The PIWI-interacting RNA CRAPIR alleviates myocardial ischemia‒reperfusion injury by reducing p53-mediated apoptosis via binding to SRSF1

Hong Yan^#^{1 2}, Han Li^#^{1 3}, Dao-Hong Yin^{1 3}, Zi-Zhen Zhang^{1 3}, Qian-Yun Zhang^{1 3}, Zhong-Yu Ren^{1 3}, Yu Hu^{1 3}, Gui-Yang Zheng^{1 3}, Yu Liu⁴, Wen-Ya Ma^{1 3}, Yi-Ning Liu^{5 6}, Xiu-Xiu Wang^{7 8}, Ben-Zhi Cai^{9 10 11}, Hong-Yang Chen^{12 13}

Affiliations

¹ Department of Pharmacy at the Second Affiliated Hospital (National Key Laboratory of Frigid Zone Cardiovascular Diseases), Harbin Medical University, Harbin, 150086, China.
² Department of Pharmacy at the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
³ Institute of Clinical Pharmacology (The Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin, 150001, China.
⁴ Department of Clinical Laboratory at the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.
⁵ 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.
⁶ Institute of Clinical Pharmacology (The Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin, 150001, China. 18846456454@163.com.
⁷ 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.
⁸ Institute of Clinical Pharmacology (The Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin, 150001, China. wangxiuxiu2017@126.com.
⁹ 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.
¹⁰ Institute of Clinical Pharmacology (The Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin, 150001, China. caibz@ems.hrbmu.edu.cn.
¹¹ NHC Key Laboratory of Cell Transplantation, The Heilongjiang Key Laboratory of Drug Research, Harbin Medical University, Harbin, 150001, China. caibz@ems.hrbmu.edu.cn.
¹² 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.
¹³ College of Pharmacy, Harbin Medical University (Daqing), Daqing, 163319, China. chenhongyang@hmudq.edu.cn.

^# Contributed equally.

PMID: 40181167
DOI: 10.1038/s41401-025-01534-6

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.

Keywords: PIWI-interacting RNA; SRSF1; apoptosis; ischemia/reperfusion injury; p53.

Acta Pharmacol Sin . 2025 Apr 3.doi: 10.1038/s41401-025-01534-6. (IF:6.900).

The PIWI-interacting RNA CRAPIR alleviates myocardial ischemia‒reperfusion injury by reducing p53-mediated apoptosis via binding to SRSF1

Abstract

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