QKI deficiency promotes FoxO1 mediated nitrosative stress and endoplasmic reticulum stress contributing to increased vulnerability to ischemic injury in diabetic heart
QKI deficiency promotes FoxO1 mediated nitrosative stress and endoplasmic reticulum stress contributing to increased vulnerability to ischemic injury in diabetic heart
复制标题
QKI 缺乏会促进 FoxO1 介导的亚硝化应激和内质网应激，从而增加糖尿病心脏缺血性损伤的脆弱性。
DOI：
10.1016/j.yjmcc.2014.07.010
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发表时间：
2014-10-01
影响因子：
5
通讯作者：
Ma, Heng
中科院分区：
文献类型：
--
作者：
Guo, Wangang;Jiang, Tiannan;Ma, Heng
糖尿病患者的心脏易受缺血/再灌注（VR）损伤。已知RNA结合蛋白Quaking（QKI）将细胞内信号传导与细胞存活联系起来，并且QKI失调可能导致人类疾病。然而，QKI在糖尿病心脏中的功能仍然未知。目前的研究试图确定新的分子机制，可能有助于糖尿病心肌缺血损伤的易感性。对糖尿病ob/ob小鼠或野生型C57 BL/6 J小鼠进行体内心肌I/R。比较心肌梗死面积、心肌细胞凋亡、QKI 5和FoxO 1表达、亚硝化应激（NS）和内质网应激。通过心肌内注射FoxO 1特异性小干扰RNA（siRNA，20 μ g）获得FoxO 1的敲低，通过注射编码-QKI 5的腺病毒获得QKI 5的上调。结果表明，ob/ob小鼠心肌组织中存在明显的NS应激反应，表现为iNOS表达、总NO含量和硝基酪氨酸含量升高。1400 W或M40401治疗可部分降低ob/ob心肌发生VR时caspase-3活性（P < 0.05）。还观察到更高的ER应激，表现为ob/ob心肌中p-PERK、p-eIF 2 α和CHOP表达增加。ER应激抑制剂对过度NS应激无影响，但可部分降低I/R诱导的ob/ob心肌caspase-3活性（P < 0.05）。FoxO 1在团块状心肌中过度激活，FoxO 1敲低可降低NS应激和ER应激水平（P < 0.05）。此外，QKI 5在ob/ob心肌中表达缺乏。上调QKI 5可降低ob/ob心肌中FoxO 1的表达以及NS和ER应激，进一步减轻MI/R损伤。最后，QKI 5过表达使心肌细胞中FoxO 1 mRNA不稳定。这些结果表明，QKI 5缺陷导致ob/ob动物FoxO 1过度激活，随后放大亚硝化应激和ER应激，从而增强糖尿病心脏的缺血耐受。(C)2014作者由Elsevier Ltd.发布。这是CC BY-NC-ND许可证下的开放获取文章（http：//creativecommons.org/licenses/by-nc-nd/3.0/）。
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/).