Zinc finger protein 91 loss induces cardiac hypertrophy through adenosine A1 receptor down‐regulation under pressure overload status

• Published in: Journal of cellular and molecular medicine Vol. 24; no. 17; pp. 10189 - 10201
• Main Authors: Wu, Xiangqi, You, Wei, Wu, Zhiming, Ye, Fei, Chen, Shaoliang
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-09-2020; John Wiley and Sons Inc
• Subjects: Adenosine; Adenosine - metabolism; adenosine A1 receptor; Animals; Aorta; cardiac hypertrophy; Cardiomegaly - metabolism; Cardiomyocytes; Coronary vessels; Down-Regulation - physiology; Female; Fluorides; Genes; Heart; Heart diseases; Homeostasis; Hypertrophy; Hypertrophy, Left Ventricular - metabolism; Isoproterenol; Male; Mice; Mice, Inbred C57BL; Myocardium - metabolism; Myocytes, Cardiac - metabolism; N6‐Cyclopentyladenosine; Original; Pressure; Proteins; Receptor, Adenosine A1 - metabolism; Transcription; Transcription factors; Ubiquitin-Protein Ligases - metabolism; Zinc finger protein 91; adenosine A1 receptor; cardiac hypertrophy; N6-Cyclopentyladenosine; zinc finger protein 91
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.15630

The function of zfp91 is mainly studied in vitro, but there is no study in vivo. Accumulative data suggest that zfp91 may be an important gene to regulate all aspects of human response. However, there are no data to date about the function of zfp91 on cardiac homeostasis. Thus, we aimed to observe the role of zfp91 gene in mouse cardiomyocytes on myocardial homeostasis and related mechanisms under pressure overload. In the study, zfp91 mRNA and protein levels were significantly reduced in TAC‐operated WT mice as compared with controls. Genetic ablation of zfp91 dramatically led to pathological cardiac dysfunction and hypertrophy after transverse aortic constriction (TAC). Adenosine A1 receptor (Adora1) mRNA and protein expressions were significantly down‐regulated in the heart of zfp91‐deletion mice with TAC. Zfp91 overexpression reversed isoproterenol‐induced cardiomyocyte hypertrophy, which was abolished by selective Adora1 antagonist. Dual‐luciferase reporter and ChIP‐qPCR assays indicated that zfp91 acted on Adora1 promoter through its binding site. Last, Adora1 agonist rescued heart dysfunction and cardiac hypertrophy in zfp91 loss mice after TAC. Zfp91 may transcriptionally regulate Adora1 expression in the heart, which mainly maintained cardiac homeostasis under pressure overload status. It will provide a new approach to treat cardiac hypertrophy.