Related Experiment Video
Updated: Jun 24, 2026
Study of In Vivo Glucose Metabolism in High-fat Diet-fed Mice Using Oral Glucose Tolerance Test (OGTT) and Insulin Tolerance Test (ITT)
Published on: January 7, 2018
Effects of the PPARgamma agonist troglitazone on endothelial cells in vivo and in vitro: differences between human
Satoko Kakiuchi-Kiyota1, Joseph A Vetro, Shugo Suzuki
1Department of Pathology and Microbiology and the Eppley Institute for Cancer Research, University of Nebraska Medical Center, 983135 Nebraska Medical Center Omaha, NE 68198-3135, USA.
Abstract:
Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists and PPARgamma/alpha dual agonists have been or are being developed for clinical use in the treatment of type 2 diabetes mellitus and hyperlipidemias. A common tumor finding in rodent carcinogenicity studies for these agonists is hemangioma/hemangiosarcoma in mice but not in rats. We hypothesized that increased endothelial cell proliferation may be involved in the mechanism of PPAR agonist-induced vascular tumors in mice, and we investigated the effects on endothelial cells utilizing troglitazone, the first clinically used PPARgamma agonist, in vivo and in vitro. Troglitazone (400 and 800 mg/kg/day) induced hemangiosarcomas in mice in a 2-year bioassay. We showed that troglitazone increased endothelial cell proliferation in brown and white adipose tissue and liver in mice at sarcomagenic doses after 4 weeks of treatment. Troglitazone was cytotoxic both to human dermal microvascular endothelial cells (HMEC1) and mouse mammary fat pad microvascular endothelial cells (MFP MVEC) at high concentrations. However, MFP MVEC were more resistant to the cytotoxic effects of troglitazone based on the much lower LC(50) in HMEC1 (17.4 muM) compared to MFP MVEC (92.2 muM). Troglitazone increased the proliferation and survival of MFP MVEC but not HMEC1 in growth factor reduced conditions. Our data demonstrate that troglitazone may induce hemangiosarcomas in mice, at least in part, through enhancement of survival and proliferation of microvascular endothelial cells. Such an effect does not occur with human cells, suggesting that human may react differently to exposure to PPAR agonists compared with mice.
Insights
Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists like troglitazone may cause vascular tumors in mice by increasing endothelial cell proliferation. Human cells show different responses, suggesting species-specific reactions to these diabetes drugs.
Area of Science:
- Pharmacology
- Toxicology
- Oncology
Background:
- PPARgamma agonists are developed for type 2 diabetes and hyperlipidemias.
- Rodent studies show hemangiosarcomas in mice but not rats with these agonists.
- The mechanism of PPAR agonist-induced vascular tumors in mice is not fully understood.
Purpose of the Study:
- Investigate the role of endothelial cell proliferation in PPAR agonist-induced vascular tumors.
- Utilize troglitazone, a PPARgamma agonist, to study its effects on endothelial cells in vivo and in vitro.
Main Methods:
- Administered troglitazone to mice in a 2-year bioassay.
- Assessed endothelial cell proliferation in mouse tissues (adipose, liver) after 4 weeks of treatment.
- Evaluated troglitazone's cytotoxic and proliferative effects on human (HMEC1) and mouse (MFP MVEC) endothelial cells in vitro.
Main Results:
- Troglitazone induced hemangiosarcomas in mice at high doses.
- Troglitazone increased endothelial cell proliferation in mouse tissues.
- Mouse endothelial cells (MFP MVEC) were more resistant to troglitazone cytotoxicity and showed increased proliferation/survival compared to human cells (HMEC1).
Conclusions:
- Troglitazone may induce hemangiosarcomas in mice by enhancing microvascular endothelial cell survival and proliferation.
- Human cells exhibit different responses to troglitazone compared to mouse cells.
- This suggests species-specific differences in reactions to PPAR agonists.
