The PIWI-Interacting RNA CRAPIR Alleviates Myocardial Ischemia‒Reperfusion Injury by Reducing p53-Mediated Apoptosis via Binding to SRSF1

Authors

• Hong Yan, Department of Pharmacy at the Second Affiliated Hospital (National Key Laboratory of Frigid Zone Cardiovascular Diseases), Harbin Medical University, Harbin, 150086, China. Department of Pharmacy at the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
• Han Li, Department of Pharmacy at the Second Affiliated Hospital (National Key Laboratory of Frigid Zone Cardiovascular Diseases), Harbin Medical University, Harbin, 150086, China. Institute of Clinical Pharmacology (The Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin, 150001, China.
• Dao-Hong Yin, Department of Pharmacy at the Second Affiliated Hospital (National Key Laboratory of Frigid Zone Cardiovascular Diseases), Harbin Medical University, Harbin, 150086, China. Institute of Clinical Pharmacology (The Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin, 150001, China.
• Zi-Zhen Zhang, Department of Pharmacy at the Second Affiliated Hospital (National Key Laboratory of Frigid Zone Cardiovascular Diseases), Harbin Medical University, Harbin, 150086, China. Institute of Clinical Pharmacology (The Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin, 150001, China.
• Qian-Yun Zhang, Department of Pharmacy at the Second Affiliated Hospital (National Key Laboratory of Frigid Zone Cardiovascular Diseases), Harbin Medical University, Harbin, 150086, China. Institute of Clinical Pharmacology (The Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin, 150001, China.
• Zhong-Yu Ren, Department of Pharmacy at the Second Affiliated Hospital (National Key Laboratory of Frigid Zone Cardiovascular Diseases), Harbin Medical University, Harbin, 150086, China. Institute of Clinical Pharmacology (The Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin, 150001, China.
• Yu Hu, Department of Pharmacy at the Second Affiliated Hospital (National Key Laboratory of Frigid Zone Cardiovascular Diseases), Harbin Medical University, Harbin, 150086, China. Institute of Clinical Pharmacology (The Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin, 150001, China.
• Gui-Yang Zheng, Department of Pharmacy at the Second Affiliated Hospital (National Key Laboratory of Frigid Zone Cardiovascular Diseases), Harbin Medical University, Harbin, 150086, China. Institute of Clinical Pharmacology (The Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin, 150001, China.
• Yu Liu, Department of Clinical Laboratory at the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
• Wen-Ya Ma, Department of Pharmacy at the Second Affiliated Hospital (National Key Laboratory of Frigid Zone Cardiovascular Diseases), Harbin Medical University, Harbin, 150086, China. Institute of Clinical Pharmacology (The Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin, 150001, China.
• Yi-Ning Liu, Department of Pharmacy at the Second Affiliated Hospital (National Key Laboratory of Frigid Zone Cardiovascular Diseases), Harbin Medical University, Harbin, 150086, China. 18846456454@163.com. Institute of Clinical Pharmacology (The Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin, 150001, China. 18846456454@163.com.
• Xiu-Xiu Wang, Department of Pharmacy at the Second Affiliated Hospital (National Key Laboratory of Frigid Zone Cardiovascular Diseases), Harbin Medical University, Harbin, 150086, China. wangxiuxiu2017@126.com. Institute of Clinical Pharmacology (The Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin, 150001, China. wangxiuxiu2017@126.com.
• Ben-Zhi Cai, Department of Pharmacy at the Second Affiliated Hospital (National Key Laboratory of Frigid Zone Cardiovascular Diseases), Harbin Medical University, Harbin, 150086, China. caibz@ems.hrbmu.edu.cn. Institute of Clinical Pharmacology (The Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin, 150001, China. caibz@ems.hrbmu.edu.cn. NHC Key Laboratory of Cell Transplantation, The Heilongjiang Key Laboratory of Drug Research, Harbin Medical University, Harbin, 150001, China. caibz@ems.hrbmu.edu.cn.
• Hong-Yang Chen, Department of Pharmacy at the Second Affiliated Hospital (National Key Laboratory of Frigid Zone Cardiovascular Diseases), Harbin Medical University, Harbin, 150086, China. chenhongyang@hmudq.edu.cn. College of Pharmacy, Harbin Medical University (Daqing), Daqing, 163319, China. chenhongyang@hmudq.edu.cn.

Document Type

Article

Publication Date

9-1-2025

Abstract

Ischemia-reperfusion (I/R) injury refers to the secondary damage that occurs when blood flow is restored to heart tissues and organs following a period of prolonged ischemia. This damage is exacerbated primarily through mechanisms such as oxidative stress, inflammatory responses and apoptosis, all of which can severely impact patient prognosis. PIWI-interacting RNAs (piRNAs) represent a novel class of small noncoding RNAs that play pivotal roles in regulating gene expression and cellular functions. However, the precise role and underlying mechanisms of piRNAs in I/R injury remain poorly understood. In this study, we investigated the role and molecular mechanisms of a cardiac regeneration-associated PIWI-interacting RNA (CRAPIR), previously identified by our team, in I/R injury. An I/R injury model was established in adult male mice. The protein levels of cleaved caspase-3, Bax, Bcl2 and p53 were assessed using Western blotting, and cardiomyocyte apoptosis was detected via TUNEL staining. Our study revealed that, in I/R-damaged heart tissues and hypoxia‒reoxygenation (H/R)-induced cardiomyocyte models, CRAPIR was upregulated 24 h after I/R and H/R but was markedly downregulated at 72 h after I/R injury and 48 h after H/R injury. In the I/R mouse model, agomir-mediated overexpression of CRAPIR alleviated heart dysfunction and reduced cardiomyocyte apoptosis caused by I/R injury. Conversely, CRAPIR knockdown via an antagomir exacerbated I/R-induced cardiac dysfunction and increased the number of apoptotic cardiomyocytes. Mechanistically, CRAPIR interacts with serine/arginine-rich splicing factor 1 (SRSF1), triggering the upregulation of murine double minute 2 (MDM2) expression. The increased MDM2 promoted p53 ubiquitination, leading to reduced p53 levels. Furthermore, silencing SRSF1 or MDM2 attenuated the protective effect of CRAPIR against cardiomyocyte apoptosis following H/R injury. These findings suggest that CRAPIR serves as a critical regulator of I/R injury via the SRSF1/MDM2/p53 signaling pathway.

Recommended Citation

Yan H, Li H, Yin DH, Zhang ZZ, Zhang QY, Ren ZY, Hu Y, Zheng GY, Liu Y, Ma WY, Liu YN, Wang XX, Cai BZ, Chen HY. The PIWI-interacting RNA CRAPIR alleviates myocardial ischemia‒reperfusion injury by reducing p53-mediated apoptosis via binding to SRSF1. Acta Pharmacol Sin. 2025 Sep;46(9):2393-2406. doi: 10.1038/s41401-025-01534-6. Epub 2025 Apr 3. PMID: 40181167; PMCID: PMC12373838.