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. Methods and 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.