Deletion of thioredoxin-interacting protein improves cardiac inotropic reserve in the streptozotocin-induced diabetic heart

Abstract

Although the precise pathogenesis of diabetic cardiac damage remains unclear, potential mechanisms include increased oxidative stress, autonomic nervous dysfunction, and altered cardiac metabolism. Thioredoxin-interacting protein (Txnip) was initially identified as an inhibitor of the antioxidant thioredoxin but is now recognized as a member of the arrestin superfamily of adaptor proteins that classically regulate G protein-coupled receptor signaling. Here we show that Txnip plays a key role in diabetic cardiomyopathy. High glucose levels induced Txnip expression in rat cardiomyocytes in vitro and in the myocardium of streptozotocin-induced diabetic mice in vivo. While hyperglycemia did not induce cardiac dysfunction at baseline, β-adrenergic challenge revealed a blunted myocardial inotropic response in diabetic animals (24-wk-old male and female C57BL/6;129Sv mice). Interestingly, diabetic mice with cardiomyocyte-specific deletion of Txnip retained a greater cardiac response to β-adrenergic stimulation than wild-type mice. This benefit in Txnip-knockout hearts was not related to the level of thioredoxin activity or oxidative stress. Unlike the β-arrestins, Txnip did not interact with β-adrenergic receptors to desensitize downstream signaling. However, our proteomic and functional analyses demonstrated that Txnip inhibits glucose transport through direct binding to glucose transporter 1 (GLUT1). An ex vivo analysis of perfused hearts further demonstrated that the enhanced functional reserve afforded by deletion of Txnip was associated with myocardial glucose utilization during β-adrenergic stimulation. These data provide novel evidence that hyperglycemia-induced Txnip is responsible for impaired cardiac inotropic reserve by direct regulation of insulin-independent glucose uptake through GLUT1 and plays a role in the development of diabetic cardiomyopathy.

Cinnamaldehyde and allopurinol reduce fructose-induced cardiac inflammation and fibrosis by attenuating CD36-mediated TLR4/6-IRAK4/1 signaling to suppress NLRP3 inflammasome activation

“…Thioredoxin-interacting protein (TXNIP) inhibits thioredoxin to increase reactive oxygen species (ROS) production in cells14. Cardiac TXNIP up-regulation is observed in mice with cardiomyocyte impairment of streptozotocin-induced diabetes15 and myocardial ischemia reperfusion injury16. Of note, CD36 inhibitor sulfosuccinimidyl oleate sodium (SSO) blocks ceramide-induced TXNIP over-expression in rat insulinoma cell line INS-117.…”

Metabolic remodelling in diabetic cardiomyopathy

“…Ubiquitously expressed and pro-apoptotic, TXNIP exerts its effect via inhibition of the antioxidant thioredoxin, but also has some thioredoxin-independent effects, 54 including direct inhibition of glucose uptake by GLUT1 55 , 56 through the transcriptional complex, MondoA:Mlx 57 . In both high dose STZ-induced T1D and ob/ob T2D mice, administration of a calcium channel blocker reduced the cardiac expression of TXNIP and cleaved caspases in vivo , 58 but it is not known if cardiac function was preserved.…”

The Emerging Role of Thioredoxin-Interacting Protein in Myocardial Ischemia/Reperfusion Injury

“…The induction of Txnip expression by glucose is mediated by a synergy between the tandem CCAAT box and carbohydrate response element motifs in the promoter region of the Txnip gene. 21,22,64 Thioredoxin-interacting protein, in turn, suppresses glucose uptake into the cell by binding directly to GLUT1, 24,25 which is a major mediator of basal glucose uptake in cardiomyocytes. The Txnip knockout cells have a higher capacity of glucose utilization through increased GLUT1 catalytic efficiency.…”

“…The Txnip knockout cells have a higher capacity of glucose utilization through increased GLUT1 catalytic efficiency. 25 We previously generated cardiomyocyte-specific Txnip knockout mice 42 and directly measured glucose uptake in these animals. In cardiomyocyte-specific Txnip knockout mice hearts, we found a robust increase in myocardial glucose uptake compared to that of the littermate controls.…”

“…23 Recent studies demonstrate that Txnip inhibits glucose transport through direct interaction with glucose transporter 1 (GLUT1). 24,25 Degradation of Txnip on energy crisis via an energy sensor-mediated mechanism results in an acute increase in GLUT1 function, thus enhancing glucose uptake. 24 Given the fact that Txnip is a potent inhibitor of glucose transport and a negative regulator of aerobic glycolysis, 1 Txnip gene is considered to be a tumor suppressor gene.…”