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Evaluation of direct and indirect effects of the PPARγ agonist troglitazone on mouse endothelial cell proliferation
Satoko Kakiuchi-Kiyota1, Lora L Arnold, Masanao Yokohira
1Department of Pathology and Microbiology, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska, USA.
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.
Insights
Peroxisome proliferator-activated receptor gamma (PPARγ) agonists like troglitazone can cause vascular tumors in mice. This study suggests a direct mitogenic effect on endothelial cells contributes to tumor formation.
Area of Science:
- Pharmacology
- Toxicology
- Oncology
Background:
- PPARγ agonists are used for type 2 diabetes and hyperlipidemia.
- Some PPAR agonists cause vascular tumors (hemangiomas/hemangiosarcomas) in mice but not rats.
- Endothelial cell (EC) proliferation is hypothesized to be involved in PPAR agonist-induced vascular tumors.
Purpose of the Study:
- To investigate the mechanism of troglitazone (TG)-induced vascular tumors in mice.
- To determine if TG directly affects endothelial cell proliferation and survival.
- To examine the role of proliferation pathways, oxidative stress, and hypoxia in TG-induced effects.
Main Methods:
- In vitro studies using mouse microvascular ECs treated with TG.
- In vivo studies in mice treated with TG, including assessments of EC proliferation, gene expression, oxidative stress, and hypoxia.
- Evaluation of vitamin E's effect on TG-induced EC proliferation.
Main Results:
- In vitro, TG increased EC proliferation and survival, altering proliferation pathway gene expression (e.g., IGF-1) but not oxidative stress pathways.
- In vivo, TG increased EC proliferation in liver and adipose tissue.
- Vitamin E did not inhibit TG-induced EC proliferation; minor hepatocellular hypoxia was observed, but not in adipose tissue.
Conclusions:
- Troglitazone has a direct mitogenic effect on mouse endothelial cells.
- This mitogenic effect on ECs likely contributes to the development of TG-induced hemangiosarcomas in mice.
- The mechanism involves proliferation pathways, not primarily oxidative stress or significant hypoxia in target tissues.
