Elevated Expression of Carboxy-Terminal Modulator Protein (CTMP) Aggravates Brain Ischemic Injury in Diabetic db/db Mice
Elevated Expression of Carboxy-Terminal Modulator Protein (CTMP) Aggravates Brain Ischemic Injury in Diabetic db/db Mice
复制标题
羧基末端调节蛋白 (CTMP) 表达升高会加重糖尿病 db/db 小鼠的脑缺血损伤
DOI：
10.1007/s11064-016-1932-y
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发表时间：
2016-09-01
影响因子：
4.4
通讯作者：
Xiong, Lize
中科院分区：
文献类型：
--
作者：
Chen, Yu;Cai, Min;Xiong, Lize
Akt信号的失调在糖尿病动物脑缺血引起的脑损伤中是重要的，其潜在机制尚未完全了解。我们研究了2型糖尿病db/db小鼠及其对照组非糖尿病db/+小鼠中羧基末端调节蛋白（CTMP）（一种内源性Akt抑制剂）在局灶性脑缺血后脑损伤中的作用。与正常生理条件下的db/+小鼠相比，db/db小鼠显示CTMP表达的显著升高。在缺血后，db/db小鼠表现出比db/+小鼠更高水平的CTMP表达、降低的Akt激酶活性、不利的神经功能缺损和脑梗死。为了进一步确定Akt信号传导对脑缺血最终结果的有效性，用Akt通路抑制剂LY 294002处理动物，其加重db/+小鼠的缺血性损伤，但不加重db/db小鼠的缺血性损伤。最终在db/db小鼠中应用RNA干扰介导的CTMP耗竭，其恢复Akt活性，改善神经评分并减少梗死体积。这些结果表明，CTMP在糖尿病小鼠中的升高抑制Akt活性，并最终对缺血的结果产生负面影响。特异性靶向CTMP的抑制剂可能有益于糖尿病患者脑缺血的治疗。
Deregulation of Akt signaling is important in the brain injuries caused by cerebral ischemia in diabetic animals, and the underlying mechanism is not fully understood. We investigated the role of carboxy-terminal modulator protein (CTMP), an endogenous Akt inhibitor, in brain injury following focal cerebral ischemia in type 2 diabetic db/db mice and their control littermates non-diabetic db/+ mice. db/db mice showed a significant elevation in the expression of CTMP compared to db/+ mice under normal physiological conditions. After ischemia, db/db mice exhibit higher levels of CTMP expression, decreased Akt kinase activity, adverse neurological deficits and cerebral infarction than db/+ mice. To further certain the effectiveness of Akt signaling to the final outcome of cerebral ischemia, the animals were treated with LY294002, an inhibitor of the Akt pathway, which aggravated the ischemic injury in db/+ mice but not in db/db mice. RNA interference-mediated depletion of CTMP were finally applied in db/db mice, which restored Akt activity, improved neurological scores and reduced infarct volume. These results suggest that elevation of CTMP in diabetic mice suppresses Akt activity and ultimately negatively affects the outcome of ischemia. Inhibitors specifically targeting CTMP may be beneficial in the treatment of cerebral ischemia in patients with diabetes.