充血性心力衰竭犬模型的转录组分析显示，胶原相关的 2-氧戊二酸依赖性双加氧酶有助于心力衰竭。
Transcriptome analysis of a dog model of congestive heart failure shows that collagen-related 2-oxoglutarate-dependent dioxygenases contribute to heart failure.
机构信息
Department of Urology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
Central Research Laboratory, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan.
出版信息
Sci Rep. 2022 Dec 29;12(1):22569. doi: 10.1038/s41598-022-26717-7.
Fibrosis is an important pathological mechanism in heart failure (HF) and is associated with poor prognosis. We analyzed fibrosis in HF patients using transcriptomic data. Genes differentially expressed between normal control and congestive HF (CHF) dogs included P3H1, P3H2, P3H4, P4HA2, PLOD1 and PLOD3, which belong to the 2-oxoglutarate-dependent dioxygenases (2OGD) superfamily that stabilizes collagen during fibrosis. Quantitative polymerase chain reaction analysis demonstrated 2OGD gene expression was increased in CHF samples compared with normal left ventricle (LV) samples. 2OGD gene expression was repressed in angiotensin converting enzyme inhibitor-treated samples. These genes, activated the hydroxylation of proline or lysin residues of procollagen mediated by 2-oxoglutaric acid and O produce succinic acid and CO. Metabolic analysis demonstrated the concentration of succinic acid was significantly increased in CHF samples compared with normal LV samples. Fibrosis was induced in human cardiac fibroblasts by TGF-ß1 treatment. After treatment, the gene and protein expressions of 2OGD, the concentration of succinic acid, and the oxygen consumption rate were increased compared with no treatment. This is the first study to show that collagen-related 2OGD genes contribute to HF during the induction of fibrosis and might be potential therapeutic targets for fibrosis and HF.
纤维化是心力衰竭（HF）的重要病理机制，并与预后不良相关。我们使用转录组数据分析 HF 患者的纤维化。在正常对照组和充血性 HF（CHF）犬之间差异表达的基因包括 P3H1、P3H2、P3H4、P4HA2、PLOD1 和 PLOD3，它们属于 2-氧戊二酸依赖性双加氧酶（2OGD）超家族，可在纤维化过程中稳定胶原蛋白。定量聚合酶链反应分析表明，与正常左心室（LV）样本相比，CHF 样本中的 2OGD 基因表达增加。血管紧张素转换酶抑制剂处理的样本中 2OGD 基因表达受到抑制。这些基因激活 2-氧戊二酸和 O 介导的原胶原脯氨酸或赖氨酸残基的羟化，产生琥珀酸和 CO。代谢分析表明，与正常 LV 样本相比，CHF 样本中琥珀酸的浓度显著增加。TGF-β1 处理诱导人心房成纤维细胞纤维化。治疗后，与未治疗相比，2OGD 的基因和蛋白表达、琥珀酸浓度和耗氧量增加。这是第一项表明胶原相关 2OGD 基因在纤维化诱导的 HF 中起作用的研究，可能是纤维化和 HF 的潜在治疗靶点。
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