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Abstract P1030: LIN28a-induced Metabolic Reprogramming Regulates New Myocyte Formation In The Heart Via Lncrna-H19

Authors :
Vagner O Rigaud
Robert Hoy
Justin Kurian
Clare Zarka
Michael Behanan
Isabella Brosious
Jennifer Pennise
Tej K Patel
Lindsay Kraus
Sadia Mohsin
Steven R Houser
Mohsin Khan
Source :
Circulation Research. 131
Publication Year :
2022
Publisher :
Ovid Technologies (Wolters Kluwer Health), 2022.

Abstract

Developmental cardiac tissue holds remarkable capacity to regenerate after injury and consists of regenerative mononuclear and diploid cardiomyocytes (MNDCMs). Upon maturation, MNDCMs become binucleated or polyploid and exit the cell cycle. Interestingly, CM metabolism undergoes a profound shift that coincides with cessation of regeneration in the postnatal heart. However, whether reprogramming metabolism promotes persistence of regenerative MNDCMs enhancing cardiac function and repair after injury is unknown. Here, we identify a novel role for RNA-binding protein LIN28a, a master regulator of cellular metabolism, in cardiac repair following injury. LIN28a was found as primarily active during cardiac development and rapidly decreases after birth. LIN28a reintroduction at P1, P3, P5, and P7 decreased maturation-associated polyploidization, nucleation, and cell size, enhancing CM cell cycle activity in LIN28a transgenic pups compared to WT littermates. Moreover, LIN28a overexpression extended CM cell cycle activity beyond P7 concurrent with increased cardiac function 30 days after apical resection. In the adult heart, LIN28a overexpression attenuated CM apoptosis, enhanced cell cycle activity, cardiac function, and survival in mice 12 weeks after myocardial infarction compared to WT littermate controls. Alternatively, LIN28a small molecule inhibitor attenuated pro-reparative effects of LIN28a on the heart. Mechanistically, Neonatal rat ventricular myocytes (NRVMs) overexpressing LIN28a showed increased glycolysis, ATP production and levels of metabolic enzymes compared to control. LIN28a immunoprecipitation followed by RNA sequencing (RIPseq) in CMs isolated from LIN28a injured hearts identified lncRNA-H19 as its most significantly altered target. Ablation of lncRNA-H19 blunted LIN28a-induced enhancement on CM metabolism and cell cycle activity. Collectively, LIN28a reprograms CM metabolism and promotes persistence of MNDCMs in the injured heart enhancing pro-reparative processes thereby linking CM metabolism to regulation of ploidy/nucleation and repair in the heart.

Details

ISSN :
15244571 and 00097330
Volume :
131
Database :
OpenAIRE
Journal :
Circulation Research
Accession number :
edsair.doi...........47108c5b5f720fbc5dde437a4dd6ed20
Full Text :
https://doi.org/10.1161/res.131.suppl_1.p1030