“The aminopeptidases which degrade hormones produced from fetus”



In normal pregnancy the fetus produces angiotensin, vasopressin and oxytocin with advancing gestation.

Although the production of vasopressin is much higher than that of oxytocin in the fetus, the ratio of vasopressin: oxytocin changes with advancing gestation. The equal ratio of vasopressin: oxytocin is achieved at later birth.

As I have shown previously, fetus increases markedly the production of both angiotensin and vasopressin at hypoxic state.

Both vasopressin and oxytocin are degraded by oxytocinase (P-LAP). We have shown the amino acid sequence of P-LAP in 1996(Ref1).The structure of oxytocin is similar to vasopressin.

The only one amino acid is different between them.

As I have shown that the blood pressure was observed in pregnant imprisoned women by administration of angiotensin.

Although there are many biological substances such as adrenaline which increase blood pressure in human, among them the most active biological substance in human body is angiotensin. In the previous blog I have introduced that angiotensinase (angiotensin degrading enzyme) research started around 1940 by gynecologists in USA. In 1981 we have shown that this enzyme has the degrading biological activity of angiotensin(blood pressure increasing activity) by cleavage of N-terminal amino acid Asp from angiotensin(,A-) and the existence of this enzyme in human placenta(Ref.2).

This enzyme is aminopeptidase A (APA). However this historical evidencethe essential role of hypertensive activity of A- is degraded by leakage of N-terminal amino acid Asp of A-, is still in dispute due to the recent armchair theory due to the new biological activity of angiotensin 1-7. We have shown that the knockout mouse of APA is hypertensive (Ref.3). We have shown that both APA and P-LAP might be the ideal drugs for both preeclampsia and preterm labor(Ref.4 ). Recently Brown CM and Garovic VD have suggested that both APA and P-LAP are novel therapeutic drugs for preeclampsia(Ref.5,6).



Ref.

1. Rogi T, et al. Human placental leucine aminopeptidase/oxytocinase: a new member of type I membrane-spanning zinc

metallopeptidase family. J Biol Chem1996271:56-61

2. Mizutani s. et al.Aminopeptidase A in human placenta. Biochim Biophys Acta. 1981;678:168-170

3. Mitsui T et al. Hypertension and angiotensin hypersensitivity in aminopeptidase A deficient mice. Mol Med 2003;9:57-62

4. Mizutani S et al. New insights into the role of aminopeptidases in the treatment for both preeclampsia and preterm labor. Expert Opin Investig drugs 2013 Nov;22(11):1425-36. doi: 10.1517/13543784.2013.825248. Epub 2013 Aug 10. PMID:23931642

5. Brown CM, Garovic VD. Mechanisms and management of hypertension in pregnant women. Curr Hypertens Rep. (2011)13:338-346. doi:10.1007/s 11906-011-0214-y

6.Brown CM,Garovic VD.Drug Treatment of Hypertension in Pregnancy.Drugs. 2014 Mar;74(3):283-96. doi: 10.1007/s40265-014-0187-7.PMID:24554373