Targeted deletion of thioredoxin-interacting protein regulates cardiac dysfunction in response to pressure overload.
Biomechanical overload induces cardiac hypertrophy and heart failure, and reactive oxygen species (ROS) play a role in both processes. Thioredoxin-Interacting Protein (Txnip) is encoded by a mechanically-regulated gene that controls cell growth and apoptosis in part through interaction with the endogenous dithiol antioxidant thioredoxin. Here we show that Txnip is a critical regulator of the cardiac response to pressure overload. We generated inducible cardiomyocyte-specific and systemic Txnip-null mice (Txnip-KO) using Flp/frt and Cre/loxP technologies. Compared with littermate controls, Txnip-KO hearts had attenuated cardiac hypertrophy and preserved left ventricular (LV) contractile reserve through 4 weeks of pressure overload; however, the beneficial effects were not sustained and Txnip deletion ultimately led to maladaptive LV remodeling at 8 weeks of pressure overload. Interestingly, these effects of Txnip deletion on cardiac performance were not accompanied by global changes in thioredoxin activity or ROS; instead, Txnip-KO hearts had a robust increase in myocardial glucose uptake. Thus, deletion of Txnip plays an unanticipated role in myocardial energy homeostasis rather than redox regulation. These results support the emerging concept that the function of Txnip is not as a simple thioredoxin inhibitor but as a metabolic control protein.
Yoshioka
Jun
J
Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Imahashi
Kenichi
K
Gabel
Scott A
SA
Chutkow
William A
WA
Burds
Aurora A
AA
Gannon
Joseph
J
Schulze
P Christian
PC
MacGillivray
Catherine
C
London
Robert E
RE
Murphy
Elizabeth
E
Lee
Richard T
RT
D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D018390:Gene Targeting / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013879:Thioredoxins / Q000235:genetics* / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology
D002352:Carrier Proteins; C445672:Txnip protein, mouse; D013879:Thioredoxins