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Updated: Sep 4, 2025
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
Cytoplasmic sequestration of p53 by lncRNA-CIRPILalleviates myocardial ischemia/reperfusion injury
Yuan Jiang1,2,3, Ying Yang1, Yang Zhang1
1Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, 150086, Harbin, Heilongjiang, P. R. China.
Abstract:
Myocardial ischemia/reperfusion (MI/R) injury is a pathological process that seriously affects the health of patients with coronary artery disease. Long non-coding RNAs (lncRNAs) represents a new class of regulators of diverse biological processes and disease conditions, the study aims to discover the pivotal lncRNA in MI/R injury. The microarray screening identifies a down-regulated heart-enriched lncRNA-CIRPIL (Cardiac ischemia reperfusion associated p53 interacting lncRNA, lncCIRPIL) from the hearts of I/R mice. LncCIRPIL inhibits apoptosis of cultured cardiomyocytes exposed to anoxia/reoxygenation (A/R). Cardiac-specific transgenic overexpression of lncCIRPIL alleviates I/R injury in mice, while knockout of lncCIRPIL exacerbates cardiac I/R injury. LncCIRPIL locates in the cytoplasm and physically interacts with p53, which leads to the cytoplasmic sequestration and the acceleration of ubiquitin-mediated degradation of p53 triggered by E3 ligases CHIP, COP1 and MDM2. p53 overexpression abrogates the protective effects of lncCIRPIL. Notably, the human fragment of conserved lncCIRPIL mimics the protective effects of the full-length lncCIRPIL on cultured human AC16 cells. Collectively, lncCIRPIL exerts its cardioprotective action via sequestering p53 in the cytoplasm and facilitating its ubiquitin-mediated degradation. The study highlights a unique mechanism in p53 signal pathway and broadens our understanding of the molecular mechanisms of MI/R injury.
Insights
Cardiac ischemia reperfusion (MI/R) injury is reduced by lncCIRPIL, a novel long non-coding RNA. LncCIRPIL protects heart cells by degrading the p53 protein, offering a new therapeutic target for MI/R injury.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- RNA Biology
Background:
- Myocardial ischemia/reperfusion (MI/R) injury poses a significant threat to patients with coronary artery disease.
- Long non-coding RNAs (lncRNAs) are emerging as critical regulators in various biological processes and diseases.
- Understanding the molecular mechanisms underlying MI/R injury is crucial for developing effective treatments.
Purpose of the Study:
- To identify pivotal long non-coding RNAs (lncRNAs) involved in myocardial ischemia/reperfusion (MI/R) injury.
- To elucidate the function and mechanism of a newly discovered lncRNA, lncCIRPIL, in the context of MI/R injury.
- To explore the potential of lncCIRPIL as a therapeutic target for cardioprotection.
Main Methods:
- Microarray screening to identify differentially expressed lncRNAs in I/R mouse hearts.
- In vitro studies using cultured cardiomyocytes exposed to anoxia/reoxygenation (A/R) to assess apoptosis.
- In vivo studies involving cardiac-specific transgenic overexpression and knockout of lncCIRPIL in mice subjected to I/R.
- Co-immunoprecipitation and Western blotting to investigate the interaction between lncCIRPIL and p53.
- Experiments with p53 overexpression and human cell lines to validate findings.
Main Results:
- A heart-enriched lncRNA, lncCIRPIL, was identified as significantly down-regulated in I/R mouse hearts.
- LncCIRPIL demonstrated a potent inhibitory effect on cardiomyocyte apoptosis induced by A/R.
- Overexpression of lncCIRPIL alleviated MI/R injury in mice, whereas its knockout exacerbated the injury.
- LncCIRPIL was found to interact with p53, promoting its cytoplasmic sequestration and subsequent ubiquitin-mediated degradation.
- Overexpression of p53 abolished the protective effects of lncCIRPIL, and a human fragment of lncCIRPIL retained protective activity.
Conclusions:
- LncCIRPIL acts as a crucial cardioprotective factor against MI/R injury.
- The cardioprotective mechanism of lncCIRPIL involves the cytoplasmic sequestration and degradation of p53.
- LncCIRPIL represents a novel therapeutic target for mitigating MI/R injury and holds potential for clinical application.
