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- W2809150823 abstract "Pregestational maternal diabetes is a significant risk factor for congenital heart defects (CHDs) in the offspring. Increased apoptosis is implicated in CHD formation, yet the underlying mechanism is still unclear. Mitochondrial fusion and fission dynamics play a key role in the regulation of cell viability. Embryonic cardiomyocytes exposed to maternal diabetes display impaired fusion and enhanced fission, suggesting that maternal diabetes represses mitofusion gene expression. Here, we demonstrated that maternal diabetes in vivo and high glucose in vitro significantly increased microRNA-140 (miR140) expression whereas down-regulated its putative target gene Mitofusin 1 (Mfn1) expression in cardiomyocytes. We found that miR140 bound to the 3’ untranslated region of Mfn1 mRNA, leading to Mfn1 mRNA degradation. A miR140 mimic induced mitochondrial fragmentation, Mfn1 reduction and cell apoptosis, whereas a miR-140 inhibitor abrogated high glucose-repressed Mfn1 expression and mitochondrial fusion. Deletion of the miR140 gene in vivo reversed diabetes-suppressed Mfn1 expression, restored mitochondrial fusion, blocked cardiac cell apoptosis leading to a significant reduction of CHDs in diabetic pregnancy. Analysis of the miR-140 gene promoter revealed several putative binding sites of the transcription factor, c-Jun, which is downstream of JNK2. Deletion of the Jnk2 (c-Jun NH2-terminal kinase 2) gene using the JNK2-/- mice mimicked the effect of miR-140 deficiency in suppressing diabetes-induced CHDs. JNK2 deletion abolished the increase of miR-140 and restored Mnf1 expression and mitochondrial fusion. Our findings support the hypothesis that the JNK2-miR140-Mfn1 circuit is critically involved in maternal diabetes-induced mitochondrial fusion impairment and CHD formation. Disclosure X. Chen: None. W. Shen: None. P. Yang: None." @default.
- W2809150823 created "2018-06-29" @default.
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- W2809150823 date "2018-07-01" @default.
- W2809150823 modified "2023-09-23" @default.
- W2809150823 title "Maternal Diabetes Induces Congenital Heart Defects by Suppressing Mitochondrial Fusion through the miR-140 Mitofusin 1 Circuit" @default.
- W2809150823 doi "https://doi.org/10.2337/db18-228-or" @default.
- W2809150823 hasPublicationYear "2018" @default.
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