PIWI‐Interacting RNA HAAPIR Regulates Cardiomyocyte Death After Myocardial Infarction by Promoting NAT10‐Mediated ac⁴C Acetylation of Tfec mRNA

Abstract

PIWI‐interacting RNAs (piRNAs) are abundantly expressed in heart. However, their functions and molecular mechanisms during myocardial infarction remain unknown. Here, a heart‐apoptosis‐associated piRNA (HAAPIR), which regulates cardiomyocyte apoptosis by targeting N‐acetyltransferase 10 (NAT10)‐mediated N4‐acetylcytidine (ac4C) acetylation of transcription factor EC (Tfec) mRNA transcript, is identified. HAAPIR deletion attenuates ischemia/reperfusion induced myocardial infarction and ameliorate cardiac function compared to WT mice. Mechanistically, HAAPIR directly interacts with NAT10 and enhances ac4C acetylation of Tfec mRNA transcript, which increases Tfec expression. TFEC can further upregulate the transcription of BCL2‐interacting killer (Bik), a pro‐apoptotic factor, which results in the accumulation of Bik and progression of cardiomyocyte apoptosis. The findings reveal that piRNA‐mediated ac4C acetylation mechanism is involved in the regulation of cardiomyocyte apoptosis. HAAPIR‐NAT10‐TFEC‐BIK signaling axis can be potential target for the reduction of myocardial injury caused by cardiomyocyte apoptosis in ischemia heart diseases.

Emerging roles of ferroptosis in cardiovascular diseases

“…At present, MI has gradually become one of the main causes of death in patients with CVDs worldwide. Previous reports hold that the adverse consequences of MI mainly include cardiomyocyte apoptosis, necrosis and autophagy [ 41 – 43 ]. However, recent studies have found that the expression of GPX4 is significantly decreased in the early and middle stages of MI [ 44 ], suggesting that MI may lead to ferroptosis in myocardial cells.…”

Antibody-Free Fluorine-Assisted Metabolic Sequencing of RNA N4-Acetylcytidine

“…Remarkably, ac 4 C (position 34) modification of tRNA Met is formed through an acetate ion without acetyltransferases . Dysregulation of NAT10 and abnormal ac 4 C acetylation have been found to be associated with diverse diseases, including cancers and premature aging syndromes. − It is therefore important to detect ac 4 C to elucidate how epitranscriptomic metabolism affects cellular physiology and may allow us to develop new therapeutic targets.…”

Acetyltransferase NAT10 regulates the Wnt/β-catenin signaling pathway to promote colorectal cancer progression via ac4C acetylation of KIF23 mRNA

“…However, studies on the role of ac 4 C, a highly conserved RNA modification that was first identified in 2018 on mRNA in individuals with some diseases, are limited [ 11 ]. It has been confirmed that ac 4 C modification is involved in several biological processes, including osteogenesis, AIDS, myocardial infarction, and cancers [ 8 , 12 – 15 ]. However, previous studies on cancers in this regard have been limited to gastric and bladder cancers [ 8 , 12 ].…”