Unmasking Protein Phosphatase 2A Regulatory Subunit B as a Crucial Factor in the Progression of Dilated Cardiomyopathy
Fang Lin,
Xiaoting Liang,
Yilei Meng,
Yuping Zhu,
Chenyu Li,
Xiaohui Zhou,
Sangyu Hu,
Na Yi,
Qin Lin,
Siyu He,
Yizhuo Sun,
Jie Sheng,
Huimin Fan,
Li Li,
Luying Peng
Affiliations
Fang Lin
State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China
Xiaoting Liang
Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China
Yilei Meng
State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China
Yuping Zhu
State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China
Chenyu Li
State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China
Xiaohui Zhou
Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China
Sangyu Hu
State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China
Na Yi
State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China
Qin Lin
State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China
Siyu He
State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China
Yizhuo Sun
State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China
Jie Sheng
State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China
Huimin Fan
Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China
Li Li
State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China
Luying Peng
State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200120, China
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 (Ppp2r5d) was altered in the peripheral blood plasma of DCM patients. Knockdown of Ppp2r5d in murine cardiomyocytes increased the intracellular levels of reactive oxygen species (ROS) and inhibited adenosine triphosphate (ATP) synthesis. In vivo knockdown of Ppp2r5d in an isoproterenol (ISO)-induced DCM mouse model aggravated the pathogenesis and ultimately led to heart failure. Mechanistically, Ppp2r5d-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 Ppp2r5d in modulating STAT3 pathway in DCM, suggesting it as a potential target for the therapy of the disease.
