胎盤プロテアーゼ : 妊娠の枠を超えた多彩な機能(第57回学術講演会講演要旨)

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The effect of various peptide hormones produced from fetus on mother might be the essence of both physiology and pathophysiology in pregnancy. I have started my research based on a working hypothesis as follows : 1. Peptide hormones produced from fetus increase with advancing gestation or fetal academia. 2. These hormones might leak into the maternal site and have an effect on pregnant women. 3. There are many aminopeptidases which degrade fetal peptide hormones and work as a barrier between fetus and mother. The fetus produces oxytocin and angiotensin actively and they act as uterotonic and vasoactive agents in the maternal site. Therefore leak of both hormones from fetus into mother might result in both preterm delivery and preeclampsia, respectively. It is essential to clarify the placental aminopeptidases which degrade both oxytocin and angiotensin II for the understanding of physiology and pathophysiology in pregnancy. Our study have clarified both oxytocin and angiotensin degrading aminopeptidases : oxytocinase_(placental leucine aminopeptidase, P-LAP) and angiotencinase_(aminopeptidase A, APA). Since their activities in pregnancy sera increase with advancing gestation, the movement of them suggests the importance of both peptide hormones in not only the onset of labor but also both preterm labor and preeclampsia. Both P-LAP and APA are existed ubiquitously. They are existed in the endometrium, ovary, fallopian tube and uterine cervix. Both expression and localization of them change during menstrual cycle. It is suggested that they are involved in conception and menstruation via regulating oxytocin and angiotensin. Both P-LAP and APA are existed in cervical, endometrial and ovarian cancer and choriocarcinoma. Their expression changes in relation to the advancing malignancy. Therefore it is suggested that they are involved in proliferation, invasion and metastasis of gynecological cancer via regulating oxytocin and angiotensin. We have cloned P-LAP and clarified the mechanisms of its expression. P-LAP is induced with differentiation of chorionic cell and localized in syncytiotrophoblast. We have found that AP-2 is the main activator, and Ikaros functions with AP-2 cooperatively for maximal expression of P-LAP gene. We also showed that forskolin treatment up-regulates P-LAP gene expression via AP-2. Our study of mice deficient in APA, spontaneously hypertensive rats and Dahl salt-sensitive rats showed that APA is essential for blood pressure regulation. In rat adipocytes, major protein of insulin-responsive glucose transporter isotype GLUT4 vesicles was named insulin-regulated membrane aminopeptidase_(IRAP). It translocates to the cell surface within GLUT4 vesicles in response to insulin. Simultaneously to our P-LAP cloning, IRAP was cloned and shown to be a rat homologue of P-LAP. Trafficking of IRAP in response to insulin means that insulin upregulates the cell surface peptidase activity and enhances the degradation of vasopressin in adipocytes. Oxytocin also stimulates the translocation of P-LAP in human vascular endothelial cells, which can be regarded as a negative feedback mechanism of oxytocin. We cloned cDNAs encoding adipocyte-derived leucine aminopeptidase (A-LAP) and leukocyte-derived arginine aminopeptidase (L-RAP) as highly homogenous proteins to P-LAP. Both A-LAP and L-RAP are the aminopeptidases localized in the endoplasmic reticulum processing antigenic peptides presented to major histocompatibility complex_(MHC) class I molecules. My research aiming placental function is now expanding into various fields of life science.
社団法人日本産科婦人科学会の論文
2005-08-01

胎盤プロテアーゼ : 妊娠の枠を超えた多彩な機能(第57回学術講演会講演要旨)

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