TY - JOUR
T1 - Evaluation of PPARγ agonists on rodent endothelial cell proliferation
AU - Kakiuchi-Kiyota, Satoko
AU - Arnold, Lora L.
AU - Yokohira, Masanao
AU - Suzuki, Shugo
AU - Pennington, Karen L.
AU - Cohen, Samuel M.
N1 - Funding Information:
We gratefully acknowledge the technical expertise of Dr. Charles Kuszynski and the Cell Analysis Facility at University of Nebraska Medical Center in the development of the methodology and performance of flow cytometry analysis, the contribution of MFP MVEC from Dr. Joe Vetro at University of Nebraska Medical Center, and the generosity of Bristol Myers Squibb Co. for providing TG and PIO for our experiments. This research was supported in part by a grant from Takeda Pharmaceutical Co .
PY - 2011/9/5
Y1 - 2011/9/5
N2 - The PPARγ agonist troglitazone (TG) induced an increased incidence of hemangiosarcomas in mice but was not carcinogenic in rats. In contrast, pioglitazone (PIO) did not induce hemangiosarcomas or any other tumors in mice. We previously demonstrated that TG increased the proliferation of endothelial cells (ECs) in liver and adipose tissue in mice, and acted as a mitogenic stimulant and an inhibitor of apoptosis in vitro in mouse, but not human, ECs. In the present study, we investigated whether TG had any effect on the proliferation of ECs in rats. We also evaluated the in vivo and in vitro effects of PIO on ECs in mice. In rats, TG did not increase the Ki-67 labeling index (LI) of ECs in liver or adipose tissue at doses used in the two-year bioassay, and did not increase hepatocyte proliferation. PIO administered to mice did not increase the Ki-67 LI of hepatocytes or ECs in liver or white adipose tissue, but slightly increased the EC proliferation in brown adipose tissue. PIO was slightly mitogenic on cultured mouse ECs after 3 days of treatment but not after 6 days, and there was no inhibition of apoptosis, in contrast to what was seen with TG. The data support the conclusion that sustained EC proliferation in mice is necessary, for the induction of hemangiosarcomas by TG, and these short-term and long-term effects are not seen with TG in the rat or with PIO in mice, treatments that also are not related to the induction of hemangiosarcomas in two-year bioassays.
AB - The PPARγ agonist troglitazone (TG) induced an increased incidence of hemangiosarcomas in mice but was not carcinogenic in rats. In contrast, pioglitazone (PIO) did not induce hemangiosarcomas or any other tumors in mice. We previously demonstrated that TG increased the proliferation of endothelial cells (ECs) in liver and adipose tissue in mice, and acted as a mitogenic stimulant and an inhibitor of apoptosis in vitro in mouse, but not human, ECs. In the present study, we investigated whether TG had any effect on the proliferation of ECs in rats. We also evaluated the in vivo and in vitro effects of PIO on ECs in mice. In rats, TG did not increase the Ki-67 labeling index (LI) of ECs in liver or adipose tissue at doses used in the two-year bioassay, and did not increase hepatocyte proliferation. PIO administered to mice did not increase the Ki-67 LI of hepatocytes or ECs in liver or white adipose tissue, but slightly increased the EC proliferation in brown adipose tissue. PIO was slightly mitogenic on cultured mouse ECs after 3 days of treatment but not after 6 days, and there was no inhibition of apoptosis, in contrast to what was seen with TG. The data support the conclusion that sustained EC proliferation in mice is necessary, for the induction of hemangiosarcomas by TG, and these short-term and long-term effects are not seen with TG in the rat or with PIO in mice, treatments that also are not related to the induction of hemangiosarcomas in two-year bioassays.
KW - Endothelial cell proliferation
KW - Hemangiosarcoma
KW - PPARγ agonist
KW - Pioglitazone
KW - Rodent
KW - Troglitazone
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U2 - 10.1016/j.tox.2011.05.019
DO - 10.1016/j.tox.2011.05.019
M3 - Article
C2 - 21684317
AN - SCOPUS:79960700881
VL - 287
SP - 91
EP - 98
JO - Toxicology
JF - Toxicology
SN - 0300-483X
IS - 1-3
ER -