Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL.
Atherosclerotic coronary heart disease is a common complication of the insulin resistance syndrome that can occur with or without diabetes mellitus. Thiazolidinediones (TZDs), which are insulin-sensitizing antidiabetic agents, can modulate the development of atherosclerosis not only by changing the systemic metabolic conditions associated with insulin resistance but also by exerting direct effects on vascular wall cells that express peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear receptor for TZDs. Here we show that troglitazone, a TZD, significantly inhibited fatty streak lesion formation in apolipoprotein E-knockout mice fed a high-fat diet (en face aortic surface lesion areas were 6.9+/-2.5% vs 12.7+/-4.7%, P<0.05; cross-sectional lesion areas were 191 974+/-102 911 micrometer(2) vs 351 738+/-175 597 micrometer(2), P<0.05; n=10). Troglitazone attenuated hyperinsulinemic hyperglycemia and increased high density lipoprotein cholesterol levels. In the aorta, troglitazone markedly increased the mRNA levels of CD36, a scavenger receptor for oxidized low density lipoprotein, presumably by upregulating its expression, at least in part, in the macrophage foam cells. These results indicate that troglitazone potently inhibits fatty streak lesion formation by modulating both metabolic extracellular environments and arterial wall cell functions.
Chen
Z
Z
Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Ishibashi
S
S
Perrey
S
S
Osuga Ji
Gotoda
T
T
Kitamine
T
T
Tamura
Y
Y
Okazaki
H
H
Yahagi
N
N
Iizuka
Y
Y
Shionoiri
F
F
Ohashi
K
K
Harada
K
K
Shimano
H
H
Nagai
R
R
Yamada
N
N
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D001161:Arteriosclerosis / Q000517:prevention & control*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D015152:Blotting, Northern; D001835:Body Weight / Q000187:drug effects; D018955:CD36 Antigens / Q000235:genetics; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000235:genetics; D008074:Lipoproteins / Q000097:blood / Q000187:drug effects; D008075:Lipoproteins, HDL / Q000097:blood / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D000077288:Troglitazone
D001057:Apolipoproteins E; D001786:Blood Glucose; D018955:CD36 Antigens; D002839:Chromans; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D008071:Lipoprotein Lipase; D000077288:Troglitazone