microRNA-130b-3p Attenuates Septic Cardiomyopathy by Regulating the AMPK/mTOR Signaling Pathways and Directly Targeting ACSL4 against Ferroptosis

Int J Biol Sci. 2023 Aug 15;19(13):4223-4241. doi: 10.7150/ijbs.82287. eCollection 2023.

Abstract

Ferroptosis is a newly identified type of programmed cell death that has been shown to contribute to the progression of septic cardiomyopathy. Although the role of miR-130b-3p as an oncogene that accelerates cancer progression by suppressing ferroptosis has been demonstrated, its role in the regulation of ferroptosis and cardiac injury in Lipopolysaccharide (LPS)-induced cardiomyopathy has not been fully clarified. In this study, we demonstrated that miR-130b-3p remarkably improved cardiac function and ameliorated morphological damage to heart tissue in LPS-induced mice. miR-130b-3p also improved cell viability and mitochondrial function and reduced the production of lipid ROS and ferroptosis in LPS-treated H9c2 cells. In addition, miR-130b-3p significantly upregulated GPX4 expression and suppressed ACSL4 activity in LPS-induced mouse heart tissue and H9c2 cells. Mechanistically, we used database analysis to locate miR-130b-3p and confirmed its inhibitory effects on the ferroptosis-related gene ACSL4 and autophagy-related gene PRKAA1 using a dual-luciferase reporter assay. In addition, we found that miR-130b-3p inhibited the activation of autophagy by downregulating the expression of the AMPK/mTOR signaling pathway. Meanwhile, our results show that RAPA (an autophagy activator) reverses the protective effect of miR-130b-3p mimic against LPS-induced ferroptosis, while CQ (an autophagy inhibitor) plays a facilitative role, suggesting that miR-130b-3p plays an important role in the development of ferroptosis by regulating autophagy in vitro. The findings reveal a novel function of miR-130b-3p in attenuating ferroptosis in cardiomyocytes, providing a new therapeutic target for ameliorating septic cardiomyopathy injury.

Keywords: ACSL4; Autophagy; Ferroptosis; PRKAA1.; Septic cardiomyopathy; microRNA-130b-3p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Cardiomyopathies* / genetics
  • Ferroptosis* / genetics
  • Lipopolysaccharides
  • Mice
  • MicroRNAs* / genetics
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases

Substances

  • AMP-Activated Protein Kinases
  • Lipopolysaccharides
  • MicroRNAs
  • TOR Serine-Threonine Kinases
  • Acsl4 protein, mouse
  • Mirn133 microRNA, mouse