Bmi‐1‐RING1B prevents GATA4‐dependent senescence‐associated pathological cardiac hypertrophy by promoting autophagic degradation of GATA4

作者：Haiyun Chen, Jiawen Zhou, Hongjie Chen, Jialong Liang, Chunfeng Xie, Xin Gu, Rong Wang, Zhiyuan Mao, Yongjie Zhang, Qing Li, Guoping Zuo, Dengshun Miao, Jianliang Jin · 发表于：Clinical and Translational Medicine · 年份：2022 · DOI：10.1002/ctm2.574 · 被引用次数：31 · 研究领域：Congenital heart defects research、Telomeres, Telomerase, and Senescence、Cardiac Fibrosis and Remodeling

AIMS: Senescence-associated pathological cardiac hypertrophy (SA-PCH) is associated with upregulation of foetal genes, fibrosis, senescence-associated secretory phenotype (SASP), cardiac dysfunction and increased morbidity and mortality. Therefore, we conducted experiments to investigate whether GATA4 accumulation induces SA-PCH, and whether Bmi-1-RING1B promotes GATA4 ubiquitination and its selective autophagic degradation to prevent SA-PCH. METHODS AND RESULTS: ) and wild-type (WT) mice were infused with angiotensin II (Ang II) to stimulate the development of SA-PCH. Through bioinformatics analysis with RNA sequencing data from cardiac tissues, we found that Bmi-1-RING1B and autophagy are negatively related to SA-PCH. Bmi-1 deficiency promoted GATA4-dependent SA-PCH by increasing GATA4 protein and hypertrophy-related molecules transcribed by GATA4 such as ANP and BNP. Bmi-1 deficiency stimulated NF-κB-p65-dependent SASP, leading to cardiac dysfunction, cardiomyocyte hypertrophy and senescence. Bmi-1 overexpression repressed GATA4-dependent SA-PCH. GATA4 degraded by Bmi-1 was mainly dependent on autophagy rather than proteasome. In human myocardium, p16 positively correlated with ANP and GATA4 and negatively correlated with LC3B, Bmi-1 and RING1B; GATA4 positively correlated with p62 and negatively correlated with Bmi-1 and LC3B. With increased p16 protein levels, ANP-, BNP- and GATA4-positive cells or areas increased; however, LC3B-positive cells or areas decreased in human...