title: Calcineurin activity is required for cardiac remodelling in pregnancy.
abstract: OBJECTIVE
  Calcium fluctuations and cardiac hypertrophy occur during pregnancy, but the role of the well-studied calcium-activated phosphatase, calcineurin, has not been studied in this setting. The purpose of this study was to determine whether calcineurin signalling is required for cardiac remodelling during pregnancy in mice.
  
  
  RESULTS
  We first examined calcineurin expression in the heart of mice during pregnancy. We found both calcineurin levels and activity were significantly increased in early-pregnancy and decreased in late-pregnancy. Since progesterone levels start to rise in early-pregnancy, we investigated whether progesterone alone was sufficient to modulate calcineurin levels in vivo. After implantation of progesterone pellets in non-pregnant female mice, cardiac mass increased, whereas cardiac function was maintained. In addition, calcineurin levels increased, which is also consistent with early-pregnancy. To determine whether these effects were occurring in the cardiac myocytes, we treated neonatal rat ventricular myocytes (NRVMs) with pregnancy-associated sex hormones. We found that progesterone treatment, but not oestradiol, increased calcineurin levels. To obtain a functional read-out of increased calcineurin activity, we measured the activity of the transcription factor NFAT, a downstream target of calcineurin. Progesterone treatment significantly increased NFAT activity in NRVMs, and this was blocked by the calcineurin inhibitor cyclosporine A (CsA), showing that the progesterone-mediated increase in NFAT activity requires calcineurin activity. Importantly, CsA treatment of mice completely blocked pregnancy-induced cardiac hypertrophy.
  
  
  CONCLUSIONS
  Our results show that calcineurin is required for pregnancy-induced cardiac hypertrophy, and that calcineurin activity in early-pregnancy is due at least in part to increased progesterone.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology and Biofrontiers Institute, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Chung
authors.forename: Fan
authors.initials: F
authors.lastname: Yeung
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Leinwand
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D004343:Drug Implants; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005865:Gestational Age; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D011374:Progesterone / Q000008:administration & dosage / Q000378:metabolism; D051381:Rats; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D065095:Calcineurin Inhibitors; D004343:Drug Implants; D004791:Enzyme Inhibitors; D050778:NFATC Transcription Factors; D011374:Progesterone; D019703:Calcineurin
keywords: Calcineurin; Cardiac hypertrophy; NFAT; Pregnancy; Progesterone