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(Circulation. 2001;103:724.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Estrogen Prevents Oxidative Stress–Induced Endothelial Cell Apoptosis in Rats

Noriko Sudoh, MD, PhD; Kenji Toba, MD, PhD; Masahiro Akishita, MD, PhD; Junya Ako, MD; Masayoshi Hashimoto, MD, PhD; Katsuya Iijima, MD; Seungbum Kim, MD, PhD; Yi-Qiang Liang, MD; Yumiko Ohike, MD; Tokumitsu Watanabe, MD; Ieharu Yamazaki, BLA; Masao Yoshizumi, MD, PhD; Masato Eto, MD, PhD; Yasuyoshi Ouchi, MD, PhD

From the Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo (N.S., K.T., M.A., J.A., M.H., K.I., S.K., Y.-Q.L., Y. Ohike, T.W., M.Y., M.E., Y. Ouchi); the Department of Geriatric Medicine, Kyorin University School of Medicine, Tokyo (K.T., M.A.); and the Department of Clinical Laboratory and Pathology, Inoue Memorial Hospital, Chiba (I.Y.), Japan.

Correspondence to Kenji Toba, MD, PhD, Department of Geriatric Medicine, Kyorin University School of Medicine, 6-20-2 Sinkawa, Mitaka, Tokyo 181-8611, Japan. E-mail toba{at}kyorin-u.ac.jp

Background—Estrogen replacement attenuates the increased risk of cardiovascular disease in postmenopausal women. Recent studies using an in vitro culture system have shown that estrogen inhibits endothelial cell (EC) apoptosis. The in vivo relevance of this finding, however, is not defined. To do so, we have developed a rat vascular injury model in which EC apoptosis induced by hydrogen peroxide plays a role.

Methods and Results—Intracarotid arterial administration of 0.01 mmol/L hydrogen peroxide for 5 minutes evoked EC apoptosis after 6 to 24 hours, determined by nuclear staining with Hoechst 33342, terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling, and electron microscopy. Apoptosis was associated with EC loss and was followed by EC regeneration at 72 hours and neointima formation at 1 to 2 weeks. Estradiol replacement in ovariectomized female Wistar rats decreased the rate of apoptotic ECs by 50%, assayed by nuclear morphology of en face specimens, resulting in increased remaining ECs and decreased neointima formation. Progesterone did not influence the effects of estradiol on EC apoptosis.

Conclusions—These results provide new insight into the cardioprotective action of estrogen as well as a paradigm of the response-to-injury hypothesis.

Key Words: hormones • apoptosis • hydrogen peroxide • atherosclerosis

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