Inhibition of intestinal absorption of cholesterol by ezetimibe or bile acids by SC-435 alters lipoprotein metabolism and extends the lifespan of SR-BI/apoE double knockout mice.
SR-BI/apoE double knockout (dKO) mice exhibit many features of human coronary heart disease (CHD), including hypercholesterolemia, occlusive coronary atherosclerosis, cardiac hypertrophy, myocardial infarctions, cardiac dysfunction and premature death. Ezetimibe is a FDA-approved, intestinal cholesterol absorption inhibitor that lowers plasma LDL cholesterol in humans and animals and inhibits aortic root atherosclerosis in apoE KO mice, but has not been proven to reduce CHD. Three-week-ezetimibe treatment of dKO mice (0.005% (w/w) in standard chow administered from weaning) resulted in a 35% decrease in cholesterol in IDL/LDL-size lipoproteins, but not in VLDL- and HDL-size lipoproteins. Ezetimibe treatment significantly reduced aortic root (57%) and coronary arterial (68%) atherosclerosis, cardiomegaly (24%) and cardiac fibrosis (57%), and prolonged the lives of the mice (27%). This represents the first demonstration of beneficial effects of ezetimibe treatment on CHD. The dKO mice were similarly treated with SC-435 (0.01% (w/w)), an apical sodium codependent bile acid transporter (ASBT) inhibitor, that blocks intestinal absorption of bile acids, lowers plasma cholesterol in animals, and reduces aortic root atherosclerosis in apoE KO mice. The effects of SC-435 treatment were similar to those of ezetimibe: 37% decrease in ILD/LDL-size lipoprotein cholesterol and 57% prolongation in median lifespan. Thus, inhibition of intestinal absorption of either cholesterol (ezetimibe) or bile acids (SC-435) significantly reduced plasma IDL/LDL-size lipoprotein cholesterol levels and improved survival of SR-BI/apoE dKO mice. The SR-BI/apoE dKO murine model of atherosclerotic occlusive, arterial CHD appears to provide a useful system to evaluate compounds that modulate cholesterol homeostasis and atherosclerosis.
Department of Biology, Massachusetts Institute of Technology, Building 68-483, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Anne
A
Braun
Ayce
A
Yesilaltay
Susan
S
Acton
Kay O
KO
Broschat
Elaine S
ES
Krul
Nida
N
Napawan
Nancy
N
Stagliano
Monty
M
Krieger
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000235:genetics; D001384:Azetidines / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000097:blood / Q000493:pharmacokinetics*; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D000069438:Ezetimibe; D005260:Female; D005355:Fibrosis; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects*; D008017:Life Expectancy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051122:Scavenger Receptors, Class B / Q000235:genetics; D015996:Survival Rate; D014280:Triglycerides / Q000097:blood; D014326:Tropanes / Q000494:pharmacology*
C466800:1-(4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl)phenoxy)butyl)-4-aza-1-azoniabicyclo(2.2.2)octane; D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D001384:Azetidines; D001647:Bile Acids and Salts; D003497:Cyclic N-Oxides; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D014280:Triglycerides; D014326:Tropanes; D002784:Cholesterol; D000069438:Ezetimibe