Lecture 28: Inflammation and Coronary Artery Disease

Question 1

What pathologies do atherosclerosis underly?

Answer 1

Coronary, cerebra, and peripheral vascular diseases

Question 2

What constitutional risk factors for atherosclerosis?

Answer 2

Genetics
Family History
Age
Male

Question 3

What modifiable risk factors for atherosclerosis?

Answer 3

Hypertension and Hyperlipidemia
Smoking
Diabetes
Vitamin Deficiencies
Obesity
Sedentary lifestyle
Inflammation

Question 4

What are some inflammatory markers?

Which one is primarily an emerging risk factor for CV disease? Why?

Answer 4

High sensitivity C-reactive protein (HSCRP)
Acute phase interleukins: IL-1, IL-6
Serum amyloid A

-HSCRP, as it promotes inflammatory response

Question 5

Where do most lesions happen in vasculature?

Answer 5

Where turbulence is more likely to happen

• openings of exiting vessels
• branch points
• posterior abdominal aorta

Question 6

What interleukins promote expression of P and E selectins on the endothelium?

Expression of these on the endothelium causes….

Answer 6

IL-1
TNF

-phenotypic change in the endothelium > which leads to proinflammatory and prothrombogenic effects

Question 7

What type of leukocyte does IL-8 attract?

Answer 7

Neutrophils

Question 8

How do lipids initiate vascular dysfunction?

What receptor on macrophages take up oxidized lipids?

Answer 8

oxidized LDLs are trapped in the mess of macrophages and leukocytes trying to fix the injury > macrophages get overwhelmed with oxidized LDLs and form foam cells > accumulation of foam cells = fatty streak

scavenger receptor CD 36
TLR-4

Question 9

What factors are important for smooth muscle cell proliferation?

What does smooth muscle cell proliferation result in?

Answer 9

PDGF
Fibroblast growth factor
TGF-α

thicker tunica intima

Question 10

What adaptive immunity cells play a role in smooth muscle proliferation?

Answer 10

Th1
Th17
B cells

Question 11

How are fatty streaks formed?

Answer 11

Expansion from foam cells and extracellular lipid

• recruited inflammatory and smooth muscles cells
• increased ECM

Question 12

How do atherosclerotic plaques form?

Answer 12

Fatty streak is covered with fibrous cap made of collagen

• center is nectroic
• surrounded by zone of inflammatory and smooth muscles cells

Question 13

What causes plaque instability?

What can be consequence of this?

Answer 13

Fibrous cap remodeling
-physical stresses/weakens can cause plaque to rupture

-Thrombus > erosion

Question 14

In new studies, what interleukin is being targeted in treating atherosclerosis?

Results/findings?

Answer 14

IL-1β (CANTOS study)

-Unfortunately, canakinumab was not approved due to no significant reduction in mortality rate.

Question 15

Give an overview on the events that cause atherosclerosis (response to injury model)

Answer 15

Dz like HTN damages endothelial linging > adhesion of immune cells to try and “fix” problem > chronic inflammation, foam cells, fat entrapment > plaque buildup > turbulent flow

Question 16

How do macrophages make the problem worse?

Answer 16

activated macrophages recruit more leukocytes to area > leukocytes produce inflammatory markers > P selectins bind leukocytes to bind in the endothelium > increased integrin affinity causing penetration into tunica intima

Question 17

What are inflammatory exudates?

Answer 17

Swelling causes recruitment of clotting proteins (initiate cascade), complement (destroy pathogens), kinins (vasodilator), fibronolytic proteins (degrades clot after healing) to area making it more crowded

Question 18

How do inflammasomes play a role in the process?

Answer 18

Activated macrophages > foam cells > cholesterol crystals form in foam cells that activate inflammasomes > produce IL-1 and IL-18 (proinflammatory, which increases the inflammatory cascade even more)

Question 19

How do neutrophils play a role in the process?

Answer 19

Use NETs against cholesterol crystals that serve as scaffold for platelet aggregation on the site
Elastase release > breaks down elasticity of the endothelium, making it stiffer

Question 20

Describe the reciprocal cycle of inflammatory responses between neutrophils and macrophages

Answer 20

IL-1 activates Neutrophils use NETs which releases DAMPS

Macrophages recognize DAMPs and releases IL-1

Question 21

What causes lipid reactive T and B cells and what is the consequence of this?

Answer 21

Endothelial lipoproteins have changed phenotype from “self”, so T cells and B cells attack them and become “autoreactive” since these weren’t the proteins they were educated with