Cardiovascular Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, China.
Department of Cardiology, Huanggang Central Hospital, Huanggang, 438021, China.
Free Radic Biol Med. 2022 Nov 1;192:13-24. doi: 10.1016/j.freeradbiomed.2022.09.004. Epub 2022 Sep 13.
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 overexpression 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 kinase 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.
糖尿病心肌病（DCM）是指在糖尿病患者中发生的心室功能障碍，独立于公认的危险因素，如冠状动脉疾病、高血压和心脏瓣膜病。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 参与非酒精性脂肪性肝病、细菌感染和心肌肥厚，并在肿瘤发生中发挥关键作用。在此，我们观察到高血糖细胞模型和高脂肪饮食（HFD）小鼠模型中 DUSP12 的表达增加。心脏特异性 DUSP12 缺陷小鼠在 HFD 诱导下表现出严重的心脏功能障碍和重构。DUSP12 缺乏加剧氧化应激损伤和细胞凋亡，而 DUSP12 过表达则具有相反的效果。在分子水平上，DUSP12 与凋亡信号调节激酶 1（ASK1）物理结合，促进其去磷酸化，并抑制其对 c-Jun N 端激酶和 p38 丝裂原活化蛋白激酶的作用。挽救实验表明，ASK1 抑制可减轻 DUSP12 缺乏引起的氧化应激损伤和细胞凋亡。因此，我们认为 DUSP12 是 DCM 中的一个重要信号通路。
