Effects of the PPAR{gamma} agonist troglitazone on endothelial cells in vivo and in vitro: Differences between human and mouse

Journal Article · Fri May 15 00:00:00 EDT 2009 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.02.028· OSTI ID:21272557

Kakiuchi-Kiyota, Satoko ^[1]; Vetro, Joseph A ^[2]; Suzuki, Shugo; Varney, Michelle L ^[1]; Han, Huai-Yun ^[2]; Nascimento, Merielen; Pennington, Karen L; Arnold, Lora L; Singh, Rakesh K ^[1]

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1. Department of Pathology and Microbiology and the Eppley Institute for Cancer Research, University of Nebraska Medical Center, 983135 Nebraska Medical Center Omaha, NE 68198-3135 (United States)
2. Center for Drug Delivery and Nanomedicine and Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198-6025 (United States)

Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists and PPAR{gamma}/{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 PPAR{gamma} 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{sub 50} in HMEC1 (17.4 {mu}M) compared to MFP MVEC (92.2 {mu}M). 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.

• OSTI ID: 21272557
• Journal Information: Toxicology and Applied Pharmacology, Vol. 237, Issue 1; Other Information: DOI: 10.1016/j.taap.2009.02.028; PII: S0041-008X(09)00101-X; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ADIPOSE TISSUE
ANGIOMAS
ANIMAL CELLS
APOPTOSIS
CELL PROLIFERATION
DIABETES MELLITUS
GROWTH FACTORS
HUMAN POPULATIONS
IN VITRO
IN VIVO
LIVER
MICE
RATS
RECEPTORS