Role of ferroptosis in increased vulnerability to myocardial ischemia-reperfusion injury in type 1 diabetic mice and the treatment effects of N-acetylcysteine

Abstract

<b>Abstract ID 23318</b> <b>Poster Board 562</b> The hearts of subjects with diabetes are vulnerable to ischemia-reperfusion injury (IRI). Interestingly, experimentally rodent hearts have been shown to be more resistant to IRI at the very early stages of diabetes induction than the heart of the non-diabetic control mice, while the specific mechanisms are still unclear. Ferroptosis, a new kind of iron-regulated cell death that differs from apoptosis and necrosis that can be induced by an oxidative stress response, has recently been shown to play an important role in myocardial IRI including that in diabetes. The present study aimed to investigate whether the antioxidant N-acetylcysteine (NAC) exerts cardioprotective effect through inhibiting ferroptosis and to explore the potential relationship between the extent of ferroptosis and the degree of myocardial vulnerability to ischemia-reperfusion injury in diabetes. Non-diabetic control (NC) and streptozotocin-induced diabetic (DM) mice were treated with 2 mmol/L of N-acetylcysteine (NAC) in drinking water for 4 weeks starting at 1 week after diabetes induction. Mice were subjected to myocardial IRI induced by occluding the coronary artery for 30 minutes followed by 2 hours of reperfusion, subsequently at 1, 2, and 5 weeks of diabetes induction. The post-ischemic myocardial infarct size in the DM group was smaller than that in NC group at 1 week of diabetes but greater than that at 5 weeks of diabetes, which were associated with a significant increase in ferroptosis at 5 weeks but not at 1 week of diabetes. NAC significantly attenuated post-ischemic ferroptosis as well as and oxidative stress and reduced infarct size at 2 and 5 weeks of diabetes. Application of erastin, a ferroptosis inducer, reverses the cardioprotective effects mediated by NAC therapy. It is concluded that increased oxidative stress and ferroptosis are the major factors attributable to the increased vulnerability to myocardial IRI in diabetes and that attenuation of ferroptosis represents a mechanism whereby NAC confers cardioprotection against myocardial IRI in diabetes. This study was supported by National Natural Science Foundation of China (82270306; 81970247).