title: Investigating the Mechanism of Hyperglycemia-Induced Fetal Cardiac Hypertrophy.
abstract: Hyperglycemia in diabetic mothers enhances the risk of fetal cardiac hypertrophy during gestation. However, the mechanism of high-glucose-induced cardiac hypertrophy is not largely understood. In this study, we first demonstrated that the incidence rate of cardiac hypertrophy dramatically increased in fetuses of diabetic mothers using color ultrasound examination. In addition, human fetal cardiac hypertrophy was successfully mimicked in a streptozotocin (STZ)-induced diabetes mouse model, in which mouse cardiac hypertrophy was diagnosed using type-M ultrasound and a histological assay. PH3 immunofluorescent staining of mouse fetal hearts and in vitro-cultured H9c2 cells indicated that cell proliferation decreased in E18.5, E15.5 and E13.5 mice, and cell apoptosis in H9c2 cells increased in the presence of high glucose in a dose-dependent manner. Next, we found that the individual cardiomyocyte size increased in pre-gestational diabetes mellitus mice and in response to high glucose exposure. Meanwhile, the expression of β-MHC and BMP-10 was up-regulated. Nkx2.5 immunofluorescent staining showed that the expression of Nkx2.5, a crucial cardiac transcription factor, was suppressed in the ventricular septum, left ventricular wall and right ventricular wall of E18.5, E15.5 and E13.5 mouse hearts. However, cardiac hypertrophy did not morphologically occur in E13.5 mouse hearts. In cultured H9c2 cells exposed to high glucose, Nkx2.5 expression decreased, as detected by both immunostaining and western blotting, and the expression of KCNE1 and Cx43 was also restricted. Taken together, alterations in cell size rather than cell proliferation or apoptosis are responsible for hyperglycemia-induced fetal cardiac hypertrophy. The aberrant expression of Nkx2.5 and its regulatory target genes in the presence of high glucose could be a principal component of pathogenesis in the development of fetal cardiac hypertrophy.
authors.affiliation: Department of Pediatrics and Neonatology, Institute of Fetal-Preterm Labor Medicine, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, China.
authors.forename: Sha-sha
authors.initials: SS
authors.lastname: Han
authors.affiliation: Division of Histology & Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou, 510632, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Pediatrics and Neonatology, Institute of Fetal-Preterm Labor Medicine, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Division of Histology & Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou, 510632, China.
authors.forename: Zheng-lai
authors.initials: ZL
authors.lastname: Ma
authors.affiliation: Department of Pediatrics and Neonatology, Institute of Fetal-Preterm Labor Medicine, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, China.
authors.forename: Wei-jing
authors.initials: WJ
authors.lastname: Jia
authors.affiliation: Department of Pediatrics and Neonatology, Institute of Fetal-Preterm Labor Medicine, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wu
authors.affiliation: Division of Histology & Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou, 510632, China.
authors.forename: Xiao-yu
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Department of Pediatrics and Neonatology, Institute of Fetal-Preterm Labor Medicine, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, China.
authors.forename: Mei-yao
authors.initials: MY
authors.lastname: He
authors.affiliation: Division of Histology & Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou, 510632, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Fetal Medicine, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, China.
authors.forename: Wei-jing
authors.initials: WJ
authors.lastname: Li
authors.affiliation: Division of Histology & Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou, 510632, China.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pediatrics and Neonatology, Institute of Fetal-Preterm Labor Medicine, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, China.
authors.forename: Guo-sheng
authors.initials: GS
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose; D006332:Cardiomegaly / Q000503:physiopathology*; D002460:Cell Line; D049109:Cell Proliferation; D048429:Cell Size; D048909:Diabetes Complications; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D005318:Fetal Heart / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D051379:Mice; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D014157:Transcription Factors / Q000096:biosynthesis
chemical_list: D001786:Blood Glucose; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors