期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 192, 期 -, 页码 13-24出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2022.09.004
关键词
DUSP12; Diabetic cardiomyopathy; ASK1; Oxidative stress injury; Apoptosis
资金
- National Natural Science Foundation of China
- [81970242]
- [82000826]
Diabetic cardiomyopathy (DCM) is a heart dysfunction that occurs in patients with diabetes mellitus (DM). This study found that dual-specificity phosphatase 12 (DUSP12) plays an important role in DCM. Overexpression of DUSP12 worsens cardiac dysfunction and increases oxidative stress and apoptosis, while DUSP12 deficiency exacerbates these effects. The study also found that DUSP12 interacts with a specific signaling pathway.
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.
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