title: Evaluation of direct and indirect effects of the PPARγ agonist troglitazone on mouse endothelial cell proliferation.
abstract: Peroxisome proliferator-activated receptor gamma (PPARγ) agonists and PPARγ/α dual agonists are used in the treatment of type 2 diabetes mellitus and hyperlipidemias. In carcinogenicity studies, some of these agonists induced hemangiomas/hemangiosarcomas in mice, but not in rats. We hypothesized that increased endothelial cell (EC) proliferation may be involved in the mechanism of PPAR agonist-induced vascular tumors in mice. We previously showed that the sarcomagenic PPARγ agonist troglitazone (TG) increased EC proliferation in brown and white adipose tissue and liver in mice at sarcomagenic doses (400 and 800 mg/kg) after four weeks of treatment. In vitro, TG had a mitogenic effect on mouse microvascular mouse ECs by increasing cell proliferation and survival. The current studies showed that treatment of mouse ECs in vitro induced alterations in proliferation pathway gene expression, especially the expression of insulin-like growth factor-1, but had no effect on mouse oxidative stress pathways. In vivo, treatment with vitamin E did not inhibit TG-induced EC proliferation in liver and adipose tissue. In addition, no hypoxic effect was detected in adipose tissue of TG-treated mice; however, TG had a minor effect on hepatocellular hypoxia. These results provide additional evidence supporting a direct mitogenic effect in the mode of action of TG-induced hemangiosarcomas in mice.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Satoko
authors.initials: S
authors.lastname: Kakiuchi-Kiyota
authors.forename: Lora L
authors.initials: LL
authors.lastname: Arnold
authors.forename: Masanao
authors.initials: M
authors.lastname: Yokohira
authors.forename: Petra
authors.initials: P
authors.lastname: Koza-Taylor
authors.forename: Shugo
authors.initials: S
authors.lastname: Suzuki
authors.forename: Michelle
authors.initials: M
authors.lastname: Varney
authors.forename: Karen L
authors.initials: KL
authors.lastname: Pennington
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D000273:Adipose Tissue / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology*; D004326:Drinking / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005234:Fatty Liver; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D006394:Hemangiosarcoma; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006651:Histocytochemistry; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists*; D015203:Reproducibility of Results; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002839:Chromans; D047495:PPAR gamma; D045162:Thiazolidinediones; D014810:Vitamin E; D007334:Insulin-Like Growth Factor I; D000077288:Troglitazone