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

Xiaoqin Zhao,Yan Zhang,Xiangying Jiao,Ruiyuan Wang,Xiaoyu Li

doi:10.1093/abbs/gmu006

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.

Highlights

With the improvement of people’s living standards, the incidence and mortality of diabetes were significantly increased
The aims of the present study were as follows: (i) to observe the extent of myocardial injury and apoptosis and to analyze its possible mechanisms in streptozotocin (STZ)-induced T2DM rats at different timepoints; (ii) to determine whether Trx activity is reduced in the T2DM heart; (iii) to identify the mechanism responsible for diabetesinduced Trx alteration; and (iv) to determine the signaling mechanism by which reduced Trx activity leading to apoptotic cardiomyocyte death in the T2DM heart
The results showed that a very low number of TUNEL-positive cells were observed in myocardial tissues from the control rats, while a significantly high number of TUNEL-positive cells were observed in myocardial tissues from the 12th week T2DM rats (Fig. 1D)

Summary

Introduction

With the improvement of people’s living standards, the incidence and mortality of diabetes were significantly increased. Cardiac event is the highest risk, and it has become a leading cause of death of diabetes [2]. The resistance of myocardial cells to injury was reduced in diabetes. Human and animal studies have clearly indicated that in the cases of myocardial ischemia and infarction, the heart damage are more severe than non-diabetic patients, as well as with expanded infarct area, increased arrhythmia, and significantly higher mortality rate [3,4]. The mechanisms of diabetic cardiac complications have been studied mainly in the coronary vascular injury, while direct injury to myocardial cells received very little attention

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Conclusion