Department of Pharmacology & Physiology, Faculty of Medicine, Université de Montréal, Montreal, Quebec H3T 1J4, Canada.
Research Center, CHU Ste-Justine, Montréal, Quebec H3T 1C5, Canada.
J Clin Endocrinol Metab. 2021 Oct 21;106(11):3295-3311. doi: 10.1210/clinem/dgab496.
Intrauterine growth restriction (IUGR) is an immediate outcome of an adverse womb environment, exposing newborns to developing cardiometabolic disorders later in life.
This study investigates the cardiac metabolic consequences and underlying mechanism of energy expenditure in developing fetuses under conditions of IUGR.
Using an animal model of IUGR characterized by uteroplacental vascular insufficiency, mitochondrial function, gene profiling, lipidomic analysis, and transcriptional assay were determined in fetal cardiac tissue and cardiomyocytes.
IUGR fetuses exhibited an upregulation of key genes associated with fatty acid breakdown and β-oxidation (Acadvl, Acadl, Acaa2), and mitochondrial carnitine shuttle (Cpt1a, Cpt2), instigating a metabolic gene reprogramming in the heart. Induction of Ech1, Acox1, Acox3, Acsl1, and Pex11a indicated a coordinated interplay with peroxisomal β-oxidation and biogenesis mainly observed in females, suggesting sexual dimorphism in peroxisomal activation. Concurring with the sex-related changes, mitochondrial respiration rates were stronger in IUGR female fetal cardiomyocytes, accounting for enhanced adenosine 5'-triphosphate production. Mitochondrial biogenesis was induced in fetal hearts with elevated expression of Ppargc1a transcript specifically in IUGR females. Lipidomic analysis identified the accumulation of arachidonic, eicosapentaenoic, and docosapentaenoic polyunsaturated long-chain fatty acids (LCFAs) in IUGR fetal hearts, which leads to nuclear receptor peroxisome proliferator-activated receptor α (PPARα) transcriptional activation in cardiomyocytes. Also, the enrichment of H3K27ac chromatin marks to PPARα-responsive metabolic genes in IUGR fetal hearts outlines an epigenetic control in the early metabolic energy switch.
This study describes a premature and sex-related remodeling of cardiac metabolism in response to an unfavorable intrauterine environment, with specific LCFAs that may serve as predictive effectors leading to IUGR.
宫内生长受限（IUGR）是不利子宫环境的直接后果，使新生儿在以后的生活中易患心脏代谢疾病。
本研究探讨宫内生长受限（IUGR）条件下胎儿能量消耗的心脏代谢后果和潜在机制。
使用以胎盘血管功能不全为特征的 IUGR 动物模型，确定胎儿心脏组织和心肌细胞中的线粒体功能、基因谱、脂质组分析和转录分析。
IUGR 胎儿表现出与脂肪酸分解和β-氧化（Acadvl、Acadl、Acaa2）相关的关键基因上调，以及线粒体肉碱穿梭（Cpt1a、Cpt2）上调，引发心脏代谢基因重编程。Ech1、Acox1、Acox3、Acsl1 和 Pex11a 的诱导表明与过氧化物酶体β-氧化和生物发生的协调相互作用主要在女性中观察到，表明过氧化物酶体激活的性别二态性。与性别相关的变化一致，IUGR 雌性胎儿心肌细胞的线粒体呼吸率更强，导致三磷酸腺苷（ATP）生成增加。过氧化物酶体增殖物激活受体α（PPARα）在 IUGR 雌性中的特定转录表达，诱导胎儿心脏中的线粒体生物发生。脂质组分析鉴定出 IUGR 胎儿心脏中花生四烯酸、二十碳五烯酸和二十二碳五烯酸等多不饱和长链脂肪酸（LCFA）的积累，导致核受体过氧化物酶体增殖物激活受体α（PPARα）在心肌细胞中的转录激活。此外，IUGR 胎儿心脏中 PPARα 反应性代谢基因的 H3K27ac 染色质标记富集勾勒出早期代谢能量转换中的表观遗传控制。
本研究描述了对不利宫内环境的心脏代谢过早和性别相关重塑，特定的 LCFAs 可能作为导致 IUGR 的预测效应物。
