Role of Thioredoxin‐interacting Protein in Diabetic Myocardial Ischemia‐Reperfusion Injury

Abstract

Background Myocardial ischemia‐reperfusion injury is a major threat to human health, causing great cardiac morbidity and mortality worldwide. Yet, it’s even more severe among diabetic patients. Thioredoxin‐interacting protein (TXNIP), a critical regulator with its inhibitory effect against antioxidation, is a novel target during myocardial ischemia‐reperfusion injury. TXNIP is also found to be highly expressed in hyperglycemic conditions, but its role in diabetic myocardial ischemia‐reperfusion injury is unclear. The current research aimed to study the role of TXNIP in myocardial ischemia‐reperfusion injury in diabetes mellitus. Methods Diabetes was induced by streptozotocin injection via tail vein (65mg/kg) in Sprague‐Dawley rats. In vivo model of myocardial ischemia‐reperfusion injury was established as 30 minutes occlusion of the left anterior descending coronary artery and then 2 hours of reperfusion. In vitro hypoxia/re‐oxygenation (H/R) model was established as 6 hours of hypoxia and 12 hours of re‐oxygenation of H9C2 cells. Also, glucose was added to the medium at a concentration of 33 mmol/L to mimic the condition of diabetes. TXNIP small interference RNA (siRNA) was introduced to knock down the expression of TXNIP. Results The expression of TXNIP significantly increased in the diabetic rat group, together with much greater infarct size and higher release of CK‐MB after myocardial ischemia‐reperfusion injury, compared to non‐diabetic group. In vitro study showed that TXNIP expression was significantly higher in high glucose (HG) group with greater cell injury and much higher LDH release after H/R treatment, compared to normal glucose (NG) group. However, TXNIP knock‐down via siRNA could alleviate this cellular injury with lower LDH release and higher cell viability. The expression of cleaved caspase‐3 significantly decreased even after H/R treatment in the TXNIP knock‐down group. Also, down‐regulation of NF‐kB and less phosphorylation of IkBα were detected after H/R in the TXNIP knock‐down group. Further study found higher conversion of LC3II from LC3I and lower expression of p62, indicating the activation of autophagy via TXNIP knock‐down. Finally, quantitative polymerase chain reaction test revealed significantly lower gene expression of TNF‐α and IL‐6. Conclusion TXNIP is highly expressed in diabetes after myocardial ischemia‐reperfusion injury. TXNIP knock‐down can alleviate myocardial ischemia‐reperfusion injury, possibly via activating autophagy and also via inhibiting inflammation. It is reasonable to believe that TXNIP would be a potential target for the treatment of diabetic myocardial ischemia‐reperfusion injury. Support or Funding Information Supported by RGC (17118619) and NSFC (81970247)