Vericiguat attenuates doxorubicin-induced cardiotoxicity through the PRKG1/PINK1/STING axis

Transl Res. 2024 Nov:273:90-103. doi: 10.1016/j.trsl.2024.07.005. Epub 2024 Jul 24.

Abstract

Doxorubicin (DOX) is restricted due to its severe cardiotoxicity. There is still a lack of viable and effective drugs to prevent or treat DOX-induced cardiotoxicity(DIC). Vericiguat is widely used to treat heart failure with reduced ejection fraction. However, it is not clear whether vericiguat can improve DIC. In the present study, we constructed a DIC model using mice and neonatal rat cardiomyocytes and found that vericiguat ameliorated DOX-induced cardiac insufficiency in mice, restored DOX-induced mitochondrial dysfunction in neonatal rat cardiomyocytes, and inhibited the expression of inflammatory factors. Further studies showed that vericiguat improved mitochondrial dysfunction and reduced mtDNA leakage into the cytoplasm by up-regulating PRKG1, which activated PINK1 and then inhibited the STING/IRF3 pathway to alleviate DIC. These findings demonstrate for the first time that vericiguat has therapeutic potential for the treatment of DIC.

Keywords: Cardiotoxicity; Doxorubicin; Inflammation; Mitochondrial dysfunction; Vericiguat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiotoxicity* / etiology
  • Cardiotoxicity* / prevention & control
  • Doxorubicin* / adverse effects
  • Doxorubicin* / toxicity
  • Male
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac* / drug effects
  • Myocytes, Cardiac* / metabolism
  • Myocytes, Cardiac* / pathology
  • PTEN-Induced Putative Kinase
  • Protein Kinases* / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • STING Protein
  • Signal Transduction / drug effects

Substances

  • Doxorubicin
  • Membrane Proteins
  • Protein Kinases
  • PTEN-Induced Putative Kinase
  • Sting1 protein, mouse
  • STING Protein