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

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.