QKI deficiency promotes FoxO1 mediated nitrosative stress and endoplasmic reticulum stress contributing to increased vulnerability to ischemic injury in diabetic heart

Hearts of diabetic individuals are susceptible to ischemia/reperfusion (VR) injury. The RNA-binding protein Quaking (QKI) is known to link intracellular signaling to cellular survival and QKI dysregulation may contribute to human diseases. However, the function of QKI in diabetic hearts remains unknown. The current study attempted to identify new molecular mechanisms that potentially contribute to the susceptibility to ischemic injury in diabetic myocardium. Diabetic ob/ob mice or wild-type C57BL/6J mice were subjected to in vivo myocardial I/R. Myocardial infarct size and apoptosis, QKI5 and FoxO1 expression, nitrosative stress (NS) and ER stress were compared. Knockdown of FoxO1 was obtained by intramyocardial injection of FoxO1 specific small interfering RNA (siRNA, 20 mu g), and upregulation of QKI5 was acquired by injecting adenovirus encoding-QKI5. Obvious NS stress was observed in the myocardium of ob/ob mice represented by elevated iNOS expression, total NO content and nitrotyrosine content. Administration of 1400W or M40401 partly reduced the caspase-3 activity in ob/ob myocardium encountering VR (P < 0.05). Higher ER stress was also observed represented by increased p-PERK, p-eIF2 alpha and expression of CHOP in ob/ob myocardium. ER stress inhibitor did not affect the excessive NS stress, but partially reduced I/R-induced caspase-3 activity in ob/ob hearts (P < 0.05). FoxO1 was overactivated in blob myocardium, and knockdown of FoxO1 attenuated both levels of NS stress and ER stress (P < 0.05). Furthermore, QKI5 expression was deficient in ob/ob myocardium. Upregulation of QKI5 diminished FoxO1 expression together with NS and ER stress in ob/ob myocardium, further reducing MI/R injury. Finally, QKI5 overexpression destabilized FoxO1 mRNA in cardiomyocytes. These results suggested that QKI5 deficiency contributed to the overactivation of FoxO1 in ob/ob animals and subsequently magnified nitrosative stress and ER stress, which enhances the ischemic intolerance of diabetic hearts. (C) 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).