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

Abstract

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.

Full-Length Transcriptome Sequencing: An Insight Into the Dog Model of Heart Failure

“…ZNF24, 250, 300, 331, 568, and 641 are known downstream effectors of JAK/STAT signaling by the KEGG analysis. Additionally, differentiated spliced TFs also function in cardiac fibrosis (e.g., KLF6) ( 19 ), angiogenesis (e.g., VEZF1) ( 20 ), cardiac structure and contractile function (e.g., VEZF1) ( 21 ), cardiac hypertrophy, inflammation, and regulatory T-cell homeostasis (e.g., ZFP91) ( 22 – 24 ) ( Figure 7A ). As critical effectors or regulators, TFs can sense multiple signal transduction pathways and metabolic perturbations in cells.…”

Problems and prospects for finding new pharmacological agents among adenosine receptor agonists, antagonists, or their allosteric modulators for the treatment of cardiovascular diseases

“…The effects of A1AR in the development of this pathological process can be realized with the participation of zinc finger proteins (ZFP91), which regulate the expression of A1AR mRNA and affect myocardial homeostasis under conditions of excessive cardiac overload. ZFP91 deletion is accompanied by a decrease in A1AR mRNA synthesis and development of left ventricular hypertrophy [61].…”

Cooperative regulation of Zhx1 and hnRNPA1 drives the cardiac progenitor-specific transcriptional activation during cardiomyocyte differentiation

“…Knockout of Gata4 or Gata6 (containing zinc fingers) resulted in the downregulated expression of cardiac genes in early embryonic development [ 14 , 15 ]. ZNF91 protects the heart by maintaining cardiac homeostasis under pressure overload and reversing isoproterenol-induced cardiac hypertrophy [ 16 ]. Both ZNF418 and ZNF307 were reported to counteract hypertensive overload-induced cardiac hypertrophy [ 17 , 18 ].…”