Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
J Cell Mol Med. 2023 Jan;27(1):89-100. doi: 10.1111/jcmm.17637. Epub 2022 Dec 10.
Myocardial infarction (MI) remains a major challenge to cardiovascular health worldwide, with poor healing leaving a direct impact on patients' quality of life and survival. Metabolic abnormalities after MI are receiving increasing attention. Our previous studies showed that enhancing proline catabolism ameliorates hypoxic damage to myocardial cells; therefore, we sought to determine whether reducing the synthesis of endogenous proline also affects MI. We analysed GEO datasets associated with MI and western blot of mouse heart tissue in an MI model to demonstrate pyrroline-5-carboxylate reductase 1 (Pycr1) expression level after MI. We constructed Pycr1 KO mice by CRISPR/Cas9 technology to explore the effect of Pycr1 gene KO after MI using transcriptomic and metabolomic techniques. In this study, we found reduced mRNA and protein expression levels of Pycr1 in the hearts of mice after MI. We observed that Pycr1 gene KO has a protective effect against MI, reducing the area of MI and improving heart function. Using transcriptomics approaches, we found 215 upregulated genes and 247 downregulated genes after KO of the Pycr1 gene, indicating that unsaturated fatty acid metabolism was affected at the transcriptional level. Metabolomics results revealed elevated content for 141 metabolites and decreased content for 90 metabolites, among which the levels of fatty acids, glycerol phospholipids, bile acids, and other metabolites increased significantly. The changes in these metabolites may be related to the protective effect of Pycr1 KO on the heart after MI. Pycr1 gene KO has a protective effect against MI and our research will lay a solid foundation for the development of future Pycr1-related drug targets.
心肌梗死（MI）仍然是全球心血管健康的主要挑战，愈合不良直接影响患者的生活质量和生存率。MI 后的代谢异常受到越来越多的关注。我们之前的研究表明，增强脯氨酸分解代谢可改善心肌细胞的缺氧损伤；因此，我们试图确定减少内源性脯氨酸的合成是否也会影响 MI。我们分析了与 MI 相关的 GEO 数据集和 MI 模型中小鼠心脏组织的 Western blot，以证明 MI 后吡咯啉-5-羧酸还原酶 1（Pycr1）的表达水平。我们通过 CRISPR/Cas9 技术构建了 Pycr1 KO 小鼠，使用转录组学和代谢组学技术探索 MI 后 Pycr1 基因 KO 的影响。在这项研究中，我们发现 MI 后小鼠心脏中 Pycr1 的 mRNA 和蛋白表达水平降低。我们观察到 Pycr1 基因 KO 对 MI 具有保护作用，可减少 MI 面积并改善心脏功能。使用转录组学方法，我们发现 KO Pycr1 基因后有 215 个上调基因和 247 个下调基因，表明不饱和脂肪酸代谢在转录水平受到影响。代谢组学结果显示 141 种代谢物的含量升高和 90 种代谢物的含量降低，其中脂肪酸、甘油磷脂、胆汁酸和其他代谢物的水平显著升高。这些代谢物的变化可能与 Pycr1 KO 对 MI 后心脏的保护作用有关。Pycr1 基因 KO 对 MI 具有保护作用，我们的研究将为未来 Pycr1 相关药物靶点的开发奠定坚实的基础。
