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ABSTRACT: Preeclampsia and preterm delivery are important potential complications in pregnancy and represent the leading causes for maternal and perinatal morbidity and mortality. The mechanisms underlying both diseases remain unknown, thus available treatments (beta2-stimulants and magnesium sulfate) are essentially symptomatic. Both molecules have molecular weights less than 5-8 kDa, cross the placental barrier, and thus exert their effects on the fetus. The fetus produces peptides that are highly vasoactive and uterotonic and increase in response to maternal stress and with continued development. Fetal peptides are also small molecules that inevitably leak across into the maternal circulation. Aminopeptidases such as placental leucine aminopeptidase (P-LAP) and aminopeptidase A (APA) are large molecules that do not cross the placental barrier. We have shown that APA acts as an antihypertensive agent in the pregnant spontaneously hypertensive rat by degrading vasoactive peptides and as a result returns the animal to a normotensive state. P-LAP also acts as an antiuterotonic agent by degrading uterotonic peptides and thus prolongs gestation in the pregnant mouse. Given the ever increasing worldwide incidences of preeclampsia and preterm labor, it is imperative that new agents be developed to safely prolong gestation. We believe that the use of aminopeptidases hold promise in this regard.
Journal of Biomedicine and Biotechnology 01/2011; 2011:286947. · 2.44 Impact Factor
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ABSTRACT: Both preeclampsia and preterm delivery are important complications in pregnancy and are leading causes for maternal and perinatal morbidity and mortality. The underlying molecular mechanisms of both diseases remain unknown, thus treatments (beta2-stimulants and magnesium sulfate) are essentially symptomatic. Both molecules have molecular weights less than 5-8 kDa and cross the placental barrier thus exerting their effects on the fetus. In addition, the fetus produces peptide hormones that are highly vasoactive and uterotonic and increase in response to maternal stress and with continued development. Fetal peptides are also small molecules that inevitably leak across into the maternal circulation. Aminopeptidases such as placental leucine aminopeptidase (P-LAP) and aminopeptidase A (APA) are large molecules that do not cross the placental barrier. We have shown that APA acts as an antihypertensive agent in the pregnant spontaneously hypertensive rat by degrading vasoactive peptides and as a result returns the animal to a normotensive state. We have also noted that P-LAP acts as an anti-uterotonic agent by degrading uterotonic peptides, and as a result prolongs gestation in the pregnant mouse. Thus, P-LAP and APA represent promising agents for the treatment of preeclampsia and preterm labor by degrading bioactive hormones derived from the feto-placental circulation.
Life sciences 10/2010; 88(1-2):17-23. · 2.56 Impact Factor
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ABSTRACT: Background: Both preeclampsia and preterm delivery are important complications in pregnancy and are still diseases of unknown causes, despite considerable research in recent times. These complications constitute obstetric emergencies that require expert knowledge and management skills. Objectives: This article reviews the emerging role of aminopeptidases in the monitoring and development of improved therapeutic strategies that provide better patient selection for therapeutic personalization. Methods: A literature review (PubMed, Medline) to the present. Results/conclusion: The fetus produces angiotensin II, vasopressin and oxytocin, which are highly vasoactive and uterotonic, and these peptides increase in parallel with fetal growth and in response to stressors such as hypoxia. Because these hormones are small molecules, it is probable that there occurs the leak out of these hormones from the feto-placental unit. Oxytocinase and angiotensinase in human placenta are identical to placental leucine aminopeptidase and aminopeptidase A, respectively. They work as barriers of peptide hormones between fetus and mother and their activities in pregnancy sera increase with advancing gestation. Aminopeptidase activities in maternal sera might be useful for monitoring of preeclampsia and predicting the prognosis of preterm delivery.
Expert Opinion on Medical Diagnostics 09/2009; 3(5):479-91.
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ABSTRACT: We have tested the effects of aminopeptidase A (APA), MgSO(4) and various conventional antihypertensive drugs on hypertension in pregnant spontaneously hypertensive rats (SHRs) and examined the effects on both fetal heart and kidney.
We used recombinant human APA, which has been recently shown to work as an antihypertensive agent in SHRs (n=5). Each drug was administered from gestational day 10 to day 20 and each dose was increased daily up to 10 fold until the end of treatment except for MgSO(4) (n=5 per each group). Blood pressure (BP) was monitored and fetal kidneys and heart were histologically examined.
The antihypertensive effects of the drugs were in the following order: hydralazine>aminopeptidase A and angiotensin receptor blockers (ARBs), candesartan>MgSO(4) and methyldopa. Microscopic examination showed that fetal exposure to candesartan is associated with poor proximal tubular differentiation in the kidney and that to MgSO(4) is associated with poor blood vessel formation in the heart, respectively.
Our present study showed that APA is one of the candidates for antihypertensive agents in hypertension during pregnancy.
Early human development 07/2009; 85(9):589-94. · 2.12 Impact Factor
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ABSTRACT: Oxytocin (OT) is the strongest uterotonic substance and has been used widely to induce labor. The physiological importance of OT in modulating the initiation and progression of labor remains unclear. In this study, we showed the roles of OT with onset of labor and also the arginine vasopressin (AVP) effect on urine volume in vivo using both wild type (WT) and placental leucine aminopeptidase (P-LAP)-deficient (KO) mice.
OT (1, 2, 2.5 U/day) or recombinant P-LAP (0.01 U/day) was continuously infused from gestation day 15.5 in WT and P-LAP KO mice. Duration until onset of labor was observed. Before and after administration of AVP (1 U/day) in WT and P-LAP KO mice, urine volume was measured.
A significant shortening of pregnancy term was observed in P-LAP KO mice. Continuous infusion of OT (1 U/day) revealed that P-LAP KO mice resulted in premature delivery (OT hypersensitivity). We could observe a significant decrease of urine volume in P-LAP KO mice by administration of AVP. Administration of recombinant P-LAP in WT mice resulted in the delay of the onset of labor about 1.5 days compared with control mice.
Our present study shows that the regulation of the onset of labor mainly depends on OT and its degradation by P-LAP and also the possible role of P-LAP in the regulation of urine output. P-LAP might be involved in the increased OT sensitivity just prior to onset of labor and also in the onset of labor by degradation of OT.
Life sciences 03/2009; 84(19-20):668-72. · 2.56 Impact Factor
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ABSTRACT: The M1 aminopeptidase family is important for the maturation or degradation of bioactive peptides by hydrolyzing their N-terminal amino acids. Some investigators have studied aminopeptidase in the maintenance of homeostasis including maintenance of normal pregnancy, memory retention, blood pressure regulation and antigen presentation. However, there are a few reports on the relation between the M1 aminopeptidase family and carcinoma. In addition to its capacity to degrade a range of peptides, placental-leucine aminopeptidase (P-LAP) has novel functions that impact on normal cells and neoplastic cells. P-LAP is the focus of this review.
Expert opinion on therapeutic targets 05/2007; 11(4):453-61. · 3.72 Impact Factor
