A novel micropeptide, Slitharin, exerts cardioprotective effects in myocardial infarction.

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Publication Year:
2024
Authors:
Ahmed G E Ibrahim, Alessandra Ciullo, Shukuro Yamaguchi, Chang Li, Travis Antes, Xaviar Jones, Liang Li, Ramachandran Murali, Innokentiy Maslennikov, Niveda Sundararaman, Daniel Soetkamp, Eugenio Cingolani, Jennifer Van Eyk, Eduardo Marban
PubMed ID:
38444254
Funding Grants:
Public Summary:
Scientists discovered a tiny new protein called Slitharin (Slt) that comes from special heart-supporting cells called cardiosphere-derived cells (CDCs). This small protein is made from a type of RNA that usually doesn’t make proteins. When heart cells were treated with Slt in the lab, they were better protected from damage caused by low oxygen. Tests in rats with heart attacks showed that Slt helped reduce the size of heart damage shortly after the injury. This suggests that Slt is a tiny protein released by heart cells that could help protect the heart after injury, making it a promising target for future heart disease treatments.
Scientific Abstract:
PURPOSE: Micropeptides are an emerging class of proteins that play critical roles in cell signaling. Here, we describe the discovery of a novel micropeptide, dubbed slitharin (Slt), in conditioned media from Cardiosphere-derived cells (CDCs), a therapeutic cardiac stromal cell type. EXPERIMENTAL DESIGN: We performed mass spectrometry of peptide-enriched fractions from the conditioned media of CDCs and a therapeutically inert cell type (human dermal fibrobasts). We then evaluated the therapeutic capacity of the candidate peptide using an in vitro model of cardiomyocyte injury and a rat model of myocardial infarction. RESULTS: We identified a novel 24-amino acid micropeptide (dubbed Slitharin [Slt]) with a non-canonical leucine start codon, arising from long intergenic non-coding (LINC) RNA 2099. Neonatal rat ventricular myocytes (NRVMs) exposed to Slt were protected from hypoxic injury in vitro compared to a vehicle or scrambled control. Transcriptomic analysis of cardiomyocytes exposed to Slt reveals cytoprotective capacity, putatively through regulation of stress-induced MAPK-ERK. Slt also exerted cardioprotective effects in rats with myocardial infarction as shown by reduced infarct size 48 h post-injury. Conclusions and clinical relavance: Thus, Slt is a non-coding RNA-derived micropeptide, identified in the extracellular space, with a potential cardioprotective function.