The N-6 methyladenosine dynamics in STEMI and the effect of IL-6 inhibition - a hypothesis generating sub-study of the ASSAIL-MI trial

• Published in: Frontiers in immunology Vol. 16; p. 1532325
• Main Authors: Dahl, Tuva B., Quiles-Jiménez, Ana, Broch, Kaspar, Anstensrud, Anne Kristine, Gullestad, Lars, Andersen, Geir Ø., Kleveland, Ola, Øgaard, Jonas, Bjerkeli, Vigdis, Rashidi, Azita, Yang, Kuan, Holven, Kirsten B., Aukrust, Pål, Bjørås, Magnar, Huse, Camilla, Halvorsen, Bente
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 2025
• Subjects: Adenosine - analogs & derivatives; Adenosine - blood; Adenosine - metabolism; Aged; epitranscriptome; Female; Humans; inflammation; Interleukin-6 - antagonists & inhibitors; Male; Middle Aged; N6-methyladenosine (m6A); RNA methylation; RNA, Messenger - genetics; ST Elevation Myocardial Infarction - blood; ST Elevation Myocardial Infarction - drug therapy; ST Elevation Myocardial Infarction - genetics; ST Elevation Myocardial Infarction - metabolism; STEMI; tocilizumab; STEMI; N6-methyladenosine (m6A); tocilizumab; epitranscriptome; inflammation; RNA methylation
• DOI: 10.3389/fimmu.2025.1532325
• ISSN: 1664-3224

Epitranscriptomics, with m A as the most prevalent in mammals, is a novel treatment target for inflammatory diseases, including cardiovascular diseases. However, little is known about m A RNA-regulation during myocardial infarction (MI). In this explorative sub-study of the ASSAIL-MI trial, we used whole blood samples from patients with acute ST-elevation MI (STEMI) (n=6) at admission and after 3-7 days, and from healthy control subjects (n=3). RNA was isolated, and m A sites were analyzed using human m A single nucleotide resolution microarray analysis. mRNA levels were analyzed using RNA sequencing analysis. Compared with controls, patients with STEMI had a strikingly different pattern of m A deposition. In total, 845 m A methylation sites in whole blood RNA were hypomethylated and 36 were hypermethylated compared with controls. Of the hypomethylated transcripts, 194 transcripts were lower expressed, while 197 transcripts were higher expressed. The m A pattern changed from an overall hypomethylation at admission to an overall hypermethylation 3-7 day after admission. Anti-inflammatory treatment with tocilizumab further altered the m A deposition. In this hypothesis generating study, m A deposition differs STEMI patients and healthy controls. The m A pattern changes over the course of 3-7 days. This response is, at least to some degree, is modulated by blocking the IL-6 receptor. Our data may suggest that this post-transcriptional regulation of RNA is involved in the immune response during STEMI, highlighting its potential as a target for therapy in MI.