Down‐Regulation of Thioredoxin‐Interacting Protein by Repeated Non‐Invasive Limb Ischemic Preconditioning Protects Diabetic Heart from Myocardial Ischemia/Reperfusion Injury

Abstract

BackgroundMyocardial ischemia/reperfusion injury (MIRI) is a major threat to human health, causing great cardiac morbidity and mortality worldwide. Yet, it's even more severe among diabetic subjects. Repeated non‐invasive limb ischemic preconditioning (rNLIP) can be effective in protecting the diabetic heart against MIRI, though the exact mechanism is still unclear. Thioredoxin‐interacting protein (TXNIP), a critical regulator with its inhibitory effect against antioxidation, is a novel target during MIRI. Also, TXNIP is found to be highly expressed concomitantly with hyperglycemia. This study aimed to investigate the role of TXNIP in the cardioprotective effect of rNLIP against MIRI in diabetes mellitus.MethodsDiabetes mellitus was induced by streptozotocin injection (65mg/kg) in Sprague‐Dawley rats. In vivo model of MIRI was established as 30 minutes occlusion of the left anterior descending coronary artery and subsequent 2 hours reperfusion. rNLIP was accomplished as three cycles of 5min ischemia (cuff inflation) and 5min reperfusion (cuff deflation) of the left hindlimb for three consecutive days before MIRI. In vitro hypoxia/re‐oxygenation (H/R) model was established as 6 hours of hypoxia and 12 hours of re‐oxygenation of H9C2 cells. Simulated remote hypoxic preconditioning (HPC), defined as three cycles of 5 min hypoxia and 5 min re‐oxygenation, was performed just 24 hours before H/R treatment to mimic the cardioprotective effect of rNLIP.ResultsThe expression of TXNIP was significantly elevated in the diabetic group, together with much greater infarct size and higher release of CK‐MB as well as lactate dehydrogenase (LDH) after MIRI, compared to non‐diabetic group. The application of rNLIP significantly reduced the infarct size, CK‐MB, and LDH release in both diabetic and non‐diabetic group. Furthermore, the expression of TXNIP, NLRP3 and IL‐1β were significantly reduced by rNLIP in both diabetic and nondiabetic group, with simultaneous suppression of apoptosis (lower cleaved caspases‐3 expression and bax/bcl‐2 ratio). In vitro study showed that TXNIP expression was significantly higher in high glucose (HG) group with concurrently greater cell injury and much higher LDH release after H/R treatment, compared to normal glucose (NG) group. HPC exhibited protective effect in both HG and NG group with reduced expression of TXNIP, NLRP3, and IL‐1β.ConclusionDown‐regulation of TXNIP and subsequent reduction of NLRP3 may represent a mechanism whereby rNLIP protects the diabetic heart from MIRI.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.