8-Formylophiopogonanone B antagonizes doxorubicin-induced cardiotoxicity by suppressing heme oxygenase-1-dependent myocardial inflammation and fibrosis

Biomed Pharmacother. 2021 Aug:140:111779. doi: 10.1016/j.biopha.2021.111779. Epub 2021 May 29.

Abstract

Doxorubicin (DOX) is a widely used antitumor drug that causes severe cardiotoxicity in patients; no effective strategy yet exists to address this problem. We previously reported that 8-formylophiopogonanone B (8-FOB), a natural isoflavone in Ophiopogon japonicas, antagonizes paraquat-induced hepatotoxicity. Here, we explored the mechanisms underlying DOX-induced cardiotoxicity as well as whether 8-FOB can alleviate DOX-induced cardiotoxicity. Acute cardiotoxicity was established by injecting C57BL/6J mice with a single dose of DOX (20 mg/kg, intraperitoneal). To elucidate the mechanisms underlying DOX-induced cardiotoxicity, differentially expressed genes between hearts from DOX-treated and control mice were identified from the Gene Expression Omnibus (GEO) database via GEO2R. Using the Cytoscape software plugin cytoHubba, five hub genes associated with DOX-induced cardiotoxicity were identified: CD68, PTEN, SERPINE1, AIF1, and HMOX1. However, of these, only HMOX1 protein expression levels were significantly increased after DOX treatment. We also confirmed that HMOX1-dependent myocardial inflammation and fibrosis were closely associated with DOX-induced cardiotoxicity. More importantly, 8-FOB protected against DOX-cardiotoxicity by ameliorating cardiac injury and dysfunction, reducing cardiac fibrosis and inflammatory cytokine release, and inhibiting HMOX1 expression. In conclusion, our results suggest that inhibition of HMOX1-dependent myocardial inflammatory insults and fibrosis is essential for 8-FOB to ameliorate DOX-caused cardiotoxicity.

Keywords: 8-Formylophiopogonanone B; Cardiotoxicity; Doxorubicin; Fibrosis; HMOX1; Inflammation.

MeSH terms

  • Animals
  • Antineoplastic Agents*
  • Cardiotonic Agents / pharmacology
  • Cardiotonic Agents / therapeutic use*
  • Cardiotoxicity / drug therapy*
  • Cardiotoxicity / genetics
  • Cardiotoxicity / metabolism
  • Cardiotoxicity / pathology
  • Cytokines / genetics
  • Doxorubicin*
  • Fibrosis
  • Heme Oxygenase-1 / antagonists & inhibitors*
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism
  • Inflammation / drug therapy
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Isoflavones / pharmacology
  • Isoflavones / therapeutic use*
  • Male
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / metabolism
  • Myocardium / pathology

Substances

  • 8-formylophiopogonanone B
  • Antineoplastic Agents
  • Cardiotonic Agents
  • Cytokines
  • Isoflavones
  • Membrane Proteins
  • Doxorubicin
  • Heme Oxygenase-1
  • Hmox1 protein, mouse