Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies.
Elevated plasma homocysteine (HCy), which results from folate (folic acid, FA) deficiency, and the mood-stabilizing drug lithium (Li) are both linked to the induction of human congenital heart and neural tube defects. We demonstrated previously that acute administration of Li to pregnant mice on embryonic day (E)6.75 induced cardiac valve defects by potentiating Wnt-beta-catenin signaling. We hypothesized that HCy may similarly induce cardiac defects during gastrulation by targeting the Wnt-beta-catenin pathway. Because dietary FA supplementation protects from neural tube defects, we sought to determine whether FA also protects the embryonic heart from Li- or HCy-induced birth defects and whether the protection occurs by impacting Wnt signaling. Maternal elevation of HCy or Li on E6.75 induced defective heart and placental function on E15.5, as identified non-invasively using echocardiography. This functional analysis of HCy-exposed mouse hearts revealed defects in tricuspid and semilunar valves, together with altered myocardial thickness. A smaller embryo and placental size was observed in the treated groups. FA supplementation ameliorates the observed developmental errors in the Li- or HCy-exposed mouse embryos and normalized heart function. Molecular analysis of gene expression within the avian cardiogenic crescent determined that Li, HCy or Wnt3A suppress Wnt-modulated Hex (also known as Hhex) and Islet-1 (also known as Isl1) expression, and that FA protects from the gene misexpression that is induced by all three factors. Furthermore, myoinositol with FA synergistically enhances the protective effect. Although the specific molecular epigenetic control mechanisms remain to be defined, it appears that Li or HCy induction and FA protection of cardiac defects involve intimate control of the canonical Wnt pathway at a crucial time preceding, and during, early heart organogenesis.
Han
Mingda
M
Division of Pediatric Cardiology, Department of Pediatrics, USF/ACH Children's Research Institute, St Petersburg, FL 33701, USA.
Serrano
Maria C
MC
Lastra-Vicente
Rosana
R
Brinez
Pilar
P
Acharya
Ganesh
G
Huhta
James C
JC
Chen
Ren
R
Linask
Kersti K
KK
D000818:Animals; D030161:Avian Proteins / Q000235:genetics / Q000378:metabolism; D002645:Chickens; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000187:drug effects; D005492:Folic Acid / Q000494:pharmacology*; D054262:Gastrulation / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006330:Heart Defects, Congenital / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000517:prevention & control*; D006334:Heart Function Tests / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006710:Homocysteine; D007294:Inositol / Q000494:pharmacology; D060850:LIM-Homeodomain Proteins; D008094:Lithium; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors; D014463:Ultrasonography; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
D030161:Avian Proteins; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; C063843:insulin gene enhancer binding protein Isl-1; D006710:Homocysteine; D007294:Inositol; D005492:Folic Acid; D008094:Lithium