Sexual dimorphism in the fetal cardiac response to maternal nutrient restriction. (July 2017)

• Record Type: Journal Article
• Authors: Muralimanoharan, Sribalasubashini; Li, Cun; Nakayasu, Ernesto S.; Casey, Cameron P.; Metz, Thomas O.; Nathanielsz, Peter W.; Maloyan, Alina
• Is Part Of: Journal of molecular and cellular cardiology. Volume 108(2017)
• Page Start: 181
• Page End: 193
• Publication Date: 2017-07
• Subjects: ALK1 activin receptor-like kinase-1 -- ATG7 autophagy-related protein-7 -- CL cardiolipin -- CTGF connective tissue growth factor -- CDX2 caudal type homeo box transcription factor 2 -- DG diglycerides -- HNF4α hepatocyte nuclear factor 4 alpha -- IUGR intrauterine growth restriction -- LC3B microtubule-associated protein 1B-light chain 3 -- MNR maternal nutrient restriction -- NFκB1 nuclear factor kappa B subunit 1 -- PC phosphatidylcholine -- PE phosphatidylethanolamine -- PI phosphatidylinositol -- PPARγ peroxisome proliferator-activated receptor gamma -- SM sphingomyelins -- TSP-1 Thrombospondin-1 -- TGFβ transforming growth factor –β -- TG triglycerides; Maternal undernutrition -- miRNA -- Lipidomics -- Cardiac fibrosis -- Sexual dimorphism -- Autophagy; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2017.06.006
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Poor maternal nutrition causes intrauterine growth restriction (IUGR); however, its effects on fetal cardiac development are unclear. We have developed a baboon model of moderate maternal undernutrition, leading to IUGR. We hypothesized that the IUGR affects fetal cardiac structure and metabolism. Six control pregnant baboons ate ad-libitum (CTRL)) or 70% CTRL from 0.16 of gestation (G). Fetuses were euthanized at C-section at 0.9G under general anesthesia. Male but not female IUGR fetuses showed left ventricular fibrosis inversely correlated with birth weight. Expression of extracellular matrix protein TSP-1 was increased (p < 0.05) in male IUGR. Expression of cardiac fibrotic markers TGFβ, SMAD3 and ALK-1 were downregulated in male IUGRs with no difference in females. Autophagy was present in male IUGR evidenced by upregulation of ATG7 expression and lipidation LC3B. Global miRNA expression profiling revealed 56 annotated and novel cardiac miRNAs exclusively dysregulated in female IUGR, and 38 cardiac miRNAs were exclusively dysregulated in males (p < 0.05). Fifteen (CTRL) and 23 (IUGR) miRNAs, were differentially expressed between males and females (p < 0.05) suggesting sexual dimorphism, which can be at least partially explained by differential expression of upstream transcription factors (e.g. HNF4α, and NFκB p50). Lipidomics analysis of fetal cardiac tissue exhibited a net increase in diacylglycerol and plasmalogens and a decrease in triglycerides and phosphatidylcholines. In summary, IUGR resulting from decreased maternal nutrition is associated with sex-dependent dysregulations in cardiac structure, miRNA expression, and lipid metabolism. If these changes persist postnatally, they may program offspring for higher later life cardiac risk. Highlights: Maternal undernutrition causes cardiac fibrosis and activates cardiac autophagy in a sex-dependent manner. The expression of fetal cardiac miRNA is dysregulated by maternal undernutrition in a sex-dependent manner. Maternal undernutrition affects fetal cardiac lipid profile.