Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Heart, Lung, and Blood Center, Pan-Vascular Research Institute, Tongji University School of Medicine, Shanghai, China.
J Cardiovasc Transl Res. 2022 Dec;15(6):1219-1238. doi: 10.1007/s12265-022-10268-3. Epub 2022 May 20.
Heart failure is one of the most common but complicated end-stage syndromes in clinical practice. Dilated cardiomyopathy is a myocardial structural abnormality that is associated with heart failure. Dual-specificity phosphatases (DUSPs) are a group of protein phosphatases that regulate signaling pathways in numerous diseases; however, their physiological and pathological impact on cardiovascular disease remains unknown. In the present study, we generated two transgenic mouse models, a DUSP7 knockout and a cardiac-specific DUSP7 overexpressor. Mice overexpressing DUSP7 showed an exacerbated disease phenotype, including severe dilated cardiomyopathy, heart failure, and cardiac death. We further demonstrated that high levels of DUSP7 inhibited ERK1/2 phosphorylation and influenced downstream c-MYC, c-FOS, and c-JUN gene expression but did not affect upstream activators. Taken together, our study reveals a novel molecular mechanism for DUSP7 and provides a new therapeutic target and clinical path to alleviate dilated cardiomyopathy and improve cardiac function.
心力衰竭是临床实践中最常见但最复杂的终末期综合征之一。扩张型心肌病是一种与心力衰竭相关的心肌结构异常。双特异性磷酸酶 (DUSPs) 是一组蛋白磷酸酶，可调节多种疾病中的信号通路；然而，它们对心血管疾病的生理和病理影响尚不清楚。在本研究中，我们生成了两种转基因小鼠模型，一种是 DUSP7 敲除小鼠，另一种是心脏特异性 DUSP7 过表达小鼠。过表达 DUSP7 的小鼠表现出更严重的疾病表型，包括严重的扩张型心肌病、心力衰竭和心脏性死亡。我们进一步证明，高水平的 DUSP7 抑制了 ERK1/2 的磷酸化，并影响了下游的 c-MYC、c-FOS 和 c-JUN 基因表达，但不影响上游激活剂。总之，我们的研究揭示了 DUSP7 的一个新的分子机制，并为缓解扩张型心肌病和改善心脏功能提供了一个新的治疗靶点和临床途径。
