title: The effect of maternal obesity on the expression and functionality of placental P-glycoprotein: Implications in the individualized transplacental digoxin treatment for fetal heart failure.
abstract: BACKGROUND
  Placental P-glycoprotein (P-gp) plays a significant role in controlling digoxin transplacental rate. Investigations on P-gp regulation in placenta of women with different pregnant pathology are of great significance to the individualized transplacental digoxin treatment for fetal heart failure (FHF). This study aimed to explore the effect of maternal obesity on the expression and functionality of placental P-gp both in human and in mice.
  
  
  METHODS
  Placenta tissues from obese and lean women were collected. Female C57BL mice were fed with either a normal chow diet or a high-fat diet for 12 weeks before mating and throughout pregnancy. Maternal plasma glucose, HDL-C, LDL-C, TC, TGs, insulin, IL-1β, IL-6 and TNF-α concentrations was detected. Placental ABCB1/Abcb1a/Abcb1b/IL-1β/IL-6/TNF-α mRNA and P-gp/IL-1β/IL-6/TNF-α protein expression were determined by real-time quantitative PCR and western-blot, respectively. Maternal plasma and fetal-unit digoxin concentrations were detected by a commercial kit assay.
  
  
  RESULTS
  Both ABCB1 gene mRNA and protein expression of obesity group was significantly lower than that of control group in human. The high-fat dietary intervention resulted in an overweight phenotype, a significant increased Lee's index, higher levels of plasma glucose, HDL-C, LDL-C, insulin and TGs, increased peri-renal and peri-reproductive gland adipose tissue weight, and larger size of adipose cell. Compared with control group at the same gestational day (E12.5, E15.5, E17.5), placental Abcb1a mRNA and P-gp expression of obese group were significantly decreased in mice, while digoxin transplacental rates were significantly increased. Higher maternal plasma IL-1β/TNF-α concentrations and placental IL-1β/TNF-α expression were observed in obesity groups in comparison with control group at the same gestational age.
  
  
  CONCLUSIONS
  Maternal obesity could inhibit placental P-gp expression and its functionality both in human and in mice, which might be resulted from a heightened inflammatory response.
authors: Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; West China Medical School of Sichuan University, Chengdu, Sichuan, China.
authors: Chuan
authors: C
authors: Wang
authors: Department of Pediatric, Chengdu Women's & Children's Central Hospital, Chengdu, Sichuan, China.
authors: Huaying
authors: H
authors: Li
authors: West China Medical School of Sichuan University, Chengdu, Sichuan, China.
authors: Chunyan
authors: C
authors: Luo
authors: Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; West China Medical School of Sichuan University, Chengdu, Sichuan, China.
authors: Yifei
authors: Y
authors: Li
authors: The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
authors: Yi
authors: Y
authors: Zhang
authors: Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; West China Medical School of Sichuan University, Chengdu, Sichuan, China.
authors: Ding
authors: D
authors: Yun
authors: Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
authors: Dezhi
authors: D
authors: Mu
authors: Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address: kaiyuzhou313@163.com.
authors: Kaiyu
authors: K
authors: Zhou
authors: Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address: nathan_hua@126.com.
authors: Yimin
authors: Y
authors: Hua
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000328:Adult; D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage; D016022:Case-Control Studies; D004077:Digoxin / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D005315:Fetal Diseases / Q000188:drug therapy; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D057285:Precision Medicine; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism*; D011897:Random Allocation
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002316:Cardiotonic Agents; D004077:Digoxin
keywords: Digoxin; Fetal heart failure; Maternal obesity; P-glycoprotein; Placenta