title: Thioredoxin-interacting protein controls cardiac hypertrophy through regulation of thioredoxin activity.
abstract: BACKGROUND
  Although cellular redox balance plays an important role in mechanically induced cardiac hypertrophy, the mechanisms of regulation are incompletely defined. Because thioredoxin is a major intracellular antioxidant and can also regulate redox-dependent transcription, we explored the role of thioredoxin activity in mechanically overloaded cardiomyocytes in vitro and in vivo.
  
  
  RESULTS
  Overexpression of thioredoxin induced protein synthesis in cardiomyocytes (127+/-5% of controls, P<0.01). Overexpression of thioredoxin-interacting protein (Txnip), an endogenous thioredoxin inhibitor, reduced protein synthesis in response to mechanical strain (89+/-5% reduction, P<0.01), phenylephrine (80+/-3% reduction, P<0.01), or angiotensin II (80+/-4% reduction, P<0.01). In vivo, myocardial thioredoxin activity increased 3.5-fold compared with sham controls after transverse aortic constriction (P<0.01). Aortic constriction did not change thioredoxin expression but reduced Txnip expression by 40% (P<0.05). Gene transfer studies showed that cells that overexpress Txnip develop less hypertrophy after aortic constriction than control cells in the same animals (28.1+/-5.2% reduction versus noninfected cells, P<0.01).
  
  
  CONCLUSIONS
  Thus, even though thioredoxin is an antioxidant, activation of thioredoxin participates in the development of pressure-overload cardiac hypertrophy, demonstrating the dual function of thioredoxin as both an antioxidant and a signaling protein. These results also support the emerging concept that the thioredoxin inhibitor Txnip is a critical regulator of biomechanical signaling.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshioka
authors.forename: P Christian
authors.initials: PC
authors.lastname: Schulze
authors.forename: Mihaela
authors.initials: M
authors.lastname: Cupesi
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Sylvan
authors.forename: Catherine
authors.initials: C
authors.lastname: MacGillivray
authors.forename: Joseph
authors.initials: J
authors.lastname: Gannon
authors.forename: Hayden
authors.initials: H
authors.lastname: Huang
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001018:Aortic Diseases / Q000150:complications; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins; D048429:Cell Size; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003251:Constriction, Pathologic / Q000150:complications; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D008026:Ligation; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010656:Phenylephrine / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D016037:Single-Blind Method; D013314:Stress, Mechanical; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D017382:Reactive Oxygen Species; C493796:TXNIP protein, rat; D000804:Angiotensin II; D010656:Phenylephrine; D013879:Thioredoxins