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

Epitranscriptomics, with m⁶A as the most prevalent in mammals, is a novel treatment target for inflammatory diseases, including cardiovascular diseases. However, little is known about m⁶A 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 m⁶A sites were analyzed using human m⁶A 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 m⁶A deposition. In total, 845 m⁶A 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 m⁶A 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 m⁶A deposition.

In this hypothesis generating study, m⁶A deposition differs STEMI patients and healthy controls. The m⁶A 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.