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

Authors

Wenbin Fu, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
Hongmei Ren, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
Jialing Shou, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
Qiao Liao, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
Liangpeng Li, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
Yu Shi, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China.
Pedro A. Jose, Division of Kidney Diseases & Hypertension, Department of Medicine and Department of Pharmacology/Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20052, USA.
Chunyu Zeng, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China. chunyuzeng01@163.com.
Wei Eric Wang, Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China. weiericwang@163.com.

Document Type

Journal Article

Publication Date

3-5-2022

Journal

Basic research in cardiology

Volume

117

Issue

1

DOI

10.1007/s00395-022-00921-y

Keywords

Cardiac regeneration; DNA repair; NPPA-AS1; SFPQ–NONO heteromer

Abstract

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.

APA Citation

Fu, Wenbin; Ren, Hongmei; Shou, Jialing; Liao, Qiao; Li, Liangpeng; Shi, Yu; Jose, Pedro A.; Zeng, Chunyu; and Wang, Wei Eric, "Loss of NPPA-AS1 promotes heart regeneration by stabilizing SFPQ-NONO heteromer-induced DNA repair" (2022). GW Authored Works. Paper 626.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/626

Department

Medicine