MicroRNA‐100‐5p Exacerbates Myocardial Ischemia–Reperfusion Injury Through Downregulation of PRMT5

• Published in: The FASEB journal Vol. 39; no. 11; pp. e70690 - n/a
• Main Authors: Wang, Zhenya, Wei, Tong‐You Wade, Chen, Jo‐Mei Maureen, Zhang, Ke, Zhang, Yiwei, Shi, Huiting, Su, Hsiang‐Chun, Hsieh, I‐Shan, Yu, Chang‐Tze Ricky, Zhao, Guo‐Jun
• Format: Journal Article
• Language: English
• Published: United States 15.06.2025
• Subjects: Animals; Apoptosis; cardiomyocyte death; Down-Regulation; Male; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; miR‐100‐5p; myocardial I/R injury; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Reperfusion Injury - genetics; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Phosphatidylinositol 3-Kinases - metabolism; PI3K‐AKT pathway; PRMT5; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; PTEN; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Signal Transduction; PTEN; PRMT5; miR‐100‐5p; myocardial I/R injury; cardiomyocyte death; PI3K‐AKT pathway
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202403196R

ABSTRACT Acute myocardial infarction (AMI) rates are rising due to the increasing prevalence of cardiac metabolic disorders, particularly diabetes mellitus (DM). While revascularization procedures such as coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) restore blood flow, they can also exacerbate myocardial ischemia–reperfusion (I/R) injury, for which current cardioprotective strategies remain insufficient. MicroRNAs are critical regulators of gene expression, but the role of miR‐100‐5p in I/R injury remains unclear. This study demonstrates that miR‐100‐5p is significantly upregulated in myocardial tissue during I/R injury, leading to the downregulation of protein arginine methyltransferase 5 (PRMT5). This reduction in PRMT5 impairs its capacity to methylate and inactivate Phosphatase and tensin homolog (PTEN), resulting in disruption of the PI3K‐AKT signaling pathway, increased cardiomyocyte apoptosis, and aggravated myocardial damage. Using antisense oligomers to inhibit miR‐100‐5p, we restored PRMT5 expression, reactivated PI3K‐AKT signaling, and reduced cardiomyocyte death, thereby mitigating myocardial injury. Our findings identify the miR‐100‐5p/PRMT5/PI3K‐AKT axis as a key regulatory pathway in myocardial I/R injury and highlight miR‐100‐5p as a potential therapeutic target to protect the heart during revascularization procedures. MiR‐100‐5p overexpression downregulates PRMT5, leading to increased PTEN activity and reduced AKT signaling. This molecular cascade promotes cardiomyocyte apoptosis, enhances fibrotic remodeling, and exacerbates cardiac dysfunction following myocardial ischemia–reperfusion injury. Inhibition of miR‐100‐5p with antisense oligonucleotides restores PRMT5 expression, attenuates PTEN activation, preserves AKT survival signaling, mitigates myocardial damage, and represents a promising therapeutic strategy to improve cardiac outcomes after reperfusion therapy. Created with BioRender.com. Chen, J. (2025) https://BioRender.com/uuhxtbs