Department of Anesthesiology, Pain and Palliative Medicine, University Medical Center St Radboud, Nijmegen, The Netherlands.
J Mol Cell Cardiol. 2010 Dec;49(6):950-61. doi: 10.1016/j.yjmcc.2010.09.023. Epub 2010 Oct 1.
α-Keto acids (α-KAs) are not just metabolic intermediates but are also powerful modulators of different cellular pathways. Here, we tested the hypothesis that α-KA concentrations are regulated by complex II (succinate dehydrogenase=SDH), which represents an intersection between the mitochondrial respiratory chain for which an important function in cardiopulmonary oxygen sensing has been demonstrated, and the Krebs cycle, a central element of α-KA metabolism. SDH subunit D heterozygous (SDHD(+/-)) and wild-type (WT) mice were housed at normoxia or hypoxia (10% O(2)) for 4 days or 3 weeks, and right ventricular pressure, right ventricle/(left ventricle+septum) ratio, cardiomyocyte ultrastructure, pulmonary vascular remodelling, ventricular complex II subunit expression, SDH activity and α-KA concentrations were analysed. In both strains, hypoxia induced increases in right ventricular pressure and enhanced muscularization of distal pulmonary arteries. Right ventricular hypertrophy was less severe in SDHD(+/-) mice although the cardiomyocyte ultrastructure and mitochondrial morphometric parameters were unchanged. Protein amounts of SDHA, SDHB and SDHC, and SDH activity were distinctly reduced in SDHD(+/-) mice. In normoxic SDHD(+/-) mice, α-ketoisocaproate concentration was lowered to 50% as compared to WT animals. Right/left ventricular concentration differences and the hypoxia-induced decline in individual α-KAs were less pronounced in SDHD(+/-) animals indicating that mitochondrial complex II participates in the adjustment of cardiac α-KA concentrations both under normoxic and hypoxic conditions. These characteristics are not related to the hemodynamic consequences of hypoxia-induced pulmonary vascular remodelling, since its extent and right ventricular pressure were not affected in SDHD(+/-) mice albeit right ventricular hypertrophy was attenuated.
α-酮酸（α-KAs）不仅是代谢中间体，还是不同细胞途径的有力调节剂。在这里，我们检验了这样一个假设，即 α-KA 浓度受复合物 II（琥珀酸脱氢酶=SDH）调节，复合物 II 是线粒体呼吸链和三羧酸循环的交汇点，而呼吸链对心肺氧感应具有重要作用，三羧酸循环则是 α-KA 代谢的核心元素。杂合子（SDHD(+/-)）和野生型（WT）SDH 亚单位 D 小鼠在常氧或低氧（10% O(2)）环境下饲养 4 天或 3 周，然后分析右心室压力、右心室/（左心室+室间隔）比值、心肌细胞超微结构、肺血管重构、心室复合物 II 亚基表达、SDH 活性和 α-KA 浓度。在两种品系中，低氧均可引起右心室压力升高和远端肺动脉肌化增强。尽管心肌细胞超微结构和线粒体形态计量参数没有改变，但 SDHD(+/-) 小鼠的右心室肥厚程度较轻。SDHD(+/-) 小鼠的 SDHA、SDHB 和 SDHC 蛋白含量以及 SDH 活性明显降低。在常氧 SDHD(+/-) 小鼠中，α-酮异己酸浓度降低至 WT 动物的 50%。右/左心室浓度差异以及低氧诱导的个体 α-KA 下降在 SDHD(+/-) 动物中不明显，表明线粒体复合物 II 参与了常氧和低氧条件下心脏 α-KA 浓度的调节。这些特征与低氧诱导的肺血管重构的血流动力学后果无关，因为尽管右心室肥厚减轻，但 SDHD(+/-) 小鼠的肺动脉重构程度和右心室压力不受影响。
