Human aspects of cardiovascular and renal pharmacology: Atherosclerosis/ hypolipidaemic agents Flashcards
Atherosclerosis- definition
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
Arteriosclerosis- definition
Loss of elasticity & physical hardening of the arterial wall from any cause
Often accompanied by calcification of the wall
Atheroma- definition
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
Complications of atherosclerosis
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
Treatment of atherosclerosis
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.
Structure of lipoproteins
‘Lipo’- cholesterol intercalated in a phospholipid membrane and cholesteryl esters
‘Protein’- apolipoproteins associated with the lipid particle
LDL
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.
HDL
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.
SREB/SCAP pathway:
Role of SCAP
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
SREB/SCAP pathway:
Role of S1P
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
SREB/SCAP pathway:
Role of S2P
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.
SREB/SCAP pathway:
Role of NH2 terminal bHLH-Zip domain
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
Enterohepatic circulation
= 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
HMG-CoA reductase
Rate limiting enzyme for cholesterol synthesis.
Converts HMG-CoA -> mevalonate
(Mevalonate is then converted -> cholesterol)
Statins
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.
Simvastin
Statin
Inhibits HMG-CoA reductase
Rosiglitazone
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.
Fibrates
One way they work is by activating PPARs
-> indirectly induce expression of ABCA1, which controls the rate limiting step in HDL synthesis
Clofibrate
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
Colestyramine
Anion exchange resin
Prevents reuptake of bile salts from the intestine -> increase in cholesterol metabolism to synthesise bile acids in the liver.
Ezetimibe
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.
Nicotinic acid
Inhibits liver triglyceride production & VLDL secretion when used in v large doses
Increases levels of t-PA
Fish oil
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.
Tangier disease
V rare, inherited disease found in some inhabitants of Tangier island in Chesapeake Bay in the USA.
Patients have extremely low HDL levels
Niemann-Pick disease
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
ApoA-I Milano
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.
PPARs e.g PPARα and PPARγ
Nuclear receptors
Induce LXR transcription
LXRs e.g LXRα
Act as metabolic sensors for cholesterol content of cells.
LXRα transcription leads to induction of ABCA1 expression.
ABCA1
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)
