Dihydro-CDDO-Trifluoroethyl Amide (dh404), a Novel Nrf2 Activator, Suppresses Oxidative Stress in Cardiomyocytes 英文参考文献.docVIP

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Dihydro-CDDO-Trifluoroethyl Amide (dh404), a Novel Nrf2 Activator, Suppresses Oxidative Stress in Cardiomyocytes 英文参考文献.doc

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Dihydro-CDDO-Trifluoroethyl Amide (dh404), a Novel Nrf2 Activator, Suppresses Oxidative Stress in Cardiomyocytes 英文参考文献

Dihydro-CDDO-TrifluoroethylAmide(dh404),aNovel Nrf2Activator,SuppressesOxidativeStressin Cardiomyocytes TomonagaIchikawa1.,JinqingLi1.,ColinJ.Meyer2,JosephS.Janicki1,MarkHannink3*,TaixingCui1* 1Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America, 2Department of Pharmacology,ReataPharmaceuticals,Inc.,Irving,Texas,UnitedStatesofAmerica,3DepartmentofBiochemistry,UniversityofMissouri-Columbia,Columbia,Missouri, UnitedStatesofAmerica Abstract Targeting Nrf2 signaling appears tobe anattractive approach for the treatmentof 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, therebyrenderingmoreNrf2tobetranslocatedintothenucleitoactivateNrf2-drivengenetranscription.AmutantKeap1 proteincontainingasinglecysteine-to-serinesubstitutionatresidue151withintheBTBdomainofKeap1wasresistantto dh404-inducedstabilizationofNrf2protein.Inaddition,dh404didnotdissociatetheinteractionofNrf2withtheKeap1- Cul3-Rbx1E3ligasecomplex.Thus,itislikelythatdh404inhibitstheabilityofKeap1-Cul3-Rbx1E3ligasecomplextotarget 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,andtosuppressangiotensinII(AngII)-inducedoxidativestressincardiomyocytes.KnockdownofNrf2almost blockedtheanti-oxidativeeffectofdh404.Dh404activatedNrf2signalingintheheart.Takentogether,dh404appearstobe anovelNrf2activatorwi