Botting K J, Loke X Y, Zhang S, Andersen J B, Nyengaard J R, Morrison J L
Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia , Adelaide, South Australia , Australia.
Discipline of Physiology, School of Medical Science, The University of Adelaide , Adelaide, South Australia , Australia.
Am J Physiol Regul Integr Comp Physiol. 2018 Jul 1;315(1):R48-R67. doi: 10.1152/ajpregu.00180.2017. Epub 2018 Mar 21.
Intrauterine growth restriction (IUGR) increases the risk of ischemic heart disease in adulthood. Studies in rats suggest cardiac vulnerability is more pronounced in males and in offspring that were exposed to hypoxia in utero. Therefore, we aimed to test the hypotheses that 1) IUGR adolescent males, but not females, have fewer cardiomyocytes and altered expression of cardiometabolic genes compared with controls; and 2) IUGR due to hypoxia has a greater effect on these parameters compared with IUGR due to nutrient restriction. IUGR was induced in guinea pigs by maternal hypoxia (MH; 10% O, n = 9) or maternal nutrient restriction (MNR; ~30% reduction in food intake, n = 9) in the second half of pregnancy and compared with control ( n = 11). At 120 days of age, postmortem was performed and the left ventricle perfusion fixed for stereological determination of cardiomyocyte number or snap frozen to determine the abundance of cardiometabolic genes and proteins by quantitative RT-PCR and Western blotting, respectively. MH reduced the number of cardiomyocytes in female ( P < 0.05), but not male or MNR, adolescent offspring. Furthermore, IUGR males had decreased expression of genes responsible for fatty acid activation in the sarcoplasm ( FACS) and transport into the mitochondria ( AMPK-a and ACC; P < 0.05) and females exposed to MH had increased activation/phosphorylation of AMP-activated protein kinase-α ( P < 0.05). We postulate that the changes in cardiomyocyte endowment and cardiac gene expression observed in the present study are a direct result of in utero programming, as offspring at this age did not suffer from obesity, hypertension, or left ventricular hypertrophy.
宫内生长受限（IUGR）会增加成年后患缺血性心脏病的风险。对大鼠的研究表明，心脏易损性在雄性以及子宫内暴露于缺氧环境的后代中更为明显。因此，我们旨在验证以下假设：1）与对照组相比，IUGR青春期雄性而非雌性的心肌细胞数量更少，且心脏代谢基因表达发生改变；2）与营养限制导致的IUGR相比，缺氧导致的IUGR对这些参数的影响更大。在豚鼠妊娠后半期，通过母体缺氧（MH；10%氧气，n = 9）或母体营养限制（MNR；食物摄入量减少约30%，n = 9）诱导IUGR，并与对照组（n = 11）进行比较。在120日龄时进行尸检，将左心室灌注固定以进行心肌细胞数量的体视学测定，或速冻以分别通过定量RT-PCR和蛋白质免疫印迹法测定心脏代谢基因和蛋白质的丰度。MH减少了雌性（P < 0.05）而非雄性或MNR青春期后代的心肌细胞数量。此外，IUGR雄性的肌浆中负责脂肪酸活化（FACS）以及转运至线粒体（AMPK-α和ACC；P < 0.05）的基因表达降低，而暴露于MH的雌性中AMP活化蛋白激酶-α的活化/磷酸化增加（P < 0.05）。我们推测，本研究中观察到的心肌细胞数量和心脏基因表达的变化是子宫内编程的直接结果，因为这个年龄段的后代并未患有肥胖、高血压或左心室肥厚。
