Loss of NPPA-AS1 promotes heart regeneration by stabilizing SFPQ–NONO heteromer-induced DNA repair

• DOI: 10.1007/s00395-022-00921-y
• Publication Date: 2022-03-05T09:02:42Z
• Authors: Wenbin Fu; Hongmei Ren; Jialing Shou; Qiao Liao; Liangpeng Li; Yu Shi; Pedro A. Jose; Chunyu Zeng; Wei Eric Wang
• Keywords: Mammals; 0303 health sciences; DNA Repair; Myocardial Infarction; RNA-Binding Proteins; Procainamide; DNA-Binding Proteins; Mice; 03 medical and health sciences; Animals; Regeneration; Myocytes, Cardiac; RNA, Long Noncoding; Atrial Natriuretic Factor; Cell Proliferation

The role of long non-coding RNA (lncRNA) in endogenous cardiac regeneration remains largely elusive. The mammalian cardiomyocyte is capable of regeneration for a brief period after birth. This fact allows the exploration of the roles of critical lncRNAs in the regulation of cardiac regeneration. Through a cardiac regeneration model by apical resection (AR) of the left ventricle in neonatal mice, we identified an lncRNA named natriuretic peptide A antisense RNA 1 (NPPA-AS1), which negatively regulated cardiomyocyte proliferation. In neonates, NPPA-AS1 deletion did not affect heart development, but was sufficient to prolong the postnatal window of regeneration after AR. In adult mice, NPPA-AS1 deletion improved cardiac function and reduced infarct size after myocardial infarction (MI), associated with a significant improvement in cardiomyocyte proliferation. Further analysis showed that NPPA-AS1 interacted with DNA repair-related molecule splicing factor, proline- and glutamine-rich (SFPQ). A heteromer of SFPQ and non-POU domain-containing octamer-binding protein (NONO) was required for double-strand DNA break repair, but NPPA-AS1 was competitively bound with SFPQ due to the overlapped binding sites of SFPQ and NONO. NPPA-AS1 deletion promoted the binding of SFPQ-NONO heteromer, decreased DNA damage, and activated cardiomyocyte cell cycle re-entry. Together, loss of NPPA-AS1 promoted cardiomyocyte proliferation by stabilizing SFPQ-NONO heteromer-induced DNA repair and exerted a therapeutic effect against MI in adult mice. Consequently, NPPA-AS1 may be a novel target for stimulating cardiac regeneration to treat MI.