Untargeted Metabolomics Identifies Altered Cardiac Metabolite and Gene Expression Patterns in Late Preterm Growth-Restricted Newborn Lambs

内分泌学 内科学 生物 基因表达 代谢组 肉碱 脂肪酸代谢 新陈代谢 血清素 糖酵解 代谢物 碳水化合物代谢 肉碱O-棕榈酰转移酶 β氧化 尿酸 代谢组学 脂肪酸 脂质代谢 下调和上调 胎儿 水通道蛋白2 基因表达谱 妊娠期 CD36 心功能曲线 基因表达调控
作者
Zahrah Azman,Charmaine R. Rock,Amy E. Sutherland,Valerie A. Zahra,Yen Pham,Darren J. Creek,Dovile Anderson,Andrew W. Gill,Suzanne L. Miller,Kristen J. Bubb,Graeme R. Polglase,Beth J. Allison,Zahrah Azman,Charmaine R. Rock,Amy E. Sutherland,Valerie A. Zahra,Yen Pham,Darren J. Creek,Dovile Anderson,Andrew W. Gill
出处
期刊:American Journal of Physiology-heart and Circulatory Physiology [American Physical Society]
标识
DOI:10.1152/ajpheart.00610.2025
摘要

Fetal growth restriction (FGR) may impair early postnatal cardiopulmonary function by limiting the heart’s ability to shift from glycolytic to fatty acid metabolism. We investigated whether the cardiac metabolic milieu is altered in newborn FGR lambs compared to control lambs 24 hours after birth. Twin-bearing ewes at 89 days gestation (d; term=148d) underwent single umbilical artery ligation to induce FGR or sham surgery (control). Lambs were delivered late preterm at 136d (~0.92 gestation) and monitored for 24 hours before postmortem tissue collection. Left ventricles were snap-frozen for untargeted metabolomics analysis via liquid chromatography/mass spectroscopy (LC-MS) and RT-qPCR, or fixed for immunohistochemical analysis. FGR lambs had lower body weights at birth (2.7 ± 0.3 vs. 4.3 ± 0.2; p=0.0002) and at 24 hours (2.7 ± 0.2 vs. 4.4 ± 0.2; p<0.0001) compared to controls. LC-MS identified 14 significantly altered metabolites in FGR hearts, with upregulated peptide and uric acid metabolism and downregulated lipid, carnitine and serotonin metabolism (fold change from control >1.5, p<0.05). RT-qPCR identified higher gene expression of long-chain fatty acid transport proteins SLC27A6 and ACADL, and lower gene expression of serotonin receptor HTR4. No differences in the gene expression of carnitine metabolism ( CPT1A, CPT1B) or uric acid metabolism ( XDH, HPRT1, GDA, PNP) were observed. Serotonin (5-hydroxytryptamine; 5-HT) density was reduced in FGR hearts (p=0.048). These findings suggest early shifts in postnatal cardiac metabolic adaptations in FGR lambs, particularly in lipid and serotonin pathways, and provide a foundation for future studies exploring the functional consequences of these changes.
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