Atherosclerosis.ppt

1、Atherosclerosis,Focal plaques within the intima containing cholesterol and cholesterol esters (CE) Affects large and medium sized arteries Causes coronary heart diseases (CHD) Hypercholesterolemia high serum cholesterol level Elevated LDL and triglycerides associated with increase risk Serum HDL lev

2、els inversely related to risk,Pathogenesis,Chronic inflammatory response of the vascular wall to endothelial injury or dysfunction Elevated plasma LDL levels causing the deposit of LDL in the subendothelium of blood vessels Oxidation of transmigrated LDL Activation of endothelial cells Recruitment o

3、f monocytes/macrophages which ingest oxLDL through scavenger receptors Formation of foam cells fatty streaks Proliferation of smooth muscle cells Deposition of extracellular matrix proteins,Monocyte Recruitment,LDL,Lipid Core,lumen,neointima,Formation of Atherosclerotic Plaques,Plaque Rupture and Th

4、rombosis,Lipid Core,Tissue Factor,Platelet Aggregation,Cholesterol and Triglyceride Metabolism,Exogenous Pathway,Route of uptake of dietary lipids. Chylomicrons (CM) complexes of TG, CE and apoproteins Chylomicron remnants CM after removal of most TG CM are degraded by lipoprotein lipase on endothel

5、ial cells of adipose tissue and muscle. After removal of TG for storage, CM remnants are transported to the liver. Results: Dietary TG is stored in adipose tissue and muscle. Cholesterol is stored in liver or excreted into the bile as cholesterol or bile acid.,Cholesterol and Triglyceride Metabolism

6、,Endogenous Pathway,Route for distribution of CE from liver to target cells VLDL secreted by the liver to plasma and transported to adipose tissue and muscle where lipoprotein lipase extracted TG. The remnant IDL is either taken up by the liver or circulates until the remaining TG is removed, formin

7、g LDL particles which are rich in cholesterol. LDL is cleared from plasma by LDL receptor-mediated endocytosis. Results: 1) Transfer of TG from liver to target cells via VLDL; 2) Transfer of CE from liver to target cells via LDL; 3) Feedback regulation of cholesterol homeostasis by LDL receptor expr

8、ession; 4) Creation of a steady state LDL-CE reserve in plasma.,Cholesterol and Triglyceride Metabolism,Reverse Transport of Cholesterol,Route for cholesterol recovery As cell dies and the cell membrane turnover, free cholesterol is released into the plasma. It is immediately absorbed onto HDL parti

9、cles, esterified with a long chain fatty acid by lecithin:cholesterol acyltransferase (LCAT), and transferred to VLDL or IDL by a cholesteryl ester transfer protein (CETP) in plasma. Eventually, it is taken up by the liver as IDL or LDL. Results: Recovery of cholesterol from cell membranes and reinc

10、orporation into LDL pool or return to liver.,Cholesterol and Triglyceride Metabolism,De Novo Cholesterol Biosynthesis,Liver synthesizes 2/3 of cholesterol made by the body. The rate limiting enzyme is 3-hydroxyl 3-methyl glutaryl (HMG)-CoA reductase. Results: Provide feedback regulation by cholester

11、ol concentrations in cells.,Cholesterol Excretion by Enterohepatic Circulation,Bile acids are synthesized from cholesterol in the liver, released into the intestine and reabsorbed in the jejunum and ileum. Results: Conversion of liver cholesterol to bile acids for recycle.,Genetic Defects of Lipid M

12、etabolism,Monogenic Familial hypercholesterolemia (homozygous or heterozygous) defect: inactive LDL receptor Familial lipoprotein lipase deficiency defect: inactive lipoprotein lipase Familial combined hyperlipidemia defect: unknown Polygenic/multifactorial commonly encountered Hypercholesterolemia

13、Hypertriglyceridemia,Therapeutic Strategy,Identify patients at risk 1. Routine screening of serum cholesterol 2. Assessment of contributing risk factors Non-pharmacologic therapy 1. Diet modification 2. Lifestyle modification C.Pharmacologic therapy,Classification of Plasma Cholesterol Concentration

14、s,Lovastatin aka “statins”(HMG-CoA reductase inhibitors),Action: competitively inhibits HMG-CoA reductase, the key enzyme for de novo cholesterol biosynthesis. Results: 1) cells express more LDL receptors; 2) decreased serum LDL levels; 3) suppresses production of VLDL in liver; 4) increased HDL lev

15、els; 5) increased HDL/LDL ratio. Advantages: specific; effective; well-tolerated. Disadvantages: hepatotoxicity; myopathy; most expensive; contradicted in pregnant and nursing women.,Bile acid sequestrants(colestipol, cholestyramine, colesevelam),Taken orally, not absorbed from the intestine. Action

16、: Anion exchange resins which bind negatively charged bile acids in the small intestine. Results: 1) increased conversion of cholesterol to bile acid in hepatocytes; 2) increased synthesis of cholesterol and LDL receptors in hepatocytes; 3) decreased serum LDL and cholesterol levels. Advantages: cli

17、nically safe; effective. Disadvantages: unpleasant GI effects; interference with GI drug absorption (e.g., coumarin); may exacerbate hypertriglyceridemia (unknown mechanism).,Ezetimibe,Action: inhibits dietary cholesterol uptake by jejunal enterocytes by binding to a key mediator of cholesterol abso

18、rption Neimann-Pick C1-Like1 (NPC1L1). Results: 1) reduction of cholesterol incorporation into chylomicrons and delivery to hepatocytes; 2) increased synthesis of cholesterol and LDL receptors in hepatocytes; 3) decreased serum LDL and cholesterol levels. Advantages: clinically safe; effective; used

19、 as monotherapy in statin-intolerant patients; also used in combination with statins in statin-tolerant patients for further reduction of serum LDL and cholesterol. Disadvantages: no effect on TG absorption; a new class of anti-atherosclerotic drug long term effect not known.,Niacin (nicotinic acid)

20、,Action: Acts through a Gi-coupled GPCR to decrease cAMP levels. Inhibits hormone-sensitive lipase involved in lipolysis in adipose tissue and decreases free fatty acid (FFA) transfer to the liver for synthesis of triglycerides. Results: 1) decreased production and release of VLDL by liver; 2) decre

21、ased serum levels of VLDL as well as LDL and TG; 3) reduced clearance of HDL or increased serum level of HDL; 4) increased HDL/LDL ratio. Advantages: long clinical experience; effective; least expensive. Disadvantages: evokes flushing, itchiness, dyspepsia and GI discomfort, contraindicated for diab

22、etic patients and pregnant women; adverse effects in hepatic diseases and reactivation of gout.,Fibrates (prototype: clofibrateUS: gemfibrozil; Europe: fenofibrate),Action: acts through peroxisome proliferator activated receptors (PPARs) to stimulate gene transcription of lipoprotein lipase; increas

23、es the clearance of VLDL and reduce plasma TG levels; decreases VLDL synthesis and lowers LDL levels moderately; increases plasma HDL by increased synthesis and/or decreased clearance. Results: decreased serum TG and cholesterol; increased HDL/LDL ratio. Advantages: recent clinical data support safe

24、ty and efficacy; well-tolerated, potential anti-thrombotic effect. Disadvantages: more effective in reducing TG than LDL; increased LDL levels in some patients; displaces anticoagulant from albumin; contraindicated in patients with renal failure. Clofibrate has toxic effect.,CETP Inhibitors (Torcetr

25、apib),Action: Inhibits the transfer of cholesterol ester from HDL to VLDL. Results: 1) increased serum level of HDL; 2) by itself, no effect on LDL levels; 3) use in combination of statins to lower LDL with further increase in HDL.,Combined Drug Therapy,Advantages: Synergistic approaches utilizes complementary mechanisms of drug actions; reduces effective doses of single drug to prevent side effects. Hypercholesterol without hypertriglycerides: Bile acid sequestrant plus lovastati