126 Pathogenesis of Atherosclerosis

Question 1

Atherosclerosis

Answer 1

• •Disease of large muscular and elastic arteries
• •Begins in areas of non-laminar flow•
• •Subintimal lesion (initially)
• •A chronic inflammatory response (eventually involving all 3 layers)

Progression:

1. Fatty streak- happens near turbulent flow, like branches (at edge of lesion continues to spread)
2. Subendothelial macrophages migrate in
3. Foam cells –> necrotic core
4. Calcifications/cholesterol crystals –> fibrous cap

5+ atheroembolism, aneurysm formation

DRIVEN BY INFLAMMATION

Question 2

Atherosclerotic artery picture

Answer 2

Question 3

Atherosclerosis as inflammatory process

Answer 3

So why does cholesterol build up in atherosclerotic lesions when the LDL receptor and its regulation are designed not to accumulate it?

• Retention of LDL particles in the subintima for extended periods leads to their modification (oxidation, aggregation, etc.)
• Modified LDL resembles naturally-occurring DAMPs and PAMPs!
• This probably explains why we have an adaptive immune response and naturally-occurring antibodies against oxidized LDL
• Macrophage scavenger receptors

recognize modified LDL

(oxidized, aggregated, acylated)

and are NOT down-regulated.

• Scavenger receptors keep taking in cholesterol, even after is has accumulated to toxic levels.

But what about the “attempts to restore healthy tissue?”

• Macrophages come in to get rid of the altered (oxidized, denatured, foreign) lipoproteins. Their innate response induces genes that allow them to do so (scavenger receptors).
• As they begin to process the oxidized lipids, transcription factors are induced that stimulate synthesis of lipid and sterol metabolizing enzymes and reverse cholesterol transport.
• This works for a while, but as more scavenger receptors are synthesized and more oxidized LDL taken up, the macrophage catabolic activity may get overwhelmed.
• Foam cells represent macrophages that have lost the war. Under ideal conditions they would die by apoptosis and be cleared by other macrophages without inducing further inflammation.
• However, the metabolic conditions that exist in the center of a lesion inhibit the clearance of apoptotic foam cells by newly-recruited macrophages. The foam cells die by secondary necrosis and contribute to the necrotic core.
• This is a major reason that lesions progress and do not “heal.”

Question 4

Statin mechanism in atherosclerosis

Answer 4

• Statins inhibit HMGCoA-Reductase, the rate-limiting step in cholesterol biosynthesis. They lower serum cholesterol levels.
• However, the beneficial effects of statins on atherosclerotic heart disease were found to be proportionally much greater than their effect on lowering cholesterol levels.
• By inhibiting HMGCoA-reductase, statins also block the production of farnesyl- and geranylgeranyl pyrophosphate, which are precursors of cholesterol, but are required themselves for the activation of Ras proteins and other pro-inflammatory signals.
• Some statins actually bind to LFA-1 (CD11a/CD18), a leukocyte integrin critical for adhesion to endothelial cells, and lock it in the “off” position.

Question 5

C-Reactive Protein (CRP)

Answer 5

• An acute phase protein released by the liver in response to acute systemic inflammation
• Elevated in people with coronary artery disease, 4x increased in people with MI; elevated levels predict risk of first MI in “healthy” men.
• JUPITER study found that statin treatment that lowered CRP levels significantly protected against MI in people out of proportion to the reduction in LDL cholesterol.
• Most sensitive marker of unstable coronary artery atherosclerosis.