CircHDAC9 regulates myocardial ischemia-reperfusion injury via miR-671-5p/SOX4 signaling axis

Am J Med Sci. 2024 Jan;367(1):49-60. doi: 10.1016/j.amjms.2023.11.001. Epub 2023 Nov 7.

Abstract

Background: Myocardial ischemia-reperfusion (I/R), a harmful process in the treatment of cardiovascular diseases, can cause secondary damage to the cardiac tissues. Circular RNAs (circRNAs) are important regulators in a number of cardiac disorders. However, the role of circHDAC9 in myocardial I/R injury has not been clarified.

Methods: Human cardiac myocytes (HCMs) were treated with hypoxia/reoxygenation (H/R) and mice were subjected to I/R. Quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) was used to analyze the expression of circHDAC9, miR-671-5p, and SOX4, and western blot was used to detect SOX4 protein. The binding relationship among circHDAC9, miR-671-5p, and SOX4 was confirmed by RNA pull-down, luciferase, and RNA immunoprecipitation (RIP) assays. The effects of circHDAC9/miR-671-5p/SOX4 axis on the apoptosis, oxidative stress and inflammation were evaluated in both myocardial I/R injury models.

Results: The expression of circHDAC9 and SOX4 was noticeably elevated, whereas miR-671-5p expression was downregulated in both myocardial I/R injury models. circHDAC9 knockdown significantly reduced the apoptosis, activities of caspase-3 and caspase-9, ROS intensity, MDA activity, and concentrations of TNF-α, IL-1β, and IL-6, but increased the viability and SOD activity in H/R-treated HCMs. Suppression of circHDAC9 dramatically reduced the levels of circHDAC9 and SOX4, while enhanced miR-671-5p expression in H/R-treated HCMs. CircHDAC9 functioned via sponging miR-671-5p to regulate SOX4 expression in vitro. Additionally, silencing of circHDAC9 improved the pathological abnormalities and cardiac dysfunction, and reduced the apoptosis, oxidative stress and inflammation in mice with myocardial I/R injury.

Conclusions: Inhibition of circHDAC9 significantly improved myocardial I/R injury by regulating miR-671-5p/SOX4 signaling pathway.

Keywords: Circhdac9; Myocardial ischemia-reperfusion injury; SOX4; miR-671-5p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Humans
  • Inflammation / pathology
  • Mice
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Myocardial Reperfusion Injury* / genetics
  • Myocardial Reperfusion Injury* / metabolism
  • Myocardial Reperfusion Injury* / pathology
  • Myocytes, Cardiac / pathology
  • RNA, Circular* / metabolism
  • SOXC Transcription Factors / genetics
  • SOXC Transcription Factors / metabolism
  • SOXC Transcription Factors / pharmacology
  • Signal Transduction

Substances

  • MicroRNAs
  • MIRN671 microRNA, human
  • SOX4 protein, human
  • SOXC Transcription Factors
  • RNA, Circular