Lecture 37: Pathogenesis of Atherosclerosis

Question 1

What is atherosclerosis?

Answer 1

Arterial INTIMAL disease of large-medium arteries characterized by lipid accumulation and inflammation
Space between endothelium and smooth muscle cell layer
Driven by lipid antigens and lipids

Question 2

What is the time course of atherosclerosis?

Answer 2

Chronic Progressive Disease
Acute clinical manifestations
20 yo can have atherosclerosis present but doesn’t present until later on in life

Question 3

What is the natural history of atherosclerosis?

Answer 3

1. Fatty streaks
2. Lipid rich
3. Internal rupture that leads to accumulation of WBCs and RBCs
4. Formation of calcified shell over lipid rich plaque
5. formation of a SCAR, fibrous cap, calcified plaque
6. Vulnerable to rupture if plaque is thin
7. Rupture of fibrous cap
8. After rupture, you get thrombus (platelets and fibrin come by to clot the rupture0
9. Myocardial infarction if platelet and fibrin occludes the artery
10. Obstructive where lipid/fibrin/SMC accumulation is so much that it obstructs the arteries

Question 4

What is the first indication of atherosclerosis?

Answer 4

Fatty streaks

Question 5

What are the clinical consequences of atherosclerosis?

Answer 5

1. Coronary heart disease
2. MI
3. sudden death/heart failure
4. Cerebro vascular disease like stroke and vascular dementia
5. Peripheral artery disease
6. Renal artery stenosis

Question 6

What are the steps towards thrombosis and plaque rupture in atherosclerosis?

Answer 6

1. Enothelial inflammation and dysfunction
2. Oxidized modified lipoproteins
3. Monocytes, macrophages, foam cells, T-cells
4. Paracrine and endocrine signals
5. Smooth muscle cells (ECM)
6. Matrix proteolysis (MMPs/TIMPs) (plaque rupture
7. Platelets driven thrombosis

Question 7

How do monocytes contribute to atherosclerosis?

Answer 7

They differentiate into inflammatory macrophage once it travels to activated endothelium
Macrophages take up modified lipoproteins to form foam cells

Question 8

How do SMCs contribute to atherosclerosis?

Answer 8

Migrate into intimal space and secrete ECM
Contributes to the BULK of the atherosclerotic lesion
Provides framework for cellular interactions
SMCs form the FIBROUS cap over the inflammatory sub-endothelial intimal lesion
As plaque evolves, it outgrows nutrient supply and induces neovascularization of the plaque from advential surface of disease vessel

Question 9

How does MMPs and TIMPs contribute to atherosclerosis?

Answer 9

MMPs degrade the protective cap
The TIMPs are downregulated and thus cant inhibit MMP activity
Degradation of cap = more likely to rupture

Question 10

What are the factors that leads to endothelial injury and dysfunction?

Answer 10

1. Shear stress (HTN)
2. Oxidant stress (smoking)
3. diet and physical inactivity
4. excess and modified lipoproteins
5. diabetes (glycation)
6. Adipocytokines (endocrine and paracrine)
7. Infection (CMV, HSV, Chlamydia, gut flora)
8. Genes can lead to injury susceptibility

Question 11

What are the consequences of mechanosignal transduction and hypercholesterolemia for the endothelium?

Answer 11

They induce endothelial cell dysfunction that promotes inflammation and fatty streak formation
Occurs in the intimal stage
Turbulent flow is more likely during a state of HTN

Question 12

What does turbulent flow do the endothelium?

Answer 12

Activates ICAM-1 and VCAM receptors
Leads to growth factors and chemokine secretion
Recruits monocytes into the vascular wall (via selectins and integrin ligands)
Monocytes then differentiate into inflamed macrophages that will turn into foam cells once it takes up oxidized LDL

Question 13

What are the hallmarks of dysfunctional endothelium?

Answer 13

1. increase of superoxide and peroxynitrite
2. Increased adhesion molecules and cytokines
3. reduced NO and prostacyclin
4. Reduced endothelium dependent vasodilation

Question 14

What are the endothelial adhesion molecules?

Answer 14

1. VCAM-1
2. ICAM-1
3. E-selectin

Question 15

What is responsible for chemotaxis of monocytes?

Answer 15

1. CCR2/MCP-1 receptor/chemokine
2. CX3CR1/CX3CL1
3. CCR5/CCL5

Question 16

What is the significance of lipid entry into vascular wall?

Answer 16

As VLDL and LDL migrates through endothelium
Gets MODIFIED
-oxidized by iNOS, NADPH, 15-LO
-or acetylated
Activates macrophages which lead to inflammation
Oxidation/aggregation of modified lipids

Question 17

What is the first step in atherosclerosis?

Answer 17

1. infiltration of LDL from arterial lumen into the arterial wall and its entrapment therein
2. Modification of LDL through
   i. oxidation
   ii. chemical derivation
3. Scavenger receptors on arterial wall macrophages recognized MOFIDIFIED LDL and internalize oxidized LDL through engulfment
4. Uptake of LDL by macrophages leads to foam cell formation, the HALLMARK of the atherosclerotic lesion

Question 18

How do you form the fatty streak?

Answer 18

Fatty streak = cholesterol rich foam cells and T cells
You form fatty streak when you get macrophages engulfing activated LDL (acetylated or oxidized)
T-cells are prominent in fatty streaks as wells

Question 19

What is the hallmark of the atherosclerotic lesion?

Answer 19

Foam cell formation

Question 20

What is scary about the scavenger receptors in relation to LDL uptake?

Answer 20

Molecules that induce atherosclerosis

Example: LDL, VLDL (especially beta-VLDL)

Question 21

What is the importance of LDL modification in foam cell formation?

Answer 21

Native LDLreceptor is downregulated and doesn’t get taken up fast
However, modified LDL through
i. acetylation
ii. Oxidation
Get taken up much faster by scavenger receptors on macrophages which are NOT downregualted
Examples of scavenger receptors that take up acetylated and oxidated LDL:
i. SRA
ii. CD36

Question 22

What is the significance of foam cell formation?

Answer 22

Foam cells are the cellular lipid reservoir responsible for chronically driving inflammation while accelerating atherosclerosis progression

Question 23

What are the athrogenic actions of oxidized LDL and oxidized phospholipids?

Answer 23

1. Induce monocyte/T-cell binding to endothelial cells
2. Increase tissue factor activity
3. Increase expression of MCSF and MCP-1
4. Increase expression of VCAM-1
5. Induce Fas-mediated apoptosis
6. Alter NO release or function
7. Increase collagen synthesis of SMCs
8. Activate nuclear factor kappabeta
9. Induce expression of type 1 metalloproteinase
10. Activate gene expression for PPARgamma, CD36 and ABCA1

Question 24

How are fatty streaks induced?

Answer 24

1. Hypercholesterolemia and mechanosignal transduction in EC
2. Adherence of monocytes and Tcells to arterial endothelium
3. Monocyte and T cell transendothelial migration
4. Phenotypic modulation of scavenger receptor expression and modified LDL
5. Fatty streak rich in cholesterol-rich foam cells and T cells

Question 25

How do LDLs get modified?

Answer 25

Inflammatory enzymes are present in endothelium | Enzymes like myeloperoxidase will modify LDL (modified lipids)

Question 26

What is the role of T lymphocytes in the atherosclerotic lesions?

Answer 26

Are present in atherosclerotic lesions CD3, CD4 and AbTCR T cells are prominent in lesiosn Moderate numbers of CD8 and some NK cells TH1 cells are dominant, expressing high levels of IFN

Question 27

What is the role of TH1 lymphcytes in atherosclerosis?

Answer 27

Lesion initiation, progression and instability plaque rupture Releases IFNgamma to stimulate macrophages Macrophages then release IL-12 to produce TH1 cells Positive feedback

Question 28

What are the proposed roles of HDL on atherosclerosis?

Answer 28

Anti-athrogenic May inhibit oxidation of LDL Reverse cholesterol transport

Question 29

What is the role of MPO in atheroscler?

Answer 29

Oxidizes LDL to modify it

Question 30

What is responsible for lesion progression?

Answer 30

1. smooth muscle cells 2. macrophages 3. Endothelial cells 4. fibrous cap 5. T-cells

Question 31

How do macrophages contribute to intermediate athero lesions?

Answer 31

Macrophages die and release lipids into necrotic core | They also secrete growth factors that lead to cell proliferation and metalloproteinases

Question 32

What role do smooth muscle cells in the progression of the intermediate lesion?

Answer 32

Migrate and replicate to increase bulk of lesion Secrete connective tissue matrix proteins Secretes chemokines, cytokines and metalloproteinases that modulate dynamic remodeling of the lesion Leads to: i. switch from contractile to synthetic phenotype ii. migrate into the neointima iii. undergo limited proliferation iv. secrete large amount of matrix v. secrete cytokines, chemokines, growth factors and inflammatory prostaglandins vi. migrate to subendothelial location at site of greatest hemodynamic stress vii. encapsulates lesion by fibrous cap viii. synthetic smooth muscle cells express scavenger receptors and can take up oxidized lipids to form subpopulation of non-macrophage foam cells

Question 33

What is the significance of calcification in atherosclerotic lesions?

Answer 33

Useful screening test for prognosis | Calcium doesn’t do shit but is just formed

Question 34

What is the role of T cells in progression of the intermediate lesion?

Answer 34

TH1 cells increase macrophage inflammation and increase metalloproteinases that degrade matrix and fibrous cap -Reduces SmC proliferation

Question 35

What is Glagov’s coronary remodeling hypothesis?

Answer 35

Plaque development is extraluminal until lesion occupies 40% of area Only then does the lumen begin to shrink Starts with compensatory expansion to maintain constant lumen (minimal/moderate CAD) At severe CAD, compensatory expansion of the lumen is overcome and lumen narrows

Question 36

What are the key characteristics of the intermediate lesion?

Answer 36

Subclinical and asymptomatic Stage at which you are at risk for plaque rupture Shoulder region Less T-lymphocytes and more foam cells

Question 37

What are the characteristics of a stable lesion?

Answer 37

``` Smooth muscle cells Fibrotic TGF-beta Thick cap around the lipid core (won’t release Lipids to lumen) ```

Question 38

What are the characteristics of an unstable lesion?

Answer 38

Foam cells predominate IFN-gamma IL-18 IL-12 present

Question 39

What are the characteristics of a “vulnerable plaque”?

Answer 39

``` Thin fibrous cap Low VSMC count Large lipid pool High oxLDL content and high macrophage count High T cell count Thin shoulder region Greater neovascularization Not related to degree of vessel stenosis ```

Question 40

What are the overlapping mechanisms that may contribute to plaque instability?

Answer 40

1. thrombus formation 2. impaired endothelial function 3. Inflammation 4. Impaired plaque stabilization (just having high BP one of these days)

Question 41

How does the thombus form?

Answer 41

If the plaque ruptures Platelets will aggregate at place of the plaque lesion

Question 42

What are the characteristic of obstructive disease?

Answer 42

Resolution of the thrombus then leads to obstructed artery | Healed prior plaque rupture is often silent

Question 43

What may leads to the regression of atherosclerosis?

Answer 43

1. Lower LDL-atherogenic lipoproteins (decrease influx) 2. Increased HDL or HDL function (lipid efflux) 3. Regulation of macrophages and plaque inflammation (macrophage egress)

Question 44

What is atherosclerosis?

Answer 44

A. A mechanical disorder characterized by endothelial injury and hemodynamic stress B. A lipoprotein disorder characterized by excess atherogenic lipoproteins, their modification and uptake into macrophage-foam cells C. An inflammatory disorder of monocytes, macrophages, T cells and others D. A vascular SMC disorder of migration, matrix secretion and fibrous cap E. A thrombotic disorder of endothelial injury, tissue factor expression and platelet activation