Zhu Wenjia, Zheng Yufan, Liu Jiaying, Zhao Chao, Sun Ning, Qu Xiuxia, Yang Hui
Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai.
Wuxi School of Medicine, Jiangnan University, Jiangsu, China.
Acta Cardiol Sin. 2023 Jul;39(4):580-598. doi: 10.6515/ACS.202307_39(4).20221219B.
Heart failure is associated with shifts in substrate preferences and energy insufficiency. Although cardiac metabolism has been explored at the organ level, the metabolic changes at the individual cell level remain unclear. This study employed single-cell ribonucleic acid (RNA) sequencing to investigate the cell-type-specific characteristics of gene expression related to fatty acid metabolism.
Single-cell RNA sequencing data from fetal hearts were processed to analyze gene expression patterns related to fatty acid metabolism. Immunofluorescence staining and Western blotting techniques were employed to validate the expression of specific proteins. Additionally, calcium recording and contractility measurements were performed to assess the functional implications of fatty acid metabolism in cardiomyocytes.
Based on single-cell RNA sequencing data analysis, we found that a decrease in overall energy requirements underlies the downregulation of fatty acid oxidation-related genes in the later period of heart maturation and the compensatory increase of fatty acid metabolism in individual cardiomyocytes during heart failure. Furthermore, we found that solute carrier family 27 member 6 (SLC27A6), a fatty acid transport protein, is involved in cardiac maturation. SLC27A6 knockdown in human induced pluripotent stem cell-derived cardiomyocytes resulted in an immature cardiomyocyte transcriptional profile, abnormal morphology, impaired Ca handling activity, and contractility.
Overall, our study offers a novel perspective for exploring cardiac fatty acid metabolism in fetal and failing hearts along with new insights into the cellular mechanism underlying fatty acid metabolic alterations in individual cardiac cells. It thus facilitates further exploration of cardiac physiology and pathology.
心力衰竭与底物偏好的改变和能量不足有关。尽管已经在器官水平上对心脏代谢进行了研究，但单个细胞水平上的代谢变化仍不清楚。本研究采用单细胞核糖核酸（RNA）测序来研究与脂肪酸代谢相关的基因表达的细胞类型特异性特征。
对来自胎儿心脏的单细胞RNA测序数据进行处理，以分析与脂肪酸代谢相关的基因表达模式。采用免疫荧光染色和蛋白质印迹技术来验证特定蛋白质的表达。此外，进行钙记录和收缩性测量以评估脂肪酸代谢在心肌细胞中的功能意义。
基于单细胞RNA测序数据分析，我们发现总体能量需求的降低是心脏成熟后期脂肪酸氧化相关基因下调以及心力衰竭期间单个心肌细胞中脂肪酸代谢代偿性增加的基础。此外，我们发现脂肪酸转运蛋白溶质载体家族27成员6（SLC27A6）参与心脏成熟。在人诱导多能干细胞衍生的心肌细胞中敲低SLC27A6会导致心肌细胞转录谱不成熟、形态异常、钙处理活性受损和收缩性降低。
总体而言，我们的研究为探索胎儿心脏和衰竭心脏中的心脏脂肪酸代谢提供了新的视角，并对单个心脏细胞中脂肪酸代谢改变的细胞机制有了新的认识。因此，它有助于进一步探索心脏生理学和病理学。
