Lin Fang, Liang Xiaoting, Meng Yilei, Zhu Yuping, Li Chenyu, Zhou Xiaohui, Hu Sangyu, Yi Na, Lin Qin, He Siyu, Sun Yizhuo, Sheng Jie, Fan Huimin, Li Li, Peng Luying
State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China.
Laboratory of Molecular Genetics and Stem Cell Differentiation, Tongji University School of Medicine, Tongji University, Shanghai 200120, China.
Biomedicines. 2024 Aug 19;12(8):1887. doi: 10.3390/biomedicines12081887.
Dilated cardiomyopathy (DCM) is one of the major causes of heart failure. Although significant progress has been made in elucidating the underlying mechanisms, further investigation is required for clarifying molecular diagnostic and therapeutic targets. In this study, we found that the mRNA level of protein phosphatase 2 regulatory subunit B' delta () was altered in the peripheral blood plasma of DCM patients. Knockdown of in murine cardiomyocytes increased the intracellular levels of reactive oxygen species (ROS) and inhibited adenosine triphosphate (ATP) synthesis. In vivo knockdown of in an isoproterenol (ISO)-induced DCM mouse model aggravated the pathogenesis and ultimately led to heart failure. Mechanistically, -deficient cardiomyocytes showed an increase in phosphorylation of STAT3 at Y705 and a decrease in phosphorylation of STAT3 at S727. The elevated levels of phosphorylation at Y705 in STAT3 triggered the upregulation of interleukin 6 (IL6) expression. Moreover, the decreased phosphorylation at S727 in STAT3 disrupted mitochondrial electron transport chain function and dysregulated ATP synthesis and ROS levels. These results hereby reveal a novel role for in modulating STAT3 pathway in DCM, suggesting it as a potential target for the therapy of the disease.
扩张型心肌病（DCM）是心力衰竭的主要病因之一。尽管在阐明其潜在机制方面已取得显著进展，但仍需进一步研究以明确分子诊断和治疗靶点。在本研究中，我们发现DCM患者外周血浆中蛋白磷酸酶2调节亚基B'δ（）的mRNA水平发生了改变。在小鼠心肌细胞中敲低可增加细胞内活性氧（ROS）水平并抑制三磷酸腺苷（ATP）合成。在异丙肾上腺素（ISO）诱导的DCM小鼠模型中体内敲低会加重发病机制并最终导致心力衰竭。机制上，缺乏的心肌细胞显示STAT3在Y705处的磷酸化增加，而在S727处的磷酸化减少。STAT3在Y705处磷酸化水平的升高触发了白细胞介素6（IL6）表达的上调。此外，STAT3在S727处磷酸化的减少破坏了线粒体电子传递链功能，并使ATP合成和ROS水平失调。这些结果揭示了在DCM中调节STAT3通路的新作用，表明它是该疾病治疗的潜在靶点。
