Effects of the PPARγ agonist troglitazone on endothelial cells in vivo and in vitro: Differences between human and mouse

Satoko Kakiuchi-Kiyota, Joseph A Vetro, Shugo Suzuki, Michelle L. Varney, Huai Yun Han, Merielen Nascimento, Karen L. Pennington, Lora L Arnold, Rakesh K Singh, Samuel Monroe Cohen

Research output: Contribution to journalArticle

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Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists and PPARγ/α 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 PPARγ 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 LC50 in HMEC1 (17.4 μM) compared to MFP MVEC (92.2 μM). 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.

Original languageEnglish (US)
Pages (from-to)83-90
Number of pages8
JournalToxicology and Applied Pharmacology
Volume237
Issue number1
DOIs
StatePublished - May 15 2009

Fingerprint

troglitazone
PPAR gamma
Endothelial cells
Endothelial Cells
Hemangiosarcoma
Adipose Tissue
Breast
Fats
Cell proliferation
Tumors
Cell Proliferation
In Vitro Techniques
White Adipose Tissue
Brown Adipose Tissue
Survival
Bioassay
Hemangioma
Medical problems
Hyperlipidemias

Keywords

  • Apoptosis
  • Endothelial cell
  • Hemangiosarcoma
  • PPARγ
  • Proliferation
  • Troglitazone

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Effects of the PPARγ agonist troglitazone on endothelial cells in vivo and in vitro : Differences between human and mouse. / Kakiuchi-Kiyota, Satoko; Vetro, Joseph A; Suzuki, Shugo; Varney, Michelle L.; Han, Huai Yun; Nascimento, Merielen; Pennington, Karen L.; Arnold, Lora L; Singh, Rakesh K; Cohen, Samuel Monroe.

In: Toxicology and Applied Pharmacology, Vol. 237, No. 1, 15.05.2009, p. 83-90.

Research output: Contribution to journalArticle

Kakiuchi-Kiyota, Satoko ; Vetro, Joseph A ; Suzuki, Shugo ; Varney, Michelle L. ; Han, Huai Yun ; Nascimento, Merielen ; Pennington, Karen L. ; Arnold, Lora L ; Singh, Rakesh K ; Cohen, Samuel Monroe. / Effects of the PPARγ agonist troglitazone on endothelial cells in vivo and in vitro : Differences between human and mouse. In: Toxicology and Applied Pharmacology. 2009 ; Vol. 237, No. 1. pp. 83-90.
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AU - Varney, Michelle L.

AU - Han, Huai Yun

AU - Nascimento, Merielen

AU - Pennington, Karen L.

AU - Arnold, Lora L

AU - Singh, Rakesh K

AU - Cohen, Samuel Monroe

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