Xiaotao Yang1,2,3,4, Ping Xu1,2,3, Fumei Zhang1,2,3, Li Zhang1,2,3,4, Yangxi Zheng1,2,3, Mingyu Hu1,2,3, Lulu Wang1,2,3, Ting-Li Han2,3,5, Chuan Peng2,3, Lianlian Wang1,2,3,6, Li Wen1,2,3, Yiwen Zeng1,2, Rufei Gao2,7, Yong Xia8, Chao Tong1,2,3, Zhu Yang2,9, Hongbo Qi1,2,3, Philip N Baker2,10. 1. Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 2. International Joint Laboratory of Reproduction and Development, Ministry of Education of China, Chongqing Medical University, Chongqing, China. 3. State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China. 4. Department of Gynaecology and Obstetrics, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China. 5. Liggins Institute, University of Auckland, Auckland, New Zealand. 6. Department of Reproduction Health and Infertility, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 7. Laboratory of Reproductive Biology, School of Public Health and Management, Chongqing Medical University, Chongqing, China. 8. Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, Ohio, USA. 9. Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. 10. College of Medicine, Biological Sciences and Psychology, University of Leicester, Leicester, United Kingdom.
Abstract
BACKGROUND/AIMS: Preeclampsia (PE) has long been assumed to be an ischemic disease of the placenta, although there is limited evidence as to how the ischemia impacts on the placenta. AMP-activated protein kinase (AMPK) is a key regulator of cellular energy metabolism and plays an important role in a variety of ischemic diseases by enhancing energy production. The present study investigated placental metabolism in PE, and the role of AMPK in regulating trophoblast function. METHODS: placentas from normal and PE complicated pregnancies were subjected to GC-MS to identify fatty acids (FA) metabolic fingerprints, and total FA oxidation was assessed by malondialdehyde (MDA) measurement. The AMPK-ACC signaling pathway was assessed by q-PCR and Western Blotting. HTR8/SVneo trophoblast cultures were exposed to different oxygenation conditions to establish an in vitro PE cell model; further analysis by GC-MS for metabolite profiling was then undertaken. Trophoblasts invasion was assessed by a matrigel transwell assay in the presence/absence of AMPK expression and after manipulations of AMPK activity, and then further validated by human villi outgrowth experiments. RESULTS: AMPK phosphorylation and MDA production were significantly elevated in placentas from pregnancies complicated by PE. Metabolism of cis double bond FA was inhibited while trans double bond FA metabolism was promoted in PE placentas. HTR8/SVneo cell culture conditions of persistent low oxygenation mimicked the hyper-activation of AMPK and enhanced the FA oxidation that was observed in PE. AMPK activation impaired trophoblast invasion, while AMPK inhibition promoted trophoblast invasion. CONCLUSION: PE complicated placentas are associated with AMPK hyper-activation and consequent alterations in FA oxidation, which inhibit trophoblast invasion.
BACKGROUND/AIMS: Preeclampsia (PE) has long been assumed to be an ischemic disease of the placenta, although there is limited evidence as to how the ischemia impacts on the placenta. AMP-activated protein kinase (AMPK) is a key regulator of cellular energy metabolism and plays an important role in a variety of ischemic diseases by enhancing energy production. The present study investigated placental metabolism in PE, and the role of AMPK in regulating trophoblast function. METHODS: placentas from normal and PE complicated pregnancies were subjected to GC-MS to identify fatty acids (FA) metabolic fingerprints, and total FA oxidation was assessed by malondialdehyde (MDA) measurement. The AMPK-ACC signaling pathway was assessed by q-PCR and Western Blotting. HTR8/SVneo trophoblast cultures were exposed to different oxygenation conditions to establish an in vitro PE cell model; further analysis by GC-MS for metabolite profiling was then undertaken. Trophoblasts invasion was assessed by a matrigel transwell assay in the presence/absence of AMPK expression and after manipulations of AMPK activity, and then further validated by human villi outgrowth experiments. RESULTS:AMPK phosphorylation and MDA production were significantly elevated in placentas from pregnancies complicated by PE. Metabolism of cis double bond FA was inhibited while trans double bond FA metabolism was promoted in PE placentas. HTR8/SVneo cell culture conditions of persistent low oxygenation mimicked the hyper-activation of AMPK and enhanced the FA oxidation that was observed in PE. AMPK activation impaired trophoblast invasion, while AMPK inhibition promoted trophoblast invasion. CONCLUSION: PE complicated placentas are associated with AMPK hyper-activation and consequent alterations in FA oxidation, which inhibit trophoblast invasion.
Authors: Richard M Griffiths; Cindy A Pru; Susanta K Behura; Andrea R Cronrath; Melissa L McCallum; Nicole C Kelp; Wipawee Winuthayanon; Thomas E Spencer; James K Pru Journal: Reproduction Date: 2020-05 Impact factor: 3.906
Authors: Stacey J Ellery; Padma Murthi; Paul A Della Gatta; Anthony K May; Miranda L Davies-Tuck; Greg M Kowalski; Damien L Callahan; Clinton R Bruce; Euan M Wallace; David W Walker; Hayley Dickinson; Rod J Snow Journal: Int J Mol Sci Date: 2020-01-26 Impact factor: 5.923
Authors: Shuyi Wang; Jun Tao; Huaguo Chen; Machender R Kandadi; Mingming Sun; Haixia Xu; Gary D Lopaschuk; Yan Lu; Junmeng Zheng; Hu Peng; Jun Ren Journal: Acta Pharm Sin B Date: 2021-07-14 Impact factor: 11.413
Authors: Tianjiao Liu; Li Wen; Shuai Huang; Ting-Li Han; Lan Zhang; Huijia Fu; Junnan Li; Chao Tong; Hongbo Qi; Richard Saffery; Philip N Baker; Mark D Kilby Journal: Front Bioeng Biotechnol Date: 2022-04-12
Authors: Wesley M Jackson; Hudson P Santos; Hadley J Hartwell; William Adam Gower; Divya Chhabra; James S Hagood; Matthew M Laughon; Alexis Payton; Lisa Smeester; Kyle Roell; T Michael O'Shea; Rebecca C Fry Journal: Pediatr Res Date: 2021-12-02 Impact factor: 3.953