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 Garcia; Pennington, Karen L.; Arnold, Lora L.; Singh, Rakesh K.; Cohen, Samuel M.

doi:10.1016/j.taap.2009.02.028

Cited by 22 publications

(32 citation statements)

References 35 publications

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“…Although we did not measure blood levels of TG, in these studies, increases in heart weight, mammary ductal hyperplasia, and endothelial proliferation were similar to previous studies (Kakiuchi-Kiyota et al 2009). …”

Section: Discussionsupporting

confidence: 85%

“…In our previous study (Kakiuchi-Kiyota et al 2009) and in Study 2, mice were fed Purina 5002 and no histological abnormality in the liver, including fatty liver, was observed. Troglitazone treatment decreased the incidence of this hepatocellular change in the mice fed AIN-76A diet.…”

Section: Discussionmentioning

confidence: 74%

“…Troglitazone increased EC proliferation in liver, BAT, and WAT in female B6C3F1 mice at the sarcomagenic doses administered for four weeks, at least in part through a direct mitogenic effect and inhibition of apoptosis on mouse microvascular ECs (MFP MVEC) (Kakiuchi-Kiyota et al 2009). To understand the mechanism of direct effects of TG in mouse ECs, we investigated the transcriptional profiles in TG-treated MFP MVEC under reduced concentrations of growth factors.…”

Section: Discussionmentioning

confidence: 99%

“…Mouse mammary fat pad microvascular endothelial cells (MFP MVEC; Kakiuchi-Kiyota et al 2009) were provided by Dr. Joseph Vetro (University of Nebraska Medical Center, Omaha, NE). They were isolated from mammary fat pad (MFP) of two female H-2Kb-ts-A58 mice (Immortomice, Charles River Laboratories).…”

Section: Study 1: Investigation Of Transcriptional Profile In Tg-treamentioning

confidence: 99%

“…Total RNA from each sample was isolated using RNeasy Plus Micro Kit (Qiagen), and cDNA was synthesized as previously described (Kakiuchi-Kiyota et al 2009). One microliter of first-strand cDNA was amplified using the following primer sets:…”

Section: Pathway Analysismentioning

confidence: 99%

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Evaluation of Direct and Indirect Effects of the PPARγ Agonist Troglitazone on Mouse Endothelial Cell Proliferation

et al. 2011

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Peroxisome proliferator-activated receptor gamma (PPARg) agonists and PPARg/a 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 PPARg 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.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Study 1: Investigation Of Transcriptional Profile In Tg-treamentioning

confidence: 99%

Section: Pathway Analysismentioning

confidence: 99%

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Evaluation of Direct and Indirect Effects of the PPARγ Agonist Troglitazone on Mouse Endothelial Cell Proliferation

et al. 2011

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Nongenotoxic or Epigenetic Carcinogenesis

Powell¹,

Berry

2009

General, Applied and Systems Toxicology

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Carcinogens are considered nongenotoxic where they cannot be shown to interact directly with DNA in a number of short‐term screening assays, but which are capable of producing tumours in laboratory rodents in bioassays. Epigenetic events, either acting alone or in concert with genetically determined events, may produce tumours. A key feature is that dose‐threshold effects may be identifiable. In both the rat and the mouse, the liver is the most common site of nongenotoxic carcinogenesis. A special sort of hepatic carcinogenesis is that produced in rodents by peroxisome proliferators; this is of questionable significance for humans. Other important sites of non‐genotoxic carcinogenesis include endocrine glands notably the thyroid, bladder and, in the rat, the forestomach. Carcinoid tumours are tumours of the diffuse neuroendocrine cell populations, found particularly in the gastrointestinal tract. Their incidence is increased with certain drugs, notably the histamine H2 antagonists. Haemangiosarcoma, which may occur at a variety of sites, clearly arises by a number of mechanisms, some of which may be genotoxic. Mesothelioma, most often of the pleura, as a human response to asbestos, may be considered a form of non‐genotoxic carcinogenesis.

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The Musculoskeletal System and Skin

Gopinath

Mowat

2014

Atlas of Toxicological Pathology

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

Cited by 22 publications

References 35 publications

Evaluation of Direct and Indirect Effects of the PPARγ Agonist Troglitazone on Mouse Endothelial Cell Proliferation

Evaluation of Direct and Indirect Effects of the PPARγ Agonist Troglitazone on Mouse Endothelial Cell Proliferation

Nongenotoxic or Epigenetic Carcinogenesis

The Musculoskeletal System and Skin

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