Thioredoxin-interacting protein controls cardiac hypertrophy through regulation of thioredoxin activity.
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.
Yoshioka
Jun
J
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass, USA.
Schulze
P Christian
PC
Cupesi
Mihaela
M
Sylvan
Jeremy D
JD
MacGillivray
Catherine
C
Gannon
Joseph
J
Huang
Hayden
H
Lee
Richard T
RT
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
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D017382:Reactive Oxygen Species; C493796:TXNIP protein, rat; D000804:Angiotensin II; D010656:Phenylephrine; D013879:Thioredoxins