Bestatin Results in Pathophysiological Changes Similar to Preeclampsia in Rats Via Induction of Placental Apoptosis

Abstract

Objective: To establish a rat preeclampsia model with fetoplacental growth restriction caused by bestatin via induction of placental apoptosis. Study design: 200 mg/kg/day of bestatin or saline as a control were infused intraperitoneally into pregnant Wistar rats from 15 days' gestation. In the first experiment, maternal blood pressure and proteinuria were examined during the pre- and postpartum periods. In the second experiment, cesarean sections were performed at 20 days' gestation and the weights of pups and placentas, and levels of proteinuria and placental apoptosis were examined. Results: Physiological decrease of blood pressure in late pregnancy was not detected in the bestatin group but proteinuria level at 20 days' gestation was elevated. The weights of pups and placentas in the bestatin group were significantly lower than those in the controls, bestatin strongly inducing apoptosis in the placenta. Conclusion: Bestatin may cause a preeclampsia-like condition through induction of placental apoptosis.

Key words

Preeclampsia - Pregnancy - Trophoblast Apoptosis - Bestatin - Animal model

References

• 1 Working Group on High Blood Pressure in Pregnancy . Report of the National High Blood Pressure Education Program.  Am J Obstet Gynecol. 2000 Jul;  183 (1) S1-S22
• 2 Roberts J M. Endothelial dysfunction in preeclampsia.  Semin Reprod Endocrinol. 1998;  16 (1) 5-15 Review
• 3 Smith S C, Baker P N, Symonds E M. Increased placental apoptosis in intrauterine growth restriction.  Am J Obstet Gynecol. 1997;  177 1395-1401
• 4 Leung D N, Smith S C, To K F, Sahota D S, Baker P N. Increased placental apoptosis in pregnancies complicated by preeclampsia.  Am J Obstet Gynecol. 2001;  184 1249-1250
• 5 Allaire A D, Ballenger K A, Wells S R, Mcmahon M J, Lessey B A. Placental apoptosis in preeclampsia.  Obstet Gynecol. 2000;  96 271-276
• 6 von Dadelszen P, Watson R W, Noorwali F, Marshall J C, Parodo J, Farine D, Lye S J, Ritchie J W, Rotstein O D. Maternal neutrophil apoptosis in normal pregnancy, preeclampsia, and normotensive intrauterine growth restriction.  Am J Obstet Gynecol. 1999;  181 408-414
• 7 DiFederico E, Genbacev O, Fisher S J. Preeclampsia is associated with widespread apoptosis of placental cytotrophoblasts within the uterine wall.  Am J Pathol. 1999;  155 293-301
• 8 Levy R, Smith S D, Yusuf K, Huettner P C, Kraus F T, Sadovsky Y, Nelson D M. Trophoblast apoptosis from pregnancies complicated by fetal growth restriction is associated with enhanced p53 expression.  Am J Obstet Gynecol. 2002 May;  186 (5) 1056-1061
• 9 Ishihara N, Matsuo H, Murakoshi H, Laoag-Fernandez J B, Samoto T, Maruo T. Increased apoptosis in the syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation.  Am J Obstet Gynecol. 2002 Jan;  186 (1) 158-166
• 10 Podjarny E, Baylis C, Losonczy G. Animal models of preeclampsia.  Semin Perinatol. 1999 Feb;  23 (1) 2-13 Review
• 11 Leyhausen G, Schuster D K, Vaith P, Zahn R K, Umezawa H, Falke D, Muller W E. Identification and properties of the cell membrane bound leucine aminopeptidase interacting with the potential immunostimulant and chemotherapeutic agent bestatin.  Biochem Pharmacol. 1983;  15 1051-1057
• 12 Ino K, Goto S, Okamoto T, Nomura S, Nawa A, Isobe K, Mizutani S, Tomoda Y. Expression of aminopeptidase N on human choriocarcinoma cells and cell growth suppression by the inhibition of aminopeptidase N activity.  Jpn J Cancer Res. 1994;  85 927-933
• 13 Ino K, Goto S, Nomura S, Isobe K, Nawa A, Okamoto T. Aminopeptidase inhibitor ubenimex (bestatin) inhibits the growth of human choriocarcinoma in nude mice through its direct cytostastic activity.  Anticancer Res. 1995;  15 2081-2087
• 14 Ino K, Goto S, Kosaki A, Nomura S, Asada E, Misawa T, Furuhashi Y, Mizutani S, Tomoda Y. Growth inhibitory effect of bestatin on choriocarcinoma cell lines in vitro.  Biotherapy. 1991;  3 351-357
• 15 Ino K, Isobe K, Goto S, Nakashima I, Tomoda Y. Inhibitory effect of bestatin on the growth of human lymphocytes.  Immunopharmacology. 1992;  23 163-171
• 16 Sakurada K, Imamura M, Kobayashi M, Tachibana N, Abe K, Tanaka M, Okabe M, Morioka M, Kasai M, Sugiura T. Inhibitory effect of bestatin on the growth of human leukemic cells.  Acta Oncol. 1990;  29 799-802
• 17 Sekine K, Fujii H, Abe F. Induction of apoptosis by bestatin in human leukemic cell lines.  Leukemia. 1999;  13 729-734
• 18 Ezawa K, Minato K, Dobashi K. Induction of apoptosis by ubenimex (bestatin) in human non-small-cell lung cancer cell lines.  Biomed Pharmacother. 1996;  50 283-289
• 19 Muller W E, Schuster D K, Zahn R K, Maidhof A, Leyhausen G, Falke D, Koren R, Umezawa H. Properties and specificity of binding sites for the immunomodulator bestatin on the surface of mammalian cells.  Int J Immunopharmacol. 1982;  4 393-400
• 20 Doering T P, Haller N A, Montgomery M A, Freeman E J, Hopkins M P. The role of AT1 angiotensin receptor activation in the pathogenesis of preeclampsia.  Am J Obstet Gynecol. 1998 Jun;  178 (6) 1307-1312
• 21 Helmbrecht G D, Farhat M Y, Lochbaum L, Brown H E, Yadgarova K T, Eglinton G S, Ramwell P W. L-arginine reverses the adverse pregnancy changes induced by nitric oxide synthase inhibition in the rat.  Am J Obstet Gynecol. 1996 Oct;  175 (4 Pt 1) 800-805
• 22 Buhimschi I, Tallampalli C, Chwalisz K, Garfield R. Preeclampsia-like conditions produced by nitric oxide inhibition: effects of L-arginine, D-arginine and steroid hormones.  Hum Reprod. 1995;  10 2723-2730
• 23 Furuhashi M, Mizutani S, Kurauchi O, Kasugai M, Tomoda Y. Effects of bestatin on intrauterine growth of rat fetuses.  Horm Metabol Res. 1989;  21 366-368
• 24 Sakakibara T, Sakai Y, Sakamoto M, Ito K, Hagiwara T, Furuta Y, Takahashi K, Tsubosaki M, Matsuda A, Konoha N. Toxicological studies on bestatin. IV. Studies on antigenicity, ocular mucosal irritation and mutagenicity.  Jpn J Antibiot. 1983;  36 3194-3203
• 25 Gallaher B W, Hille R, Raile K, Kiess W. Apoptosis: live or die - hard work either way!.  Horm Metab Res 2001. Sep;  33 (9) 511-519
• 26 Smith S C, Baker P N, Symonds E M. Placental apoptosis in normal human pregnancy.  Am J Obstet Gynecol. 1997 Jul;  177 (1) 57-65
• 27 Levy R, Smith S D, Chandler K, Sadovsky Y, Nelson D M. Apoptosis in human cultured trophoblasts is enhanced by hypoxia and diminished by epidermal growth factor.  Am J Physiol Cell Physiol. 2000 May;  278 (5) C982-C988
• 28 Hung T H, Skepper J N, Charnock-Jones D S, Burton G J. Hypoxia-reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia.  Circ Res. 2002 Jun 28;  90 (12) 1274-1281
• 29 Redman C W, Sargent I L. Placental debris, oxidative stress and pre-eclampsia.  Placenta. 2000 Sep;  21 (7) 597-602 Review
• 30 Lyall F, Myatt L. The role of the placenta in pre-eclampsia - a workshop report.  Placenta. 2002 Apr;  23 Suppl A S142-S145
• 31 Urabe A, Mutoh Y, Mizoguchi H, Takaku F, Ogawa N. Ubenimex in the treatment of acute nonlymphocytic leukemia in adults.  Ann Hematol. 1993;  67 63-66
• 32 Suzuki K, Kobayashi M, Kobayashi K, Shiraishi Y, Goto S, Hoshino T. Structual and functional change of blood vessel labyrinth in maturing placenta of mice.  Trophoblast Res. 1997;  9 155-164
• 33 Rosenzwajg M, Tailleux L, Gluckman J C. CD13/N-aminopeptidase is involved in the development of dendritic cells and macrophages from cord blood CD34 (+) cells.  Blood. 2000;  95 453-460