Thioredoxin-Interacting Protein: Pathophysiology and Emerging Pharmacotherapeutics in Cardiovascular Disease and Diabetes

Abstract

The thioredoxin system, which consists of thioredoxin (Trx), nicotinamide adenine dinucleotide phosphate (NADPH) and thioredoxin reductase (TrxR), has emerged as a major anti-oxidant involved in the maintenance of cellular physiology and survival. Dysregulation in this system has been associated with metabolic, cardiovascular, and malignant disorders. Thioredoxin-interacting protein (TXNIP), also known as vitamin D-upregulated protein or thioredoxin-binding-protein-2, functions as a physiological inhibitor of Trx, and pathological suppression of Trx by TXNIP has been demonstrated in diabetes and cardiovascular diseases. Furthermore, TXNIP effects are partially Trx-independent; these include direct activation of inflammation and inhibition of glucose uptake. Many of the effects of TXNIP are initiated by its dissociation from intra-nuclear binding with Trx or other SH-containing proteins: these effects include its migration to cytoplasm, modulating stress responses in mitochondria and endoplasmic reticulum, and also potentially activating apoptotic pathways. TXNIP also interacts with the nitric oxide (NO) signaling system, with apparent suppression of NO effect. TXNIP production is modulated by redox stress, glucose levels, hypoxia and several inflammatory activators. In recent studies, it has been shown that therapeutic agents including insulin, metformin, angiotensin converting enzyme inhibitors and calcium channel blockers reduce TXNIP expression, although it is uncertain to what extent TXNIP suppression contributes to their clinical efficacy. This review addresses the role of TXNIP in health and in cardiovascular and metabolic disorders. Finally, the potential advantages (and disadvantages) of pharmacological suppression of TXNIP in cardiovascular disease and diabetes are summarized.

Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

“…Importantly, our experiments with THP1 cells cultured under various HG/NG conditions revealed an association between persistent DNA-me triggered by prior history of HG exposure and enhanced TXNIP expression in response to HG in vitro. We, thus, speculate that transient hyperglycemic episodes during the EDIC Study would induce more TXNIP overexpression and cellular dysfunction in cases vs. controls because of TXNIP hypo-me, which is in line with the reported adverse cellular roles of TXNIP (43)(44)(45)48). This type of cellular response to episodic HG provides mechanistic information toward understanding the connections between persistent DNA hypo-me at TXNIP and its gene expression and hence, metabolic memory of diabetic complications.…”

“…TXNIP expression is highly induced by HG in various cell types (46)(47)(48), which by inhibiting thioredoxin, subsequently causes oxidative stress and apoptosis. Recently, TXNIP up-regulation in the diabetic kidney was reported to be associated with changes in certain histone PTMs (49).…”

Cardiac metabolism — A promising therapeutic target for heart failure

“…It has been shown that Trx2 levels are reduced in the hearts of patients with DCM, and that Trx2 knock-out mice have a progressive decline in LV function leading to death by HF (Huang, et al, 2015). These effects may be related to the upregulation of TXNIP, which inhibits Trx2 (Chong, et al, 2014). In a mouse pressureoverload model of HF, TXNIP knock-out mice initially had reduced cardiac hypertrophy and preserved LV contractile reserve compared to their wild-type litter mates (Yoshioka, et al, 2012).…”

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.…”