Abstract Noncoding RNAs (ncRNAs) are increasingly recognized as bioactive. Here we report the development of TY1, a synthetic ncRNA bioinspired by a naturally-occurring human small Y RNA with immunomodulatory properties. TY1 upregulates TREX1, an exonuclease that rapidly degrades cytosolic DNA. In preclinical models of myocardial infarction (MI) induced by ischemia/reperfusion, TY1 reduced scar size. The cardioprotective effect of TY1 was abrogated by prior depletion of macrophages and mimicked by adoptive transfer of macrophages exposed either to TY1 or TREX1. Inhibition of TREX1 in macrophages blocked TY1 cardioprotection. Consistent with a central role for TREX1, TY1 attenuated DNA damage in the post-MI heart. This novel mechanism—pharmacologic upregulation of TREX1 in macrophages—establishes TY1 as the prototype for a new class of ncRNA drugs with disease-modifying bioactivity. One Sentence Summary Upregulation of three prime exonuclease, TREX1, in macrophages enhances tissue repair post myocardial infarction.

Augmentation of DNA exonuclease TREX1 in macrophages as a therapy for cardiac ischemic injury