Muscle Research and Mitochondrial Function Laboratory, Cellex - IDIBAPS, Faculty of Medicine and Health Science, University of Barcelona, Internal Medicine Service, Hospital Clínic of Barcelona, Barcelona, Spain; CIBERER, Madrid, Spain.
BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Deu), Clinical Institute of Obstetrics, Gynecology and Neonatology, IDIBAPS, University of Barcelona, Barcelona, Spain; CIBERER, Madrid, Spain.
Biochim Biophys Acta Gen Subj. 2018 May;1862(5):1157-1167. doi: 10.1016/j.bbagen.2018.02.006. Epub 2018 Feb 13.
Intrauterine growth restriction (IUGR) is associated with cardiovascular remodeling persisting into adulthood. Mitochondrial bioenergetics, essential for embryonic development and cardiovascular function, are regulated by nuclear effectors as sirtuins. A rabbit model of IUGR and cardiovascular remodeling was generated, in which heart mitochondrial alterations were observed by microscopic and transcriptomic analysis. We aimed to evaluate if such alterations are translated at a functional mitochondrial level to establish the etiopathology and potential therapeutic targets for this obstetric complication.
Hearts and placentas from 16 IUGR-offspring and 14 controls were included to characterize mitochondrial function.
Enzymatic activities of complexes II, IV and II + III in IUGR-hearts (-11.96 ± 3.16%; -15.58 ± 5.32%; -14.73 ± 4.37%; p < 0.05) and II and II + III in IUGR-placentas (-17.22 ± 3.46%; p < 0.005 and -29.64 ± 4.43%; p < 0.001) significantly decreased. This was accompanied by a not significant reduction in CI-stimulated oxygen consumption and significantly decreased complex II SDHB subunit expression in placenta (-44.12 ± 5.88%; p < 0.001). Levels of mitochondrial content, Coenzyme Q and cellular ATP were conserved. Lipid peroxidation significantly decreased in IUGR-hearts (-39.02 ± 4.35%; p < 0.001), but not significantly increased in IUGR-placentas. Sirtuin3 protein expression significantly increased in IUGR-hearts (84.21 ± 31.58%; p < 0.05) despite conserved anti-oxidant SOD2 protein expression and activity in both tissues.
IUGR is associated with cardiac and placental mitochondrial CII dysfunction. Up-regulated expression of Sirtuin3 may explain attenuation of cardiac oxidative damage and preserved ATP levels under CII deficiency.
These findings may allow the design of dietary interventions to modulate Sirtuin3 expression and consequent regulation of mitochondrial imbalance associated with IUGR and derived cardiovascular remodeling.
宫内生长受限（IUGR）与成年后持续存在的心血管重塑有关。线粒体生物能对于胚胎发育和心血管功能至关重要，其受到作为沉默调节蛋白的核效应物的调节。本研究建立了一种兔 IUGR 及心血管重塑模型，通过显微镜和转录组分析观察到心脏线粒体的改变。本研究旨在评估这些改变是否在功能性线粒体水平上转化，以确定这种产科并发症的病因和潜在治疗靶点。
纳入 16 例 IUGR 后代和 14 例对照的心脏和胎盘，以表征线粒体功能。
IUGR 心脏（-11.96±3.16%；-15.58±5.32%；-14.73±4.37%；p<0.05）和 IUGR 胎盘（-17.22±3.46%；p<0.005 和-29.64±4.43%；p<0.001）中复合物 II、IV 和 II+III 的酶活性显著降低。这伴随着 CI 刺激的耗氧量和胎盘内复合物 II SDHB 亚单位表达的无显著减少（-44.12±5.88%；p<0.001）。线粒体含量、辅酶 Q 和细胞内 ATP 水平保持不变。IUGR 心脏中的脂质过氧化显著减少（-39.02±4.35%；p<0.001），但 IUGR 胎盘中的脂质过氧化没有显著增加。IUGR 心脏中 Sirtuin3 蛋白表达显著增加（84.21±31.58%；p<0.05），尽管在两种组织中抗氧化 SOD2 蛋白表达和活性均保持不变。
IUGR 与心脏和胎盘线粒体 CII 功能障碍有关。Sirtuin3 的上调表达可能解释了 CII 缺乏下心脏氧化损伤的减轻和 ATP 水平的维持。
这些发现可能允许设计饮食干预措施来调节 Sirtuin3 表达，并随后调节与 IUGR 相关的线粒体失衡和衍生的心血管重塑。
