Cell death-inducing DFFA-like effector C/CIDEC gene silencing alleviates diabetic cardiomyopathy via upregulating AMPKa phosphorylation
Cell death-inducing DFFA-like effector C/CIDEC gene silencing alleviates diabetic cardiomyopathy via upregulating AMPKa phosphorylation
复制标题
细胞死亡——诱导 DFFA——样效应器 C/CIDEC 基因沉默通过上调 AMPKa 磷酸化缓解糖尿病心肌病
DOI：
10.1096/fj.202002562r
复制
发表时间：
2021-05-01
期刊：
影响因子：
4.8
通讯作者：
Zhong，Ming
中科院分区：
文献类型：
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作者：
Zhou，Hui-Min;Ti，Yun;Zhong，Ming
细胞死亡诱导DFFA样效应物C（CIDEC）是代谢紊乱和胰岛素抵抗的原因，被认为是糖尿病心肌病（DCM）发展的重要触发因素。为了研究CIDEC是否在DCM中起关键作用，通过高脂饮食和单次注射低剂量链脲佐菌素（27.5 mg/kg）诱导DCM大鼠模型。DCM大鼠表现为严重的代谢紊乱、胰岛素抵抗、心肌肥厚、间质纤维化、异位脂质沉积、炎症反应和心功能不全，并伴有CIDEC升高。CIDEC基因沉默后，DCM大鼠上述病理生理特征明显改善，心功能明显改善。AMP活化蛋白激酶（AMPK）α活化增强参与了潜在的病理生理分子机制。为了进一步探索CIDEC促进体外胶原合成的潜在机制，采用高糖（15.5 mmol/L）和高胰岛素（104μU/mL）诱导胰岛素抵抗心脏成纤维细胞（CF）模型。我们观察到胰岛素抵抗刺激显著提高了CF中的CIDEC表达并促进了CIDEC核转位。AMPKα2几乎完全分布于CF核内。结果进一步证明CIDEC在CF核中与AMPKα2而不是AMPKα1发生生物化学相互作用和共定位，这为CIDEC促进胶原合成提供了新的机制。本研究提示CIDEC基因沉默可通过AMPKα信号转导途径在体内外抑制DCM的发生，提示CIDEC可能是治疗DCM的有效靶点。
Cell death‐inducing DFFA‐like effector C (CIDEC) is responsible for metabolic disturbance and insulin resistance, which are considered to be important triggers in the development of diabetic cardiomyopathy (DCM). To investigate whether CIDEC plays a critical role in DCM, DCM rat model was induced by a high‐fat diet and a single injection of low‐dose streptozotocin (27.5 mg/kg). DCM rats showed severe metabolic disturbance, insulin resistance, myocardial hypertrophy, interstitial fibrosis, ectopic lipid deposition, inflammation and cardiac dysfunction, accompanied by CIDEC elevation. With CIDEC gene silencing, the above pathophysiological characteristics were significantly ameliorated accompanied by significant improvements in cardiac function in DCM rats. Enhanced AMP‐activated protein kinase (AMPK) α activation was involved in the underlying pathophysiological molecular mechanisms. To further explore the underlying mechanisms that CIDEC facilitated collagen syntheses in vitro, insulin‐resistant cardiac fibroblast (CF) model was induced by high glucose (15.5 mmol/L) and high insulin (104μU/mL). We observed that insulin‐resistant stimulation dramatically raised CIDEC expression and promoted CIDEC nuclear translocation in CFs. Meanwhile, AMPKα2 was observed to distribute almost completely inside CF nucleus. The results further proved that CIDEC biochemically interacted and co‐localized with AMPKα2 rather than AMPKα1 in CF nucleus, which provided a novel mechanism of CIDEC in promoting collagen syntheses. This study suggested that CIDEC gene silencing alleviates DCM via AMPKα signaling both in vivo and in vitro, implicating CIDEC may be a promising target for treatment of human DCM.