Novel therapeutic insights into pathological cardiac hypertrophy : tRF-16-R29P4PE regulates PACE4 and metabolic pathways

被引：0

作者：

Wang, Feng ^{[1
]}

Li, Ping ^{[2
]}

Yan, Xinxin ^{[1
]}

Yue, Anna ^{[3
]}

Xu, Jingyi ^{[2
]}

Shao, Yaqing ^{[3
]}

Zhang, Kaiyu ^{[3
]}

Zhang, Qian ^{[1
]}

Li, Yuan ^{[3
]}

Sun, Kangyun ^{[3
]}

机构：

[1] Nanjing Med Univ, Affiliated Suzhou Hosp, Suzhou Municipal Hosp, Dept Pharm,Gusu Sch, Suzhou 215008, Peoples R China

[2] Nanjing Med Univ, Affiliated Suzhou Hosp, Suzhou Municipal Hosp, Dept Cent Lab,Gusu Sch, Suzhou 215008, Peoples R China

[3] Nanjing Med Univ, Affiliated Suzhou Hosp, Suzhou Municipal Hosp, Dept Cardiol,Gusu Sch, 242 Guangji Rd, Suzhou 215008, Peoples R China

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH | 2025年 / 1872卷 / 03期

关键词：

Pathological cardiac hypertrophy (PCH); tRNA-derived small RNAs (tsRNAs); PACE4; HIF-1 alpha/PPAR alpha signaling pathway; Cardiomyocyte metabolism; HEART; ALPHA; MODEL;

D O I：

10.1016/j.bbamcr.2025.119920

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Pathological cardiac hypertrophy (PCH) is a complex condition with an incompletely understood pathogenesis. Emerging evidence suggests that transfer RNA-derived small RNAs (tsRNAs) may play a significant role in various cellular processes, yet their impact on PCH remains unexplored. In this study, we performed tsRNA sequencing on plasma samples from PCH patients and identified a marked decrease in the expression of tRNArelated fragment 16-R29P4PE (tRF-16-R29P4PE), a specific tsRNA fragment, with a diagnostic area under the curve value of 0.7750. Using Angiotensin II (Ang II)-stimulated H9c2 cardiomyocytes as an in vitro model and Sprague-Dawley rats as an in vivo model, we investigated the effects of tRF-16-R29P4PE minic/inhibitors and silencing of the paired basic amino acid cleaving system 4 (PACE4) gene. Our results demonstrated that modulating tRF-16-R29P4PE expression significantly reduced brain natriuretic peptide (BNP) and free fatty acid levels while enhancing ATP production, glucose levels, and mitochondrial membrane potential. These effects were accompanied by the downregulation of PACE4, hypoxia-inducible factor-1 alpha (HIF-1 alpha), glucose transporter-4 (GLUT-4), and medium-chain acyl-CoA dehydrogenase (MCAD), as well as the upregulation of peroxisome proliferator-activated receptor alpha (PPAR alpha). Animal experiments revealed that tRF-16-R29P4PE minic improved cardiac function, reduced myocardial fibrosis, and mitigated metabolic disorders and mitochondrial damage. Furthermore, co-immunoprecipitation (Co-IP) and molecular docking assays confirmed a direct interaction between PACE4 and HIF-1 alpha, and luciferase reporter assays identified PACE4 as a direct target of tRF-16-R29P4PE. By regulating the PACE4 and HIF-1 alpha/PPAR alpha signaling pathways, tRF-16-R29P4PE alleviates PCH, providing a promising molecular target for therapeutic intervention.

引用

页数：15