Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor-deficient mice.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand-activated nuclear receptor expressed in all of the major cell types found in atherosclerotic lesions: monocytes/macrophages, endothelial cells, and smooth muscle cells. In vitro, PPARgamma ligands inhibit cell proliferation and migration, 2 processes critical for vascular lesion formation. In contrast to these putative antiatherogenic activities, PPARgamma has been shown in vitro to upregulate the CD36 scavenger receptor, which could promote foam cell formation. Thus, it is unclear what impact PPARgamma activation will have on the development and progression of atherosclerosis. This issue is important because thiazolidinediones, which are ligands for PPARgamma, have recently been approved for the treatment of type 2 diabetes, a state of accelerated atherosclerosis. We report herein that the PPARgamma ligand, troglitazone, inhibited lesion formation in male low density lipoprotein receptor-deficient mice fed either a high-fat diet, which also induces type 2 diabetes, or a high-fructose diet. Troglitazone decreased the accumulation of macrophages in intimal xanthomas, consistent with our in vitro observation that troglitazone and another thiazolidinedione, rosiglitazone, inhibited monocyte chemoattractant protein-1-directed transendothelial migration of monocytes. Although troglitazone had some beneficial effects on metabolic risk factors (in particular, a reduction of insulin levels in the diabetic model), none of the systemic cardiovascular risk factors was consistently improved in either model. These observations suggest that the inhibition of early atherosclerotic lesion formation by troglitazone may result, at least in part, from direct effects of PPARgamma activation in the artery wall.
Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, UCLA School of Medicine, Los Angeles, California, USA.
A R
AR
Collins
W P
WP
Meehan
U
U
Kintscher
S
S
Jackson
S
S
Wakino
G
G
Noh
W
W
Palinski
W A
WA
Hsueh
R E
RE
Law
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000209:etiology / Q000517:prevention & control*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D004041:Dietary Fats / Q000008:administration & dosage; D004730:Endothelium, Vascular / Q000166:cytology; D005419:Flavonoids / Q000494:pharmacology; D005632:Fructose / Q000008:administration & dosage; D006801:Humans; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone; D014407:Tumor Cells, Cultured; D014665:Vasodilator Agents / Q000494:pharmacology*; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001786:Blood Glucose; D018932:Chemokine CCL2; D002839:Chromans; D004040:Dietary Carbohydrates; D004041:Dietary Fats; D005419:Flavonoids; D005632:Fructose; D007328:Insulin; D008055:Lipids; D011973:Receptors, LDL; D000077154:Rosiglitazone; D013844:Thiazoles; D045162:Thiazolidinediones; D000077288:Troglitazone; D014665:Vasodilator Agents; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one