RNA Binding Patterns of Ischemic Heart Failure Prognosis Indicator Eukaryotic Translation Initiation Factor 3m Reveal its Unique Role in Regulation of Nitrative Damage after Myocardial Ischemia-Reperfusion [Ribo-Seq]

ABSTRACT: RNA undergoes various modifications in a manner similar to DNA, thereby opening up the research field of epitranscriptomics. Regulators of mRNA modifications play a role in many molecular processes, biological functions, and disease prognosis. Differential expression profile of RNA modification regulators from HFrEF patients’ hearts remains deficient at present, let alone their affections on the prognosis. A risk score model based on two modifications-related modulators (eIF3m and Nudt12) was built and screened out with a LASSO regression analysis. Translation dysregulation upon eIF3m knock down in cardiomyocytes was examined by combined high-throughput methods of transcriptome sequencing, ribosome profiling, proteome research, and Clip analyses. Metabolic assays and flux analysis were used to characterize the effects of eIF3m and its downstream mediator in metabolic reprogramming with high-level exogenous TNF-α to mimic a highly oxidative inflammatory injury. eIF3m deficiency leads to decoupling of the major steps in translation initiation and elongation. It stabilizes eIF3m-f-h subcomplex through proteasome dependent-polyubiquitination, and controls translational response of specific mRNAs. eIF3m directly binds to Mt2 5’ leader to upregulate its translation in NRCMs and H9c2 cells. eIF3m knockdown induced expression of genes involved in proinflammatory and oxidative stress, resulting in 3-NT modification to a key glycolysis enzyme Pfkfb3 when co-cultured with exogenous TNF-α. CM-specific eIF3m deletion deteriorates cardiac function and increases infarction size after I/R operation, whereas CM-specific eIF3m overexpression reverses the phenotype. Additionally, eIF3m overexpression inhibits whereas RNAi-mediated Mt2 knockdown activates NF-κB signaling and aggravates nitrative damage. Metabolic analyses highlighted the role for eIF3m in promoting glycolysis and biosynthesis required for functional recovery of the myocardium. Our study demonstrates that the prognosis indicator eIF3m alleviates oxidative inflammatory injury and promotes glycolytic reprograming mainly by binding to Mt2 mRNA. Therapeutic strategies enhancing eIF3m level may possess therapeutic potential against I/R injury.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE217295 | GEO | 2025/11/04

REPOSITORIES: GEO