Upregulation of SPI1 during myocardial infarction aggravates cardiac tissue injury and disease progression through activation of the TLR4/NFκB axis

This study demonstrated that upregulation of SPI1, caused by reduced DNA methylation, augmented development of myocardial infarction by activating the TLR4/NFκB axis.

A murine model of MI was established. HL-1 cells were exposed to hypoxic treatment to simulate an MI-like condition. Tissue injury, inflammatory infiltration, and fibrosis in the cardiac tissues, and the apoptosis and the production of inflammation-related factors in cells were examined. Expression of SPI1 was determined. The downstream targets of SPI1 were identified by bioinformatics tools and luciferase assays. Artificial up- or downregulation of SPI1 and toll like receptor 4 (TLR4) were induced to examine their involvements in MI progression.

Spleen focus forming virus proviral integration oncogene (SPI1) belongs to the ETS family of transcription factors participating in an array of cellular processes such as inflammation and cell apoptosis. This research focused on the role of SPI1 in the myocardial infarction (MI).

SPI1 was expressed at high levels in the cardiac tissues of MI mice and in hypoxia-induced HL-1 cells. SPI1 downregulation reduced apoptosis and the production of inflammatory cytokines in the hypoxia-induced HL-1 cells. SPI1 bound to TLR4 promoter to induce transcriptional activation. TLR4 induced NFκB phosphorylation and blocked the protective role of SPI1 silencing in cells. In vivo, SPI1 inhibition restored the cardiac function and ameliorated MI-induced inflammation and fibrosis in mice. The protective role of SPI1 inhibition in mice was blocked by TLR4 activation. Aberrant upregulation of SPI1 was caused by the reduced DNA methylation during MI.