PDF(Pubmed)
Abstract：
Cardiovascular disease and heart failure doubles in patients with chronic kidney disease (CKD), but the underlying mechanisms remain obscure. Mitochondria are central to maintaining cellular respiration and modulating cardiomyocyte function. We took advantage of our novel swine model of CKD and left ventricular diastolic dysfunction (CKD-LVDD) to investigate the expression of mitochondria-related genes and potential mechanisms regulating their expression. CKD-LVDD and normal control pigs (n=6/group, 3 males/3 females) were studied for 14 weeks. Renal and cardiac hemodynamics were quantified by multidetector-CT, echocardiography, and pressure-volume loop studies, respectively. Mitochondrial morphology (electron microscopy) and function (Oroboros) were assessed ex vivo. In randomly selected pigs (n=3/group), cardiac mRNA-, MeDIP-, and miRNA-sequencing (seq) were performed to identify mitochondria-related genes and study their pre- and post -transcriptional regulation. CKD-LVDD exhibited cardiac mitochondrial structural abnormalities and elevated mitochondrial H2O2 emission but preserved mitochondrial function. Cardiac mRNA-seq identified 862 mitochondria-related genes, of which 69 were upregulated and 33 downregulated (fold-change ≥2, false discovery rate≤0.05). Functional analysis showed that upregulated genes were primarily implicated in processes associated with oxidative stress, whereas those downregulated mainly participated in respiration and ATP synthesis. Integrated mRNA/miRNA/MeDIP-seq analysis showed that upregulated genes were modulated predominantly by miRNAs, whereas those downregulated were by miRNA and epigenetic mechanisms. CKD-LVDD alters cardiac expression of mitochondria-related genes, associated with mitochondrial structural damage but preserved respiratory function, possibly reflecting intrinsic compensatory mechanisms. Our findings may guide the development of early interventions at stages of cardiac dysfunction in which mitochondrial injury could be prevented, and the development of LVDD ameliorated.
摘要：
慢性肾脏病（CKD）患者的心血管疾病和心力衰竭加倍，但是潜在的机制仍然模糊。线粒体是维持细胞呼吸和调节心肌细胞功能的核心。我们利用我们的新型猪CKD和左心室舒张功能不全（CKD-LVDD）模型来研究线粒体相关基因的表达以及调节其表达的潜在机制。CKD-LVDD和正常对照猪（n=6/组，3名男性/3名女性）进行了14周的研究。肾脏和心脏血流动力学通过多探测器CT定量，超声心动图,和压力-体积回路研究，分别。离体评估线粒体形态(电子显微镜)和功能(Oroboros)。在随机选择的猪（n=3/组）中，心脏mRNA-，MedIP-,和miRNA测序（seq）进行鉴定线粒体相关基因并研究其转录前和转录后调控。CKD-LVDD表现出心脏线粒体结构异常和线粒体H2O2发射升高，但保留了线粒体功能。心脏mRNA-seq鉴定出862个线粒体相关基因，其中69例上调，33例下调（倍数变化≥2，错误发现率≤0.05）。功能分析显示，上调的基因主要涉及与氧化应激相关的过程，而那些下调主要参与呼吸和ATP合成。整合的mRNA/miRNA/MeDIP-seq分析显示上调的基因主要由miRNA调节,而下调的是miRNA和表观遗传机制。CKD-LVDD改变线粒体相关基因的心脏表达，与线粒体结构损伤相关，但呼吸功能得到保留，可能反映了内在的补偿机制。我们的发现可以指导在心脏功能障碍阶段的早期干预措施的发展，在这些阶段可以预防线粒体损伤，LVDD的发展得到了改善。
