title: Triterpenoid dihydro-CDDO-trifluoroethyl amide protects against maladaptive cardiac remodeling and dysfunction in mice: a critical role of Nrf2.
abstract: OBJECTIVE
  Nuclear factor E2-related factor 2 (Nrf2) appears to be an attractive therapeutic target for the treatment of cardiac disease. We investigated whether a synthetic triterpenoid derivative of dihydro-CDDO-trifluoroethylamide (dh404), a novel Nrf2 activator, protects against pathological cardiac responses to hemodynamic stress in mice.
  
  
  METHODS
  Cardiac maladaptive remodeling and dysfunction were established by transverse aortic constriction (TAC) in mice. Hypertrophic growth of rat neonatal cardiomyocytes was induced by angiotensin II (Ang II). Cell death of rat neonatal cardiomyocytes was induced with hydrogen peroxide (H₂O₂). Cellular proliferation of rat neonatal cardiac fibroblasts was induced by Ang II, norepinephrine (NE) and phenylephrine (PE). Protein expression was assessed by immunochemical staining and Western blots. Gene expression was determined by real time reverse transcription-polymerase chain reaction (Q-PCR).
  
  
  RESULTS
  TAC suppressed myocardial Nrf2 expression, increased myocardial 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine levels, and induced cardiac hypertrophy, fibrosis and apoptosis, and overt heart failure and death in mice. Administration of dh404 inhibited the pathological cardiac remodeling and dysfunction, and reduced the mortality. Moreover, dhd404 elevated myocardial levels of Nrf2 and Nrf2 nuclear translocation with a dramatic suppression of the oxidative stress in the heart. Dh404 inhibited hypertrophic growth and death in primary culture of rat neonatal cardiomyocytes and suppressed proliferation in primary culture of rat neonatal cardiac fibroblasts. However, these effects of dh404 were blunted by knocking down of Nrf2.
  
  
  CONCLUSIONS
  These findings demonstrate that dh404 prevents pathological cardiac remodeling and dysfunction by activating Nrf2, indicating a therapeutic potential of dh404 for cardiac disease.
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Jinan, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Xing
authors.forename: Ting
authors.initials: T
authors.lastname: Niu
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Wang
authors.forename: Jinqing
authors.initials: J
authors.lastname: Li
authors.forename: Siying
authors.initials: S
authors.lastname: Li
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Janicki
authors.forename: Stacey
authors.initials: S
authors.lastname: Ruiz
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Meyer
authors.forename: Xing Li
authors.initials: XL
authors.lastname: Wang
authors.forename: Dongqi
authors.initials: D
authors.lastname: Tang
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Zhao
authors.forename: Taixing
authors.initials: T
authors.lastname: Cui
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003250:Constriction; D005355:Fibrosis / Q000188:drug therapy; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D006984:Hypertrophy / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D011312:Pressure / Q000009:adverse effects; D015854:Up-Regulation / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C547749:dh404 compound; D009828:Oleanolic Acid