miRNA‐27a Transcription Activated by c‐Fos Regulates Myocardial Ischemia‐Reperfusion Injury by Targeting ATAD3a

Abstract

MicroRNA-27a (miR-27a) has been implicated in myocardial ischemia-reperfusion injury (MIRI), but the underlying mechanism is not well understood. This study is aimed at determining the role of miR-27a in MIRI and at investigating upstream molecules that regulate miR-27a expression and its downstream target genes. miR-27a expression was significantly upregulated in myocardia exposed to ischemia/reperfusion (I/R) and cardiomyocytes exposed to hypoxia/reoxygenation (H/R). c-Fos could regulate miR-27a expression by binding to its promoter region. Moreover, overexpression of miR-27a led to a decrease in cell viability, an increase in LDH and CK-MB secretion, and an increase in apoptosis rates. In contrast, suppression of miR-27a expression resulted in the opposite effects. ATPase family AAA-domain-containing protein 3A (ATAD3a) was identified as a target of miR-27a. miR-27a regulated the translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus and H/R-induced apoptosis via the regulation of ATAD3a. It was found that inhibiting miR-27a in vivo by injecting a miR-27a sponge could ameliorate MIRI in an isolated rat heart model. In conclusion, our study demonstrated that c-Fos functions as an upstream regulator of miR-27a and that miR-27a regulates the translocation of AIF from the mitochondria to the nucleus by targeting ATAD3a, thereby contributing to MIRI. These findings provide new insight into the role of the c-Fos/miR-27a/ATAD3a axis in MIRI.

NF‐κB1 promotes miR‐27a‐5p upregulation in acrylamide‐induced toxicity in rats

“…Specifically, MyoD binds to and activates the miR‐27a‐3p promoter, with binding sites located within the core promoter region (−234/−165 bp) (Tao et al., 2022). Furthermore, c‐Fos was found to promote miR‐27a expression by specifically binding to the miR‐27a promoter region (−983 to −974 region) and subsequently leading to enhance ischemia/reperfusion‐induced myocardial apoptosis in vitro (Bao et al., 2021). These findings highlight the significant role of transcription factors in regulating the expression of miR‐27a.…”

Identification of novel prognostic targets in coronary artery disease and related complications using bioinformatics and next generation sequencing data analysis

“…TLR4 [500], ABCA1 [501], CCR2 [502], LDLR (low density lipoprotein receptor) [503], SIRT1 [504] and NOD2 [505] might crucially contribute to the development of hypercholesterolemia. ABCA1 [506], TLR5 [507], PTGS2 [508], TGFA (transforming growth factor alpha) [509], PDK4 [510], JAK2 [511], TLR2 [512], NEK7 [513], CCR1 [514], BACH1 [515], NCOA4 [195], LATS2 [516], PELI1 [517], EGR1 [518], CYBB (cytochrome b-245 beta chain) [519], MEFV (MEFV innate immuity regulator, pyrin) [520], CLEC4E [521], GCLC (glutamate-cysteine ligase catalytic subunit) [522], KLF3 [523], TP53INP1 [524], ITGB1 [525], IRF9 [526], PHLPP1 [527], NOD2 [528], ACSL4 [529], FGL2 [530], PF4 [531], VEGFB (vascular endothelial growth factor B) [532], CCR7 [533], IGFBP4 [534], TRPM4 [535], BAG1 [536], LGALS3 [537] and ATAD3A [538] could induce ischemic heart disease. Therefore, the data suggest that the identified DEGs which enriched in GO terms and pathways might participant in the development of CAD and its associated complications, and contribute to CAD and CAD related complications treatment.…”

Fra‐1 induces apoptosis and neuroinflammation by targeting S100A8 to modulate TLR4 pathways in spinal cord ischemia/reperfusion injury

“…In various types of cells and stimuli, Fos family members perform different functions, although they have similar structures [ 45 ]. Previous studies have shown that c‐Fos, a member of the Fos family, promotes apoptosis by regulating miR‐27a expression after myocardial I/R injury [ 7 ]. Fra‐1 is a member of the Fos family, with members that dimerize with Jun family members [ 4 ], but the function of Fra‐1 after I/R has been unclear.…”

“…AP-1 transcription factors are signal activated, and they regulate apoptosis and stress responses [5,6]. Increasing evidence has indicated that c-Fos and c-Jun can be induced to high expression levels after ischemia injury and that this upregulation moderates apoptosis [7,8].…”