Abstract Body: Background: The nuclear factor of activated T-cell (NFAT) family, especially NFATc3, exerts various effects on cardiovascular diseases, but its role in myocardial infarction (MI) remains poorly understood.
Aims: We aimed to investigate the role of NFATc3 in angiogenesis of endothelial cells (EC) after MI and explore the therapeutic effect of targeting NFATc3 in ECs for MI treatment.
Methods: We administrated mice receiving MI operation with NFAT inhibitor and re-analyzed the single nuclear RNA sequencing (snRNA-seq) data from mice with MI to explore NFATc3 as the key factor of NFAT family in MI and the NFATc3 expression in different cell types. EC-specific NFATc3 knock-out and knock-in mice were generated to determine the effect of NFATc3 on MI. Histological experiments and snRNA-seq were conducted to study the role of NFATc3 in ECs in cardiac injury after MI. Seahorse assays and transmission electron microscopy were used to determine the effect of NFATc3 on mitochondrial function in ECs. Chromatin immunoprecipitation assays and luciferase reporter assays were performed to explore the transcriptional function of NFATc3.
Results: NFAT inhibition could slightly aggravate MI instead of alleviating it. NFATc3 was upregulated in ECs of myocardium after MI. EC-specific NFATc3 deletion aggravated cardiac injury after MI whereas EC-specific NFATc3 overexpression inhibited MI progression. EC-specific NFATc3 deletion reduced endothelial angiogenesis and promoted mitochondrial dysfunction. Mechanistically, NFATc3 transcriptionally upregulated metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) to facilitate mitochondrial function in ECs. Deletion of MALAT1 in ECs reversed the beneficial effect of NFATc3 overexpression by aggravating mitochondria damage and thus impairing angiogenesis function of ECs.
Conclusion: Endothelial NFATc3 promotes angiogenesis function by upregulating lncRNA MALAT1 to facilitate mitochondrial function, thereby mitigating cardiac injury after MI. Our study uncovers the novel role of endothelial NFATc3 in MI and provides insights into targeting NFATc3 in EC as a therapeutic strategy of MI.