Open AccessThioredoxin1 Inactivation Mediates the Impairment of Ischemia-Induced Angiogenesis and Further Injury in Diabetic Myocardium
Author(s) -
Rongrong Hou,
Mingzhi Shen,
Rutao Wang,
Haitao Liu,
Chao Gao,
Jing Xu,
Tao Lei,
Zhiyong Yin,
Tao Yin
Publication year - 2020
Publication title -
journal of vascular research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.58
H-Index - 74
eISSN - 1423-0135
pISSN - 1018-1172
DOI - 10.1159/000505455
Subject(s) - txnip , angiogenesis , gene knockdown , medicine , ischemia , downregulation and upregulation , diabetes mellitus , cancer research , thioredoxin interacting protein , endocrinology , biology , oxidative stress , apoptosis , thioredoxin , biochemistry , gene
Diabetes mellitus (DM)-induced impairment of collateral formation has been demonstrated in subjects with coronary artery disease, which contributes to unfavorable prognosis among diabetic individuals. In our previous studies, thioredoxin1 (Trx1) activity was shown to be decreased in diabetic cardiac tissues, but the reason of Trx1 inactivation and whether it mediates the impaired angiogenesis in ischemic myocardium is still to be identified. As thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of Trx, is overexpressed in DM due to carbohydrate response element within its promoter, we hypothesized that inhibition of Trx1 by enhanced TXNIP expression in endothelial cells may play a role in hyperglycemia-induced impairment of angiogenesis. In the present study, we found that high glucose-mediated increase of TXNIP expression and TXNIP-Trx1 interaction induced the impairment in endothelial cell function and survival, since these detrimental effects are rescued by silencing TXNIP with small interfering RNA. In diabetic mice, TXNIP knockdown or recombinant human Trx1 treatment counteracted the impairment of angiogenesis, alleviated myocardial ischemic injury, and improved survival rate. All these data implicate that TXNIP upregulation and subsequently the increased formation of TXNIP-Trx1 complex is a novel pathologic pathway by which DM induces insufficient angiogenesis and thereby exacerbates myocardial ischemia injury.