized by lipid accumulation and inflammation in the “neo-intimal” space
T/F: Atherosclerosis is as acute of a disease as its clinical manifestations are.
- false; it is a chronic progressive disease but with acute clinical manifestations
- substantion accumulation of atherosclerotic plaque prior to any arterial obstruction and often with sudden rupture leading to platelet-rich thrombotic occlusion with acute MI/acute coronary syndrome (ACS) as initial presentation
Why is atherosclerosis a systemic disease?
- it has wide areas of clinical consequences
1. CHD, MI, sudden death, heart failure
2. cerebro-vascular diseases, stroke, vascular dementia
3. peripheral artery disease, renal artery stenosis
Clinical risk factors for atherosclerosis
- age and gender
- lipoprotein disorders
- HTN
- DM
- family history of premature CHD
- smoking
_____________ is one of the earliest defects in the initiation of atherosclerosis.
- endothelial injury and dysfunction
- many risk factors and lifestyle behaviors (and genes) promote endothelial injury. Shear stress (HTN), circulating hormones and vasoactive pepties, as well as local cytokines, modified (oxidized, glycated) lipids and proteins mediate this process.
Ultimately, what is the underlying root of atherosclerosis?
-high lipids; if these are low enough, no atherosclerosis develops
Mechanosignal transduction and hypercholesterolemia induce endothelial cell dysfunction that promotes _______ and ________ formation.
- inflammation
- fatty stream formation
Describe the process of recruitment of monocytes into the vascular wall.
- activated endothelium expresses receptors that attack leukocytes and facilitate rolling, adhesion, and migration to the subendothelial space
- selectins for rolling and VCAM,ICAM for adhesion annd MCP, oxLDL, for migration
Molecules involved in monoyte binding and recruitment to the arterial intima
- endothelial adhesion mlcs: VCAM1, ICAM1, E-selectin
- chemotaxis of monocytes into subendothelium from endothelial cells and T cells: CCR2/MCP-1, CCR5, etc
The first step in atherosclerosis in the ___________. The second step is the _____________. What does this second step allow for? Hint: its the hallmark of the atherosclerotic lesion.
- filtration of LDL from arterial lumen into arterial wall and its entrapment here
- modification of LDL either by oxidation or chemical derivation
- scavenger receptors on arterial wall macrophages recognize modified LDL and internalize it leading to cholesterol accumulation and ultimately to foam cell formation
T/F: Foam cells are dynamic.
-true: can migrate, apoptosis or stay
Difference in LDLR regulation in macrophage scavenger receptors. Is the native LDLR this way as well?
- they are not down regulated with the intracellular accumulation of cholesterol, as other cells in the liver are
- native LDLR is downregulated normal, the others are not.
What are fatty streaks composed of?
-rich in cholesterol-rich foam cells and T cells
Modified lipoproteins, in particular LDL, play a unique role in atherosclerosis by promoting ________ while also directly contributing to ________.
- inflammation
- foam cell formation
Role of T Lymphocytes in atherosclerotic lesions
- CD3. CD4 aBTCR+ T cells prominent in lesions, with less CD* and NK cells
- Th1 cells dominant: express high levels of IFNy. IL12, and TNFa
Do Th1 or Th2 T cells dominate in atherosclerotic lesions?
- Th1: secrete IFNy, IL12, TNFa
- only low amts of Th2 cytokines IL4,5,10 are detected
Actions of IL12 and IFNy in atherosclerotic lesions
- Macrophages secrete IL12 which drives formation of Th1 cells
- Th1 cells release IFNy which stimulate macrophages and cause even more IL12 release
- IFNy also drives the migration of SMCs
Did knockout experiments shown IL-10 to be good or bad?
- good; knocking out IL10 caused worse atherosclerosis
- it is an anti-inflammatoy cytokine shown to protect against experimental atherosclerosis
Differences in macrophage and T cell importance in atherosclerosis
- Monocytes/macrophages are essential for lesion initiation and progression
- Lymphocytes are more complex and are not obligatory for lesion initiation or progression if in the presence of hypercholesterolemia. Howevere, Th1 lymphocytes can exert a new pro-thrombotic effect unless atherogenic pressures
In what ways are modified LDL particles similar to “bacterial infections”?
- recognized as foreign and thus spur huge immune cell reactions
- endothelial cells release cytokines and ICAMs to recruit more macrophages
4 anti-atherogenic properties of HDL
- reverse C transport from subendothelial space foam cells back into lumen where cleared by liver as bile
- suppresses inflammatory pathways in endothelial cells, like adhesion mlcs
- inhibits LDL modification and oxidation in subendo space
- upregulates NO and PGI2 and suppresses thrombosis
Macrophage foam cells, T cells, SMCs and endothelial cells release chemokines, cytokines, and growth factors that play a coordinated role in lesion progression. How?
- alter SMC phenotype to synthetic and migratory
- macrophages die and release lipids into necrotic core
- endothelial cells die and slough off which can form thrombosis
- fibrous cap forms but may rupture and also form thrombi
What is responsible for the bulk increase of the lesion?
-medial SMC migration and proliferation with matrix secretion
Discuss the change in phenotype of medial SMCs in atherosclerosis
-change from contractile quiescent form to synthetic and inflammatory form that migrates to neointima, undergoes limited proliferation, and secretes many cytokines and ECM in tissue remodeling/fibrous cap
