Dual-specificity phosphatase 12 attenuates oxidative stress injury and apoptosis in diabetic cardiomyopathy via the ASK1-JNK/p38 signaling pathway
Dual-specificity phosphatase 12 attenuates oxidative stress injury and apoptosis in diabetic cardiomyopathy via the ASK1-JNK/p38 signaling pathway
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DOI：
10.1016/j.freeradbiomed.2022.09.004
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发表时间：
2022-09-18
影响因子：
7.4
通讯作者：
Zhang, Yan-Zhou
中科院分区：
文献类型：
--
作者：
Li, Huan;Yang, Qin;Zhang, Yan-Zhou
糖尿病心肌病(DCM)是发生在糖尿病(DM)患者中的独立于公认的危险因素，如冠状动脉疾病、高血压和瓣膜心脏病等的心功能障碍。双特异性磷酸酶12(DUSP12)是一种在所有组织中表达的双特异性磷酸酶。全基因组连锁研究发现DUSP12与2型糖尿病(T2D)之间存在关联。然而，DUSP12在DCM中的作用在很大程度上仍不清楚。广泛表达的DUSP12参与了非酒精性脂肪性肝病、细菌感染和心肌肥大，并在肿瘤的发生中发挥了关键作用。在此，我们观察到DUSP12在高血糖细胞模型和高脂饮食(HFD)小鼠模型中的表达增加。心脏特异的DUSP12缺陷小鼠表现出严重的心功能障碍和由HFD引起的重塑。DUSP12缺乏加剧氧化应激损伤和细胞凋亡，而DUSP12过表达则相反。在分子水平上，DUSP12与凋亡信号调节蛋白1(ASK1)物理结合，促进其去磷酸化，并抑制其对c-jun氨基末端Ki-Nase和p38丝裂原活化蛋白激酶的作用。抢救性实验表明，由于DUSP12缺乏而加重的氧化应激损伤和细胞凋亡，可通过抑制ASK1而减轻。因此，我们认为DUSP12在DCM中是一个重要的信号通路。
Diabetic cardiomyopathy (DCM) is ventricular dysfunction that occurs in patients with diabetes mellitus (DM), independent of recognized risk factors, such as coronary artery disease, hypertension, and valvular heart disease. Dual-specificity phosphatase 12 (DUSP12) is a dual-specificity phosphatase expressed in all tissues. Genome-wide linkage studies have found an association between DUSP12 and type 2 diabetes (T2D). However, the role of DUSP12 in DCM remains largely unknown. Ubiquitously expressed DUSP12 is involved in nonalcoholic fatty liver disease, bacterial infection, and myocardial hypertrophy and plays a critical role in tumorigenesis. Herein, we observed an increased expression of DUSP12 in a hyperglycemia cell model and a high-fat diet (HFD) mouse model. Heart-specific DUSP12-deficient mice showed severe cardiac dysfunction and remodeling induced by an HFD. DUSP12 deficiency exacerbated oxidative stress injury and apoptosis, whereas DUSP12 over -expression had the opposite effect. At the molecular level, DUSP12 physically bound to apoptotic signal -regulated kinase 1 (ASK1), promoted its dephosphorylation, and inhibited its action on c-Jun N-terminal ki-nase and p38 mitogen-activated protein kinase. Rescue experiments have shown that oxidative stress injury and apoptosis, exacerbated by DUSP12 deficiency, are alleviated by ASK1 inhibition. Therefore, we consider DUSP12 an important signaling pathway in DCM.