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Pioglitozone inhibits the progression, but does not reverse development of atherosclerosis, in LDL receptor‐deficient mice
Author(s) -
Nakaya Hideaki,
Nicholson Andrew C,
Han Jihong,
Summers Barbara,
Gotto Antonio M,
Hajjar David P
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1075-b
Subject(s) - pioglitazone , medicine , oil red o , endocrinology , ldl receptor , lipid metabolism , peroxisome proliferator activated receptor , lesion , receptor , cholesterol , insulin resistance , lipid profile , glucose homeostasis , adipogenesis , biology , insulin , adipose tissue , diabetes mellitus , lipoprotein , type 2 diabetes , pathology
Peroxisome proliferator‐activated receptor‐γ (PPARγ) is a ligand‐activated transcriptional regulator of genes encoding proteins involved in adipogenesis, lipid metabolism and glucose homeostasis. Synthetic ligands of PPARγ (thiazolidinediones such as pioglitazone) are utilized for improving insulin resistance. PPARγ ligands have been shown to inhibit the development of atherosclerosis in murine models of this disease, but their effect on preexisting atherosclerosis is unknown. We tested the hypothesis that pioglitazone could reverse atherosclerosis in LDL‐receptor null (LDLR−/−) mice. Methods LDLR−/− mice (5 week old males) were divided into 3 groups (20 mice/group) and fed a high fat diet for 8 weeks. At this time 1/3 of the mice were sacrificed to establish a baseline of atherosclerotic lesion development. The remaining mice were continued on a high fat diet and half were given pioglitazone (15mg/kg/day) in the diet for 6 more weeks prior to sacrifice. Aortas were dissected and neutral lipid was stained with oil‐red‐o. Lipid stained lesion areas were quantified. rtPCR was performed using peritoneal macrophage RNA to quantify mRNA of efflux proteins, ABCA1/G1. Results Lesion area in pioglitazone‐treated mice was 36% less (p<0.05) than in mice fed with high‐fat diet alone for 14 weeks, but not different from mice fed with diet alone for 8 weeks. Blood glucose and lipid profiles did not differ between the three groups. Results of gene expression studies are pending. Conclusion Pioglitazone inhibited progression of atherosclerosis but did not decrease the size of pre‐existing lesions. Studies to evaluate the effect of longer‐term treatment are in progress. Supported by NHLBI PO1‐ HL072942 /The Silbermann and Abercrombie Foundations