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Volume 6 Issue 1
Jan.  2026
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Article Navigation >  Frigid Zone Medicine  > 2026  >  6(1): 1-14
Han Wu, Weitao Jiang, Xinyue Zhang, Fangting Yao, Ping Pang, Tengfei Pan, Yulia Lutokhina, Baofeng Yang, Yu Bian. Cold exposure aggravates myocardial ischemia-reperfusion injury via m6A-mediated circRNA-mRNA regulatory networks[J]. Frigid Zone Medicine, 2026, 6(1): 1-14. doi: 10.1515/fzm-2026-0001
Citation: Han Wu, Weitao Jiang, Xinyue Zhang, Fangting Yao, Ping Pang, Tengfei Pan, Yulia Lutokhina, Baofeng Yang, Yu Bian. Cold exposure aggravates myocardial ischemia-reperfusion injury via m6A-mediated circRNA-mRNA regulatory networks[J]. Frigid Zone Medicine, 2026, 6(1): 1-14. doi: 10.1515/fzm-2026-0001
shu

Cold exposure aggravates myocardial ischemia-reperfusion injury via m6A-mediated circRNA-mRNA regulatory networks

doi: 10.1515/fzm-2026-0001
  • 1.

    Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, the State-Province Key Laboratories of BiomedicinePharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China

  • 2.

    Department on internal medicine No. 1, Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenovskiy University), Moscow 119991, Russia

Funds:

the National Natural Science Foundation of China 82330011

Key Research and Development Program of Heilongjiang Province 2025ZX05A01

the Basic Research Support Program for Excellent Young Teachers in Heilongjiang Province YQJH2025126

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    Abstract
  •   Objective  Myocardial ischemia-reperfusion (I/R) injury remains a major contributor to cardiac morbidity and mortality, and accumulating evidence suggests that epitranscriptomic regulation may critically influence cardiac stress responses. N6-methyladenosine (m6A) modification and circular RNAs (circRNAs) have emerged as important regulators of cardiovascular pathology; however, their integrated roles in myocardial I/R injury, particularly under chronic cold stress, remain poorly defined.  Methods  A mouse model of myocardial I/R injury was established under room-temperature or chronic cold exposure conditions. Cardiac function, infarct size, histopathology, and serum injury markers were assessed. Global m6A levels were quantified, and m6A-modified circRNA profiles were analyzed using epitranscriptomic microarrays and bioinformatics approaches. Differentially expressed circRNAs were validated in vivo and in hypoxia-reoxygenation-treated neonatal cardiomyocytes. Circular structures and stability were confirmed by Sanger sequencing, divergent/convergent PCR, and actinomycin D assays. Competing endogenous RNA (ceRNA) networks were constructed to identify downstream regulatory pathways.  Results  Myocardial I/R injury resulted in significant cardiac dysfunction, increased infarct size, histological damage, and elevated serum CK-MB and LDH levels, accompanied by a marked increase in global m6A methylation. Epitranscriptomic profiling identified 391 circRNAs with altered m6A modification following I/R injury, involving pathways related to molecular binding, cellular processes, and kinase signaling. Multiple circRNAs exhibited consistent dysregulation in both in vivo and in vitro I/R models and displayed high structural stability. Importantly, chronic cold exposure significantly exacerbated I/R-induced cardiac dysfunction and infarct severity while further modulating the expression of specific m6A-modified circRNAs. ceRNA network analysis revealed that cold-responsive circRNAs potentially regulate myocardial injury through miRNA-mediated signaling pathways.  Conclusion  This study identifies m6A-modified circRNAs as key epitranscriptomic regulators of myocardial I/R injury and demonstrates that chronic cold stress amplifies circRNA-mediated regulatory networks. These findings provide novel mechanistic insight into temperature-dependent epigenetic regulation in ischemic heart disease and highlight m6A-circRNAs as potential therapeutic targets.

     

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