Key Takeaways & Executive Findings
- •• piR-000699 is upregulated in aging cardiomyocytes under hypoxia/reoxygenation, promoting ferroptosis. • SLC39A14 is identified as a direct target of piR-000699, mediating ferroptosis in aging myocardial I/R injury. • Ferroptosis is a key cell death pathway in aging myocardial I/R injury, both in vivo and in vitro. • Targeting piR-000699/SLC39A14 axis may offer a novel therapeutic strategy for aged myocardial I/R injury.
Abstract
Myocardial ischemia/reperfusion (I/R) injury is a classic type of cardiovascular disease characterized by injury to cardiomyocytes leading to different types of cell death. The degree of irreversible myocardial damage is closely related to age, and ferroptosis is involved in cardiomyocyte damage. However, the mechanisms underlying ferroptosis regulation in aging myocardial I/R injury are still unclear. The present study aims to explore the underlying mechanism of piRNA regulation in ferroptosis. Using left anterior descending coronary artery ligation in an aging rat model and a D-galactose-induced rat cardiomyocyte line (H9C2) to construct an aging cardiomyocyte model, we investigate whether ferroptosis occurs after reperfusion injury in vitro and in vivo. This study focuses on the upregulation of piR-000699 after hypoxia/reoxygenation treatment in aging cardiomyocytes by observing hypoxia/reoxygenation (H/R) injury indicators and ferroptosis-related indicators and clarifying the role of piR-000699 in H/R injury caused by ferroptosis in aging cardiomyocytes. Bioinformatics analysis reveals that SLC39A14 is a gene that binds to piR-000699. Our data show that ferroptosis plays an important role in I/R injury both in vivo and in vitro. Furthermore, the results show the potential role of piR-000699 in regulating SLC39A14 in ferroptosis in aging cardiomyocytes under hypoxia/reoxygenation conditions. Together, our results reveal that the mechanism by which piR-000699 binds to SLC39A14 regulates ferroptosis in aging myocardial I/R injury.
1. Introduction
Ischemia-reperfusion (I/R) is a prominent pathological process that occurs in numerous organs and diseases [1]. Myocardial I/R injury represents an inevitable risk event for acute myocardial infarction, resulting in morbidity and mortality among elderly patients worldwide [2]. Although significant advances have been made in the treatment of I/R injuries, the development of cardioprotective therapeutics remains a formidable challenge, with the severity of damage closely associated with age [3]. However, the underlying mechanism remains largely elusive; hence, it is imperative to explore novel therapeutic targets for managing aged myocardial I/R injury.
Ferroptosis, a recently defined iron-dependent form of cell death, is characterized by the generation of reactive oxygen species (ROS) and lipid peroxidation [4]. In contrast to apoptosis, necrosis, and autophagy, which are distinct in morphology, biochemistry, and genetics [5], ferroptosis primarily arises due to dysregulated iron metabolism leading to excessive ROS production and lipid peroxide accumulation, culminating in cellular death [6]. Numerous studies have reported associations between ferroptosis and pathophysiological processes implicated in various diseases, including cancer progression, tissue or organ damage, stroke occurrence, I/R injury and renal degeneration [7]. A previous study confirmed that proteins related to ferroptosis are involved in the process of myocardial ischaemia-reperfusion injury, which is supported by evidence suggesting that selective inhibition of ferroptosis within cardiomyocytes may alleviate myocardial damage [8]. Gao et al. [9] reported that the overexpression of growth and differentiation factor 15 significantly inhibits MIRI while improving cardiac function by alleviating MIRI-induced ferroptotic cell death. However, the regulatory mechanisms governing ferroptosis during MIRI remain unknown, particularly concerning aging-related myocardial I/R injury.
P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are recently discovered small noncoding RNAs found in germ and somatic cells that consist of 24‒31 nucleotides (nt) with a preference for adenosine at the 10th position or a 5′-terminal uridine [10,11]. These piRNAs lack distinct secondary structure motifs, yet they exert regulatory control over gene expression in somatic cells through various mechanisms, such as transposon silencing, epigenetic programming, DNA rearrangement, mRNA turnover, and translation [12,13]. Alterations in the expressions of numerous piRNAs have been associated with myocardial hypertrophy [14]. In progenitor cells within the mesoderm and cardiomyocytes alone, a total of 447 piRNA transcripts were identified; among
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Hongyang Chi, Yue’e Chai, Lingju Ma, Yichen Wang, Qianqian Wu, Lexin Wang, Junjie Zhai, Fufun Ma, Yancheng Tian, Ning Qi, Jianhong Peng, Youjuan Fu, Xiaoling Yang, Hui Huang, Shengchao Ma (2026). The mechanism by which piR-000699 targets SLC39A14 regulates ferroptosis in aging myocardial ischemia/reperfusion injury. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024024
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Frequently Asked Questions
What is the role of piR-000699 in aging myocardial ischemia/reperfusion injury?
piR-000699 is upregulated in aging cardiomyocytes under hypoxia/reoxygenation and promotes ferroptosis by targeting SLC39A14, thereby exacerbating myocardial I/R injury.
How does SLC39A14 contribute to ferroptosis in aging cardiomyocytes?
SLC39A14 is a zinc transporter that, when bound by piR-000699, leads to increased ferroptosis, likely through dysregulation of iron metabolism and increased oxidative stress.
What experimental models were used in this study?
The study used an aging rat model with left anterior descending coronary artery ligation and a D-galactose-induced H9C2 cardiomyocyte line to mimic aging conditions, along with hypoxia/reoxygenation treatment to simulate I/R injury.
What are the potential therapeutic implications of this research?
Targeting the piR-000699/SLC39A14 axis may provide a novel therapeutic strategy to mitigate ferroptosis and reduce myocardial damage in elderly patients with I/R injury.
How was SLC39A14 identified as a target of piR-000699?
Bioinformatics analysis predicted SLC39A14 as a potential binding partner of piR-000699, and subsequent experiments confirmed the interaction and its role in regulating ferroptosis.
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