Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
Division of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R. China.
Immun Inflamm Dis. 2023 Sep;11(9):e998. doi: 10.1002/iid3.998.
Endoplasmic reticulum (ER) stress is common in different human pathologies, including cardiac diseases. Sphingosine kinase-1 (SPHK1) represents an important player in cardiac growth and function. Nevertheless, its function in cardiomyocyte ER stress remains vague. This study sought to evaluate the mechanism through which SPHK1 might influence ER stress during myocardial infarction (MI).
MI-related GEO data sets were queried to screen differentially expressed genes. Murine HL-1 cells exposed to oxygen-glucose deprivation (OGD) and mice with MI were induced, followed by gene expression manipulation using short hairpin RNAs and overexpression vectors. The activating transcription factor 3 (ATF3) and SPHK1 expression was examined in cells and tissues. Cell counting kit-8, TUNEL, DHE, HE, and Masson's staining were conducted in vitro and in vivo. The inflammatory factor concentrations in mouse serum were measured using ELISA. Finally, the transcriptional regulation of SPHK1 by ATF3 was validated.
ATF3 and SPHK1 were upregulated in vivo and in vitro. ATF3 downregulation reduced the SPHK1 transcription. ATF3 and SPHK1 downregulation increased the viability of OGD-treated HL-1 cells and decreased apoptosis, oxidative stress, and ER stress. ATF3 and SPHK1 downregulation narrowed the infarction area and attenuated myocardial fibrosis in mice, along with reduced inflammation in the serum and ER stress in the myocardium. In contrast, SPHK1 reduced the protective effect of ATF3 downregulation in vitro and in vivo.
ATF3 downregulation reduced SPHK1 expression to attenuate cardiomyocyte injury in MI.
内质网（ER）应激在包括心脏病在内的多种人类疾病中很常见。鞘氨醇激酶-1（SPHK1）是心脏生长和功能的重要参与者。然而，其在心肌细胞 ER 应激中的作用尚不清楚。本研究旨在评估 SPHK1 在心肌梗死（MI）期间影响 ER 应激的机制。
查询与 MI 相关的 GEO 数据集以筛选差异表达基因。诱导 HL-1 细胞暴露于氧葡萄糖剥夺（OGD）和 MI 小鼠，然后使用短发夹 RNA 和过表达载体进行基因表达操作。在细胞和组织中检测激活转录因子 3（ATF3）和 SPHK1 的表达。体外和体内进行细胞计数试剂盒-8、TUNEL、DHE、HE 和 Masson 染色。使用 ELISA 测量小鼠血清中的炎症因子浓度。最后，验证了 ATF3 对 SPHK1 的转录调控。
ATF3 和 SPHK1 在体内和体外均上调。ATF3 下调减少了 SPHK1 的转录。ATF3 和 SPHK1 下调增加了 OGD 处理的 HL-1 细胞的活力，减少了细胞凋亡、氧化应激和 ER 应激。ATF3 和 SPHK1 下调缩小了小鼠的梗死面积，减轻了心肌纤维化，并降低了血清中的炎症因子和心肌中的 ER 应激。相反，SPHK1 减少了 ATF3 下调在体外和体内的保护作用。
ATF3 下调减少了 SPHK1 的表达，从而减轻了 MI 中的心肌细胞损伤。
