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1 34 6 Vol. 34 No Journal of Jinan University Medicine Edition Dec Ang Hocher Berthold University of Potsdam Institute of Nutritional Science Nuthetal-Potsdam Germany 1-7 Ang 1-7 Ⅱ AngⅡ Ang 1-7 AngⅡ Logistic Ang 1-7 AngⅡ Ang 1-7 /AngⅡ ± ± ng /L P < ± ± ng /L P = Ang 1-7 /AngⅡ ± ± P = Ang 1-7 AngⅡ ± ± ng /L P = ± ± ng /L P = Ang 1-7 /AngⅡ ± ± P = Logistic Ang 1-7 OR % ~ P < % ~ P = Ang Ⅱ R A Impact of both maternal and neonatal plasma angiotensin 1-7 levels on preterm delivery LU Yongping 1 CHEN Youpeng 1 LIU Zhiwei 1 CHEN Wenjing 2 LIANG Xujing 1 CHEN Xin 3 WEN Wangrong 2 HOCHER Berthold 4 XIAO Xiaomin 3 1. Department of Infectious Diseases 2. Centre for Clinical Laboratory Medicine 3. Department of Obstetrics and Gynecology the First Affiliated Hospital Jinan University Guangzhou China 4. University of Potsdam Institute of Nutritional Science Nuthetal-Potsdam Germany Abstract Aim To investigate the impact of both maternal and neonatal plasma angiotensin 1-7 Ang 1-7 and angiotensinii AngⅡ levels on preterm delivery and intrauterine fetal growth. Methods 309 cases of pregnant women were prospectively participated in this study. The pregnant women were divided into two groups of preterm birth and full-term birth according to the gestational weeks as low Hocher Tel typchen@ jnu. edu. cn

2 6 Ang er than 37 weeks n = 17 and 37 weeks or more n = 292. Maternal and neonatal plasma Ang 1-7 and AngⅡ concentrations were tested by enzyme-linked immunosorbent assay. The risk factors of preterm birth were done by logistic regression analysis. Results Compared with full-term birth group maternal plasma Ang 1-7 AngⅡconcentrations and ratio of Ang 1-7 /AngⅡin preterm group were significantly lower. Neonatal plasma Ang 1-7 and AngⅡ levels of umbilical cord in preterm group were also significantly lower than those in full-term birth group. However no significant difference of the ratio of neonatal plasma Ang 1-7 /AngⅡ in umbilical cord was shown. Logistic regression analysis was shown that the risk factors of preterm delivery are premature rupture of membranes OR = P < and low level of neonatal plasma Ang 1-7 OR = % CI P = after adjusted for the confusing factors such as preeclampsia. Conclusion Low neonatal plasma Ang 1-7 level might have the high risk for preterm delivery. Key words angiotensin 1-7 angiotensinⅡ pregnant preterm delivery intrauterine fetal growth 2 angiotensin-converting enzyme type 2 ACE2-1-7 angiotensin 1-7 Ang 1-7 -Mas - renin-angiotensin system RAS ACE-AngⅡ- Ⅱ 1 angiotensinⅡ type 1 receptor AT 1 R AngⅡ Ang RAS RAS body mass index BMI 7-8 Ang 1-7 AngⅡ RAS Apgar RSA Ang 1-7 AngⅡ Ang 1-7 AngⅡ 3 ml 4 Ang r /min 7 min 1-7 /AngⅡ HIV 2 Ang 1-7 AngⅡ 5 ml ELISA Ang 1-7 Ang Ⅱ Ang ~ ng /L AngⅡ 1. 5 ~ ng /L 5

3 ± ± ± P < 0. 01Apgar P > 1. 3 SPSS ± x 珋 ± s t ± ± ng /L 2 Contiuity Correction Logistic ± ng /L Ang 1- P < P > ± ± ± ± cm BMI ± ± kg /m ± ± ± ± Logistic % % 0. 3% 0% Ang 1-7 AngⅡ Ang 1-7 Ang ± 7 /AngⅡ ± ± P < Ang 1-7 / AngⅡ ± ± Ang 1-7 Ang Ⅱ Ang 1-7 /AngⅡ 0% ~ 33. 3% 33. 4% ~ 66. 6% 66. 7% ~ 100% 3 1 BMI > % % P > Ang 1-7 Ang 1-7 AngⅡ Ang P > Ⅱ Ang 1-7 /AngⅡ BMI > 24 P < Ang Ang 1-7 OR ± Table 1 1 Comparison of clinical characteristics in pregnant women between the two groups of full-term birth and preterm birth BMI < > 24 < 10 kg 10 ~ 15 kg > 15 kg % % % % % % % % % % 0 0% % % % % % % % % % % % % % % 0 0% 0 0% 0 0% % % OR t/ P < < < < Table 2 2 Comparison of clinical parameters of the neonates between the two groups of full-term birth and preterm birth /d /g /g Apgar < ~ > min 5 min 10 min ± ± % % % ± ± ± ± ± % % 0 0% ± ± ± t / P < < <

4 6 Ang Table 3 3 Ang 1-7 AngII Ang 1-7 /AngⅡ Plasma Ang 1-7 and AngII concentrations and Ang 1-7 / AngII ratio in pregnant women and their neonates Ang 1-7 / AngⅡ / Ang 1-7 / AngⅡ Ang 1-7 / AngⅡ / Ang 1-7 / ± ± ± ± ± ± ± ± ± ± ± ± t P < AngⅡ Table 4 4 Univariate regression analysis of risk factor for preterm birth B SE OR 95% CI P BMI > ~ ~ < ~ ~ < ~ ~ < ~ < Ang ~ Ang ~ AngⅡ ~ AngⅡ ~ Ang 1-7 /AngⅡ ~ Ang 1-7 /AngⅡ ~ Logistic A Ang 1-7 OR ~ % ~ A B OR % CI ~ P B B OR % CI ~ ~ P Ang 1-7 B OR % CI ~ ~ P RAS RAS Ang % ~ % AngⅡ A Logistic B 5-12 Ang 1-7 Ang 1-7 /AngⅡ 5 Table 5 Multiple regression analysis of risk factor for preterm birth AngⅡ Ang 1-7 Th1 -α Tumor Necrosis Factorα TNF-α -6 Interleukin-6 IL Ang 1-7 Ang 1-7 /AngⅡ

5 SAMPAIO W O HENRIQUE D E CASTRO C SANTOS R A et al. Angiotensin- 1-7 counterregulates angioten- Ang 1-7 AngⅡ sin II signaling in human endothelial cells J. Hypertension TNF-α IL-6-2 /-8 /-9 Matrix metalloproteinase-2 /-8 /-10 MMP-2 MMP-8 MMP /-8 /-9 I Ⅱ 3 COSTA A P FAGUNDES-MOURA C R PEREIRA V M et al. Angiotensin- 1-7 a novel peptide in the ova % ry J. Endocrinology HBsAg 4 MITSUBE K MIKUNI M MATOUSEK M et al. Role HBsAg of the angiotensin II system in regulation of ovulation and 34 30% ~ 40% blood flow in the rat ovary J. Reproduction PEREIRA V M REIS F M SANTOS R A et al. Gonadotropin stimulation increases the expression of angioten % % sin- 1-7 and Mas receptor in the rat ovary J. Reprod Ang 1-7 Logistic Sci Ang REIS F M BOUISSOU D R PEREIRA V M et al. Angiotensin- 1-7 its receptor Mas and the angiotensin- Ang 1-7 TNF-α IL-6 converting enzyme type 2 are expressed in the human ovary J. Fertil Steril OR % ~ VAZ-SILVA J CARNEIRO M M FERREIRA M C et al. The vasoactive peptide angiotensin- 1-7 its receptor Mas and the angiotensin-converting enzyme type 2 are Ang 1-7 AngⅡ expressed in the human endometrium J. Reprod Sci Ang 1-7 AngⅡ PIASTOWSKA-CIESIELSKA A W P UCIENNIK E 15 - Ang 1-7 Ang Ⅱ 17 W JCIK-KROWIRANDA K et al. Analysis of the expression of angiotensin II type 1 receptor and VEGF in Ang 1-7 /AngⅡ endometrial adenocarcinoma with different clinicopathological characteristics J. Tumour Biol % 9 PRINGLE K G TADROS M A CALLISTER R J et al % The expression and localization of the human placental ACE2-Ang 1-7 -Mas ACE-AngⅡ-AT 1 R prorenin /renin-angiotensin system throughout pregnancy RAS roles in trophoblast invasion and angiogenesis J. Placenta XIA Y WEN H Y KELLEMS R E. Angiotensin II inhibits human trophoblast invasion through AT1 Ang 1-7 receptor 2 LEAL M C PINHEIRO S V FERREIRA A J et al. The role of angiotensin- 1-7 receptor Mas in spermatogenesis in mice and rats J. J Anat Ang 1-7 /AngⅡ activation J. J Biol Chem TOWER C L LUI S CHARLESWORTH N R et al. Differential expression of angiotensin II type 1 and type 2 Ang 1-7 AngⅡ RAS receptors at the maternal-fetal interface potential roles in early placental development J. Reproduction NEVES L A STOVALL K JOYNER J et al. ACE2 and ANG- 1-7 in the rat uterus during early and late gestation J. Am J Physiol Regul Integr Comp Physiol

6 6 Ang HOCHER B COLE A A CHUBINSKAYA S SCHUMACHER B et 1-7 -Mas al. Chondrocyte matrix metalloproteinase-8. Human articular chondrocytes express neutrophil collagenase J. J J Biol Chem MERRILL D C KAROLY M CHEN K et al. Angiotensin- 1-7 in normal and preeclamptic pregnancy J. Endocrine BROSNIHAN K B NEVES L A ANTON L et al. Enhanced expression of Ang- 1-7 during pregnancy J. Braz J Med Biol Res VALD S G NEVES L A ANTON L et al. Distribution of angiotensin- 1-7 and ACE2 in human placentas of normal and pathological pregnancies J. Placenta Dent Res / ROH C R OH W J YOON B K et al. Up-regulation of 18 SHOBOKSHI A SHAARAWY M. Maternal serum and amniotic fluid cytokines in patients with preterm premature rupture of membranes with and without intrauterine infection J. Int J Gynecol Obstet DUBICKE A AKERUD A SENNSTROM M et al. Different secretion patterns of matrix metalproteinases and IL-8 and effect of corticotropin-releasing hormone in preterm and term cervical fibroblasts J. Mol Hum Reprod SHYNLOVA O TSUI P JAFFER S et al. Integration of endocrine and mechanical signals in the regulation of myometria1 functions during pregnancy and labour J. Eur J Obstet Gynecol Reprod Biol S2 - S VEGA-SANCHEZ R GOMEZ-LOPEZ N FLORES- PLIEGO A et al. Placental blood leukocytes are functional and phenotypically different than peripheral leukocytes during human labor J. J Reprod Immuno SUZUKI Y RUIZ-ORTEGA M LORENZO O et al. Inflammation and angiotensin II J. Int J Biochem Cell Biol RUIZ-ORTEGA M RUP REZ M ESTEBAN V et al. Angiotensin II a key factor in the inflammatory and fibrotic response in kidney diseases J. Nephrol Dial Transplant MARCHESI C PARADIS P SCHIFFRIN E L. Role of the renin-angiotensin system in vascular inflammation J. Trends Pharmacol Sci da SILVEIRA K D COELHO F M VIEIRA A T et al. Anti-inflammatory effects of the activation of the angiotensin- 1-7 receptor MAS in experimental models of arthritis J. J Immunol HOCHER B SOUZA L L COSTA-NETO C M. Angiotensin- 1-7 decreases LPS-induced inflammatory response in J. macrophages J. J Cell Physiol HANEMAAIJER R SORSA T KONTTINEN Y T et al. Matrix metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and endothelial cells. Regulation by tumor necrosis factor-alpha and doxycycline J. J Biol Chem PALOSAARI H WAHLGREN J LARMAS M et al. The expression of MMP-8 in human odontablasts and dental pulp cells is downregulated by TGF-beta l J. J matrix metalloproteinase-9 in human myometrium during labour a cytokine-mediated process in uterine smooth muscle cells J. Mol Hum Reprod MANO Y SHIBATA K SUMIGAMA S et al. Tocilizumab inhibits interleukin-6-mediated matrix metalloproteinase-2 and-9 secretions from human amnion cells in preterm premature rupture of membranes J. Gynecol Obstet Invest LEE S Y BUHIMSCHI I A DULAY A T et al. IL-6 trans-signaling system in trans-amniotic inflammation preterm birth and preterm premature rupture of the membranes J. J Immunol MERCER B M. Preterm premature rupture of the membranes J. Obstet Gynecol HBsAg J BUCHBINDER A SIBAI B M CARITIS S et al. Adverse perinatal outcomes are significantly higher in severe gestational hypertension than in mild preeclampsia J. Am J Obstet Gynecol HEARD A R DEKKER G A CHAN A et al. Hypertension during pregnancy in South Australia part 1 pregnancy outcomes J. Aust N Z J Obstet Gynaecol HABLI M LEVINE R J QIAN C et al. Neonatal outcomes in pregnancies with preeclampsia or gestational hypertension and in normotensive pregnancies that delivered at or 37 weeks of gestation J. Am J Obstet Gynecol e1-7.

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