Human aspects of cardiovascular and renal pharmacology: Atherosclerosis/ hypolipidaemic agents

Question 1

Atherosclerosis- definition

Answer 1

Disease affecting the intima of large & medium sized arteries
Caused by formation of complex plaques (focal thickenings of the intima)- which are deposits of fibrous tissues & lipids

Question 2

Arteriosclerosis- definition

Answer 2

Loss of elasticity & physical hardening of the arterial wall from any cause
Often accompanied by calcification of the wall

Question 3

Atheroma- definition

Answer 3

Accumulation of a soft, flaky, yellowish material at the centre of large plaques. Composed of macrophages nearest the lumen of the artery. Process is progressive, effects cumulative.
Can progress to more complex lesions with underlying areas of cholesterol crystals, & calcification in more advanced stages

Question 4

Complications of atherosclerosis

Answer 4

Atheroma leads to stenosis & compromises the arterial supply.
Myocardial ischaemia, leading to angina/ ischaemic heart diseaes
Parts of the atheromatous tissue can break off/ form good substrate for clot formation -> Myocardial infarction
Chronic under-perfusion of myocardium -> congestive heart failure
Dysrhythmias if conductive tissue subject to infarction/ ischaemia

Question 5

Treatment of atherosclerosis

Answer 5

Can try to prevent development of atherosclerosis using hypolipidaemic drugs.
Reducing plasma lipids can be beneficial in reducing incidence of serious events arising from atherosclerosis.
Excessive LDL especially predispose to atheroma.

Question 6

Structure of lipoproteins

Answer 6

‘Lipo’- cholesterol intercalated in a phospholipid membrane and cholesteryl esters
‘Protein’- apolipoproteins associated with the lipid particle

Question 7

LDL

Answer 7

Has apolipoprotein B (ApoB)
Excessive levels predispose to atheroma
Involved in delivering cholesterol needed to synthesise bile salts to the liver: Binds to receptors on hepatocyte plasma membrane, LDL-receptor complex taken up by receptor-mediated endocytosis.

Question 8

HDL

Answer 8

Has apolipoprotein A (ApoA) - type proteins (mainly)
Seem to be protective against atheroma development

Mediates reverse cholesterol transport.
Rate limiting step in HDL formation = removal of cellular phospholipids & cholesterol by ApoA of lipid-poor HDL from peripheral cells and tissues. Controlled by ABCA1.

Question 9

SREB/SCAP pathway:

Role of SCAP

Answer 9

Transports precursor SREBPs from ER -> golgi.

Allows site 1 cleavage to be activated when cell is deprived of sterols. Inhibits this process when sterols are abundant

Question 10

SREB/SCAP pathway:

Role of S1P

Answer 10

Located at the golgi
First cleavage (site 1 cleavage): cleaves SREBPs into 2 halves, both of which remain membrane bound.
Cleaves in luminal loop between 2 membrane-spanning sequences

Question 11

SREB/SCAP pathway:

Role of S2P

Answer 11

Located at the golgi
Second cleavage (once 2 halves of SREBP are separated) 
Cleaves NH2 terminal bHLH-Zip domain at a site located within the membrane-spanning region.

Question 12

SREB/SCAP pathway:

Role of NH2 terminal bHLH-Zip domain

Answer 12

Liberated from membrane bound rest of SREPB by S2P. Then leaves the membrane, carrying 3 hydrophobic residues at its COOH terminus
Enters the nucleus ->activates SRE (SRE1) -> increased transcription of LDL receptor gene

Question 13

Enterohepatic circulation

Answer 13

= Circulating pool of bile salts & cholesterol
Cholesterol is synthesised in the liver de novo/ taken up from the blood (RME of LDLs).
Liver produces bile (containing cholesterol & bile salts)
Bile secreted into duodenum via bile duct: emulsification & absorption of fats
Much of the bile, + emulsified fats, is absorbed by later sections of the GI tract.
Back to liver via portal vein

Question 14

HMG-CoA reductase

Answer 14

Rate limiting enzyme for cholesterol synthesis.
Converts HMG-CoA -> mevalonate

(Mevalonate is then converted -> cholesterol)

Question 15

Statins

Answer 15

Inhibit HMG-CoA reductase
-> lower sterol levels in cell -> -> -> activation of SRE1 -> increased LDL receptor synthesis -> increased cholesterol uptake into liver from blood

Also pleiotropic cholesterol independent effects:

• Improved endothelial function
• Enhanced stability of atherosclerotic plaques
• Decrease in oxidative stress and inflammation
• Inhibition of thrombus formation
• Beneficial extrahepatic effects on immune system, CNS, bone
• Implicated in inhibiting development of pathological changes associated with Alzheimer’s Disease.

Question 16

Simvastin

Answer 16

Statin

Inhibits HMG-CoA reductase

Question 17

Rosiglitazone

Answer 17

PPARγ agonist (-> induces LXR transcription including LXRα -> induces expression ABCA1, the rate limiting step in HDL synthesis)

Reported to reduce atherosclerosis in experimental models & clinical trials in humans.

Question 18

Fibrates

Answer 18

One way they work is by activating PPARs

-> indirectly induce expression of ABCA1, which controls the rate limiting step in HDL synthesis

Question 19

Clofibrate

Answer 19

Fibric acid derivative
Lowers VLDL and, to a lesser extent, LDL
Stimulates lipoprotein lipase- releasing triglycerides from VLDL and chylomicrons. Lipid can then be taken up & stored in fat/ metabolised in skeletal muscle

Also may activate PPARs

Question 20

Colestyramine

Answer 20

Anion exchange resin
Prevents reuptake of bile salts from the intestine -> increase in cholesterol metabolism to synthesise bile acids in the liver.

Question 21

Ezetimibe

Answer 21

Inhibits intestinal absorption of cholesterol
Binds to & inhibits ‘Niemann-Pick C1-Like 1’ (NPC1L1) a protein that mediates sterol transport across the brush border of the intestinal epithelium, & helps the reabsorption of cholesterol from bile in the liver.
Circulates enterohepatically- repeatedly re-delivered to the intestine, has action repeatedly.

Question 22

Nicotinic acid

Answer 22

Inhibits liver triglyceride production & VLDL secretion when used in v large doses
Increases levels of t-PA

Question 23

Fish oil

Answer 23

Reduces hypertriglyceridaemia (mechanism unknown). Reduces pancreatitis due to hypertriglyceridaemia.

Anti-thrombotic. Contains eicosapentaenoic acid:

• substitutes for arachidonic acid in production of prostaglandins & thromboxanes
• Produces PGI[3] instead of PGI[2] in endothelial cells, without a great change in antithrombotic activity
• Produces TXA[3] instead of TXA[2] in platelets- much less effective at causing platelet aggregation.

Question 24

Tangier disease

Answer 24

V rare, inherited disease found in some inhabitants of Tangier island in Chesapeake Bay in the USA.
Patients have extremely low HDL levels

Question 25

Niemann-Pick disease

Answer 25

Genetic, ultimately fatal lipid storage conditions, lead to abnormal accumulation of sphingolipids in brain, liver, spleen & bones.
Three types: A, B, C.

Mutations in NPC1 and NPC2 (protein, mediates sterol transport across intestinal epithelial brush border) lead to type C

Rare, but more common than Tangiers

Question 26

ApoA-I Milano

Answer 26

Mutant form of ApoA-I found in a family in Milan.
People found to have little heart disease, tended to live long lives.
Has a point substitution of cysteine for arginine at position 173 - allows disulphide dimer formation.

Experimentally:

• repeated administration of recombinant ApoA-I Milano reduced atheromatous lesions in the ileofemoral arteries of cholesterol fed rabbits.
• serum free cholesterol (measure of tissue cholesterol mobilisation) was increased significantly within 1 hour, and remained significantly elevated 48 hours after ApoA-I Milano injection.
• 2003 clinical trials of recombinant ApoA-I Milano in individuals with signifiant atherosclerosis- some reduction in plaque thickness seen.

Question 27

PPARs e.g PPARα and PPARγ

Answer 27

Nuclear receptors

Induce LXR transcription

Question 28

LXRs e.g LXRα

Answer 28

Act as metabolic sensors for cholesterol content of cells.

LXRα transcription leads to induction of ABCA1 expression.

Question 29

ABCA1

Answer 29

ATP-binding casette transporter
Transfers cholesterol from non-hepatic peripheral tissues to HDL.

Expression is tightly regulated by cellular cholesterol content via ‘liver X receptors’ (LXRs)