Dihydro-CDDO-trifluoroethyl amide (dh404), a novel Nrf2 activator, suppresses oxidative stress in cardiomyocytes

PLoS One. 2009 Dec 21;4(12):e8391. doi: 10.1371/journal.pone.0008391.

Abstract

Targeting Nrf2 signaling appears to be an attractive approach for the treatment of maladaptive cardiac remodeling and dysfunction; however, pharmacological modulation of the Nrf2 pathway in the cardiovascular system remains to be established. Herein, we report that a novel synthetic triterpenoid derivative, dihydro-CDDO-trifluoroethyl amide (dh404), activates Nrf2 and suppresses oxidative stress in cardiomyocytes. Dh404 interrupted the Keap1-Cul3-Rbx1 E3 ligase complex-mediated Nrf2 ubiquitination and subsequent degradation saturating the binding capacity of Keap1 to Nrf2, thereby rendering more Nrf2 to be translocated into the nuclei to activate Nrf2-driven gene transcription. A mutant Keap1 protein containing a single cysteine-to-serine substitution at residue 151 within the BTB domain of Keap1 was resistant to dh404-induced stabilization of Nrf2 protein. In addition, dh404 did not dissociate the interaction of Nrf2 with the Keap1-Cul3-Rbx1 E3 ligase complex. Thus, it is likely that dh404 inhibits the ability of Keap1-Cul3-Rbx1 E3 ligase complex to target Nrf2 for ubiquitination and degradation via modifying Cys-151 of Keap1 to change the conformation of the complex. Moreover, dh404 was able to stabilize Nrf2 protein, to enhance Nrf2 nuclear translocation, to activate Nrf2-driven transcription, and to suppress angiotensin II (Ang II)-induced oxidative stress in cardiomyocytes. Knockdown of Nrf2 almost blocked the anti-oxidative effect of dh404. Dh404 activated Nrf2 signaling in the heart. Taken together, dh404 appears to be a novel Nrf2 activator with a therapeutic potential for cardiac diseases via suppressing oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Carrier Proteins / metabolism
  • Cell Line
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cullin Proteins / metabolism
  • Cytoskeletal Proteins / metabolism
  • Humans
  • Hypertrophy
  • Mice
  • Myocardium / metabolism
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • NF-E2-Related Factor 2 / metabolism*
  • Oleanolic Acid / analogs & derivatives*
  • Oleanolic Acid / chemistry
  • Oleanolic Acid / pharmacology
  • Oxidative Stress / drug effects*
  • Protein Stability / drug effects
  • Protein Transport / drug effects
  • Rats
  • Reactive Nitrogen Species / metabolism
  • Reactive Oxygen Species / metabolism
  • Transcription, Genetic / drug effects
  • Ubiquitination / drug effects

Substances

  • 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
  • Carrier Proteins
  • Cullin Proteins
  • Cytoskeletal Proteins
  • NF-E2-Related Factor 2
  • Reactive Nitrogen Species
  • Reactive Oxygen Species
  • dh404 compound
  • Oleanolic Acid