Maternal diabetes induces congenital heart defects in mice by altering the expression of genes involved in cardiovascular development.
BACKGROUND
Congenital heart defects are frequently observed in infants of diabetic mothers, but the molecular basis of the defects remains obscure. Thus, the present study was performed to gain some insights into the molecular pathogenesis of maternal diabetes-induced congenital heart defects in mice.


RESULTS
We analyzed the morphological changes, the expression pattern of some genes, the proliferation index and apoptosis in developing heart of embryos at E13.5 from streptozotocin-induced diabetic mice. Morphological analysis has shown the persistent truncus arteriosus combined with a ventricular septal defect in embryos of diabetic mice. Several other defects including defective endocardial cushion (EC) and aberrant myofibrillogenesis have also been found. Cardiac neural crest defects in experimental embryos were analyzed and validated by the protein expression of NCAM and PGP 9.5. In addition, the protein expression of Bmp4, Msx1 and Pax3 involved in the development of cardiac neural crest was found to be reduced in the defective hearts. The mRNA expression of Bmp4, Msx1 and Pax3 was significantly down-regulated (p < 0.001) in the hearts of experimental embryos. Further, the proliferation index was significantly decreased (p < 0.05), whereas the apoptotic cells were significantly increased (p < 0.001) in the EC and the ventricular myocardium of the experimental embryos.


CONCLUSIONS
It is suggested that the down-regulation of genes involved in development of cardiac neural crest could contribute to the pathogenesis of maternal diabetes-induced congenital heart defects.
Kumar
Srinivasan Dinesh
SD
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore - 117597. dinesh@nus.edu.sg
Dheen
S Thameem
ST
Tay
Samuel Sam Wah
SS
D000818:Animals; D017209:Apoptosis; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000032:analysis / Q000235:genetics; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000737:chemistry; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D006345:Heart Septal Defects, Ventricular / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051957:MSX1 Transcription Factor / Q000032:analysis / Q000235:genetics; D051379:Mice; D032383:Myocytes, Cardiac / Q000737:chemistry* / Q000648:ultrastructure; D019006:Neural Cell Adhesion Molecules / Q000032:analysis / Q000235:genetics; D009432:Neural Crest / Q000737:chemistry* / Q000196:embryology / Q000473:pathology; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000032:analysis / Q000235:genetics; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D014339:Truncus Arteriosus, Persistent / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D043222:Ubiquitin Thiolesterase / Q000032:analysis / Q000235:genetics
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D051957:MSX1 Transcription Factor; C484084:Msx1 protein, mouse; D019006:Neural Cell Adhesion Molecules; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; C068686:Pax3 protein, mouse; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse