Dihydro-CDDO-trifluoroethyl amide (dh404), a novel Nrf2 activator, suppresses oxidative stress in cardiomyocytes.
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.
Ichikawa
Tomonaga
T
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA.
Li
Jinqing
J
Meyer
Colin J
CJ
Janicki
Joseph S
JS
Hannink
Mark
M
Cui
Taixing
T
D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D044842:Cullin Proteins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D006984:Hypertrophy; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D002352:Carrier Proteins; D044842:Cullin Proteins; D003598:Cytoskeletal Proteins; D051267:NF-E2-Related Factor 2; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C547749:dh404 compound; D009828:Oleanolic Acid