Division of Cardiology, Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado.
Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
Am J Physiol Heart Circ Physiol. 2020 Apr 1;318(4):H787-H800. doi: 10.1152/ajpheart.00494.2019. Epub 2020 Feb 14.
Despite advances in both medical and surgical therapies, individuals with single ventricle heart disease (SV) remain at high risk for the development of heart failure (HF). However, the molecular mechanisms underlying remodeling and eventual HF in patients with SV are poorly characterized. Cardiolipin (CL), an inner mitochondrial membrane phospholipid, is critical for proper mitochondrial function, and abnormalities in CL content and composition are known in various cardiovascular disease etiologies. The purpose of this study was to investigate myocardial CL content and composition in failing and nonfailing single right ventricle (RV) samples compared with normal control RV samples, to assess mRNA expression of CL biosynthetic and remodeling enzymes, and to quantitate relative mitochondrial copy number. A cross-sectional analysis of RV myocardial tissue from 22 failing SV (SVHF), 9 nonfailing SV (SVNF), and 10 biventricular control samples (BVNF) was performed. Expression of enzymes involved in CL biosynthesis and remodeling were analyzed using RT-qPCR and relative mitochondrial DNA copy number determined by qPCR. Normal phase high-pressure liquid chromatography coupled to electrospray ionization mass spectrometry was used to quantitate total and specific CL species. While mitochondrial copy number was not significantly different between groups, total CL content was significantly lower in SVHF myocardium compared with BVNF controls. Despite having lower total CL content however, the relative percentage of the major tetralinoleoyl CL species is preserved in SVHF samples relative to BVNF controls. Correspondingly, expression of enzymes involved in CL biosynthesis and remodeling were upregulated in SVHF samples when compared with both SVNF samples and BVNF controls. The mechanisms underlying heart failure in the single ventricle (SV) congenital heart disease population are largely unknown. In this study we identify alterations in cardiac cardiolipin metabolism, composition, and content in children with SV heart disease. These findings suggest that cardiolipin could be a novel therapeutic target in this unique population of patients.
尽管在医学和外科治疗方面取得了进展，但患有单心室心脏病 (SV) 的个体仍然存在心力衰竭 (HF) 发展的高风险。然而，SV 患者重塑和最终 HF 的分子机制尚未得到很好的描述。心磷脂 (CL) 是一种线粒体内膜磷脂，对正常的线粒体功能至关重要，并且在各种心血管疾病病因中已知存在 CL 含量和组成的异常。本研究旨在比较衰竭和非衰竭的单右心室 (RV) 样本与正常对照 RV 样本中的心肌 CL 含量和组成，评估 CL 生物合成和重塑酶的 mRNA 表达，并定量相对线粒体拷贝数。对 22 例衰竭性单心室 (SVHF)、9 例非衰竭性单心室 (SVNF) 和 10 例双心室对照 (BVNF) 的 RV 心肌组织进行了横断面分析。使用 RT-qPCR 分析了参与 CL 生物合成和重塑的酶的表达，并用 qPCR 确定了相对线粒体 DNA 拷贝数。使用正相高压液相色谱法结合电喷雾电离质谱法定量总和特定 CL 种类。尽管各组之间的线粒体拷贝数没有显著差异，但 SVHF 心肌中的总 CL 含量明显低于 BVNF 对照组。然而，尽管总 CL 含量较低，但 SVHF 样本中主要的四油酰心磷脂的相对百分比相对于 BVNF 对照组是保持不变的。相应地，与 SVNF 样本和 BVNF 对照组相比，SVHF 样本中参与 CL 生物合成和重塑的酶的表达上调。SV 先天性心脏病患者心力衰竭的机制在很大程度上尚不清楚。在这项研究中，我们在患有 SV 心脏病的儿童中发现了心脏心磷脂代谢、组成和含量的改变。这些发现表明心磷脂可能是这一独特患者群体的新的治疗靶点。
