Costunolide Protects Myocardium From Ischemia Reperfusion Injury by Inhibiting Oxidative Stress Through Nrf2/Keap1 Pathway Activation

J Cardiovasc Pharmacol. 2023 Aug 1;82(2):117-127. doi: 10.1097/FJC.0000000000001422.

Abstract

Costunolide (Cos) is a naturally occurring sesquiterpene lactone that exhibits antioxidative properties. In this study, we demonstrate the protective mechanism of Cos against ischemia/reperfusion (I/R)-induced myocardial injury. Cos significantly decreased levels of reactive oxygen species and ameliorated apoptosis of I/R cardiomyocytes both in vitro and in vivo. Further investigation revealed that Cos increased expression of the antioxidant proteins HO-1 and NQO-1 and decreased the Bax/Bcl-2 ratio, thus protecting cardiac cells. NF-E2-related factor 2 (Nrf2) silencing significantly attenuated the protective effects of Cos in tert-butyl hydroperoxide (TBHP)-treated H9C2 cells. Additionally, Cos significantly intensified the I/R- or TBHP-induced dissociation of the Kelch-like ECH-associated protein 1 (Keap1)/Nrf2 complex both in vitro and in vivo. These results suggest that activation of Nrf2/Keap1 using Cos may be a therapeutic strategy for myocardial I/R injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / genetics
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Myocardial Reperfusion Injury* / metabolism
  • Myocardial Reperfusion Injury* / prevention & control
  • Myocardium / metabolism
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress
  • Reperfusion Injury* / metabolism
  • Sesquiterpenes* / metabolism
  • Sesquiterpenes* / pharmacology

Substances

  • NF-E2-Related Factor 2
  • Kelch-Like ECH-Associated Protein 1
  • costunolide
  • Sesquiterpenes