Variations of thioredoxin system contributes to increased susceptibility to apoptosis in cardiomyocytes of type 2 diabetic rats

Abstract

Cardiac complications are the leading cause of death in diabetes. However, the mechanism of diabetes in inducing myocardial injury and apoptosis, and whether the thioredoxin (Trx) system is involved remain unclear. In this study, male Sprague -Dawley rats were randomly divided into two groups: the control and the diabetes groups, and then were randomly divided into five different timepoints (the 1st, 2nd, 4th, 12th, and 24th week). The results showed that diabetes-induced cardiac injury was enhanced in the type 2 diabetes rats, as evidenced by aggravated cardiac dysfunction, biochemical indicators, and increased myocardial apoptosis (TUNEL and caspase-3 activity). The activity of myocardial Trx and Trx reductase (TR) in diabetic rats was significantly decreased from the second week and continually aggravated with the disease progression. In diabetic rats, the mRNA expression of Trx1, Trx2, TR1, and TR2 was decreased first and then increased after the fourth week. Meanwhile, the protein expression of these Trx system members was significantly increased at the 12th week. Trx nitration was cleared, the Trx/ASK1 interaction was significantly decreased, and the activity of p38 was significantly enhanced in cardiac tissues at the 12th week. These results demonstrated that diabetes may cause myocardial injury and apoptosis, and the extent of which was accompanied with the development of the disease. The mechanism is associated with the development of diabetes and the decreased activity of Trx and TR. The reasons for decreased Trx activity may include: decrease of Trx and TR protein expression; nitration modification of Trx; and up-regulation of TXNIP expression.

Thioredoxin plays a key role in retinal neuropathy prior to endothelial damage in diabetic mice

“…Chen [ 57 ], Shalev [ 58 ] and Corbett [ 59 ] reported similar results. Txnip can induce apoptosis in certain contexts, such as in the T2D rat model [ 60 ].…”

Regulation of Signal Transduction by Reactive Oxygen Species in the Cardiovascular System

“…This increased Ras activity in response to α-adrenergic receptor stimulation is blocked by overexpression of thioredoxin-1. 165 ASK1, which is a redox sensitive kinase due to Trx binding in its reduced form, 168 and Akt 169 activate NFκB which transcribes inflammatory genes involved in the hypertrophic response. Oxidative stress can also mediate JNK activation and PKC activation of ETS-1, which contributes to the increase in MMP activity and reduction in collagen synthesis 170 that is observed in myocardial remodeling.…”

Modulation of signaling mechanisms in the heart by thioredoxin 1

“…In type 2 diabetes cardiac injury models, cardiac dysfunction is enhanced, Trx1-ASK1 interaction is significantly reduced and apoptosis is stimulated [33]. In addition, Ang II activates ASK1 to promote hypertrophy in cardiomyocytes [34].…”