Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
Department of Pediatrics, Division of Endocrinology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
PLoS One. 2018 Mar 28;13(3):e0193583. doi: 10.1371/journal.pone.0193583. eCollection 2018.
Intrauterine growth restriction (IUGR) results from a lack of nutrients transferred to the developing fetus, particularly oxygen and glucose. Increased expression of the cytoprotective mitochondrial peptide, humanin (HN), and the glucose transporter 8, GLUT8, has been reported under conditions of hypoxic stress. However, the presence and cellular localization of HN and GLUT8 in IUGR-related placental pathology remain unexplored. Thus, we undertook this study to investigate placental expression of HN and GLUT8 in IUGR-affected versus normal pregnancies.
We found 1) increased HN expression in human IUGR-affected pregnancies on the maternal aspect of the placenta (extravillous trophoblastic (EVT) cytoplasm) compared to control (i.e. appropriate for gestational age) pregnancies, and a concomitant increase in GLUT8 expression in the same compartment, 2) HN and GLUT8 showed a protein-protein interaction by co-immunoprecipitation, 3) elevated HN and GLUT8 levels in vitro under simulated hypoxia in human EVT cells, HTR8/SVneo, and 4) increased HN expression but attenuated GLUT8 expression in vitro under serum deprivation in HTR8/SVneo cells.
There was elevated HN expression with cytoplasmic localization to EVTs on the maternal aspect of the human placenta affected by IUGR, also associated with increased GLUT8 expression. We found that while hypoxia increased both HN and GLUT8, serum deprivation increased HN expression alone. Also, a protein-protein interaction between HN and GLUT8 suggests that their interaction may fulfill a biologic role that requires interdependency. Future investigations delineating molecular interactions between these proteins are required to fully uncover their role in IUGR-affected pregnancies.
宫内生长受限（IUGR）是由于向发育中的胎儿输送的营养物质（特别是氧气和葡萄糖）不足引起的。在缺氧应激条件下，已报道细胞保护线粒体肽人源素（HN）和葡萄糖转运蛋白 8（GLUT8）的表达增加。然而，HN 和 GLUT8 在与 IUGR 相关的胎盘病理中的存在和细胞定位仍未得到探索。因此，我们进行了这项研究，以调查 IUGR 相关胎盘组织中人源素（HN）和 GLUT8 的表达。
我们发现 1）与对照组（即适合胎龄）相比，在人类 IUGR 受影响的妊娠中，HN 在胎盘母面（绒毛外滋养细胞（EVT）细胞质）的表达增加，同时同一部位的 GLUT8 表达增加，2）HN 和 GLUT8 通过共免疫沉淀显示出蛋白-蛋白相互作用，3）在模拟缺氧的条件下，HN 和 GLUT8 在体外的水平升高，在人类 EVT 细胞 HTR8/SVneo 中，4）在 HTR8/SVneo 细胞中血清剥夺下，HN 表达增加但 GLUT8 表达减弱。
在受 IUGR 影响的人类胎盘母面 EVT 中，HN 表达增加且定位于细胞质，同时 GLUT8 表达增加。我们发现，虽然缺氧会增加 HN 和 GLUT8 的表达，但血清剥夺会单独增加 HN 的表达。此外，HN 和 GLUT8 之间的蛋白-蛋白相互作用表明，它们的相互作用可能具有需要相互依赖的生物学作用。需要进一步研究以阐明这些蛋白质之间的分子相互作用，以充分揭示它们在 IUGR 受影响的妊娠中的作用。
