272-OR: Impact of Maternal Diabetes on MicroRNA Expression in Fetal Tissue

Abstract

In utero diabetes (DM) exposure alters offspring metabolic memory and increases future cardiovascular risk (CVD) risk. MicroRNAs (miR), small noncoding RNAs that repress mRNA translation, have been proposed as an epigenetic mechanism that alters metabolic programming. Using an unbiased sequencing approach, the impact of in utero DM exposure on miR abundance in human umbilical vein endothelial cells (HUVEC) from 6 DM-exposed infants and 6 infants born to mothers with normal glycemia matched for infant sex, ethnicity, and gestational age was examined. Computational target prediction algorithms were used to identify genes targeted by the most abundant miRNAs. The gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the most abundant miRNAs and their mRNA targets were annotated. MiRNA expression was quantified using RT-PCR. GO target enrichment analysis suggested the targets of the most abundant miRNAs were involved in transport, protein binding, mitochondria, DNA transcription, and cell cycle. The KEGG analysis found the most significantly enriched pathways were PI3K-Akt, AGE-RAGE signaling in diabetic complications, apoptosis, FoxO signaling, MAPK signaling, and cell senescence. In HUVEC from infants exposed to DM in utero, 31 miRNAs were more abundant including miR-210, miR-130b-3p, miR-491-5p while 6 miRs were less abundant including miR-146b-5p, mIR-192-3p, and miR-30e-5p (p<0.05) compared to matched controls. Analysis with RT-PCR revealed a 25% decrease in miR-146b (p 0.03) from the HUVEC of DM-exposed infants (N = 23) compared to controls (N = 39). MiRNA-146b is an anti-inflammatory molecule that targets IRAK1 and TRAF6 both of which modulate the NF-kB inflammatory pathway and affect the progression of CVD. MiRNA-146b is reduced in hypercholesterolemia and is protective to cardiomyocytes under chronic hypoxia. Sortilin, a target of miR-146b, is also associated with CVD. Thus, miR-146b may play a role in the development of excess CVD risk noted after in utero DM exposure. Disclosure A. Rughani: None. J. B. Tryggestad: None.