{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:41:57Z","timestamp":1790505717696,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T00:00:00Z","timestamp":1649289600000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81871097"],"award-info":[{"award-number":["81871097"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81571371"],"award-info":[{"award-number":["81571371"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81200491 to J.J."],"award-info":[{"award-number":["81200491 to J.J."]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81730066 to D.M."],"award-info":[{"award-number":["81730066 to D.M."]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20151554 to J.J."],"award-info":[{"award-number":["BK20151554 to J.J."]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>Senescence\u2010associated pathological cardiac hypertrophy (SA\u2010PCH) is associated with upregulation of foetal genes, fibrosis, senescence\u2010associated secretory phenotype (SASP), cardiac dysfunction and increased morbidity and mortality. Therefore, we conducted experiments to investigate whether GATA4 accumulation induces SA\u2010PCH, and whether Bmi\u20101\u2010RING1B promotes GATA4 ubiquitination and its selective autophagic degradation to prevent SA\u2010PCH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p><jats:italic>Bmi\u20101<\/jats:italic>\u2010deficient (<jats:italic>Bmi\u20101<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>), transgenic <jats:italic>Bmi\u20101<\/jats:italic> overexpressing (<jats:italic>Bmi\u20101<jats:sup>Tg<\/jats:sup><\/jats:italic>) and wild\u2010type (WT) mice were infused with angiotensin II (Ang II) to stimulate the development of SA\u2010PCH. Through bioinformatics analysis with RNA sequencing data from cardiac tissues, we found that Bmi\u20101\u2010RING1B and autophagy are negatively related to SA\u2010PCH. <jats:italic>Bmi\u20101<\/jats:italic> deficiency promoted GATA4\u2010dependent SA\u2010PCH by increasing GATA4 protein and hypertrophy\u2010related molecules transcribed by GATA4 such as ANP and BNP. <jats:italic>Bmi\u20101<\/jats:italic> deficiency stimulated NF\u2010\u03baB\u2010p65\u2010dependent SASP, leading to cardiac dysfunction, cardiomyocyte hypertrophy and senescence. <jats:italic>Bmi\u20101<\/jats:italic> overexpression repressed GATA4\u2010dependent SA\u2010PCH. GATA4 degraded by Bmi\u20101 was mainly dependent on autophagy rather than proteasome. In human myocardium, p16 positively correlated with ANP and GATA4 and negatively correlated with LC3B, Bmi\u20101 and RING1B; GATA4 positively correlated with p62 and negatively correlated with Bmi\u20101 and LC3B. With increased p16 protein levels, ANP\u2010, BNP\u2010 and GATA4\u2010positive cells or areas increased; however, LC3B\u2010positive cells or areas decreased in human myocardium. GATA4 is ubiquitinated after combining with Bmi\u20101\u2010RING1B, which is then recognised by p62, is translocated to autophagosomes to form autophagolysosomes and degraded. Downregulated GATA4 ameliorated SA\u2010PCH and cardiac dysfunction by reducing GATA4\u2010dependent hypertrophy and SASP\u2010related molecules. Bmi\u20101 combined with RING1B (residues 1\u2013179) and C\u2010terminus of GATA4 (residues 206\u2013443 including zinc finger domains) through residues 1\u201395, including a RING\u2010HC\u2010finger. RING1B combined with C\u2010terminus of GATA4 through the C\u2010terminus (residues 180\u2013336). Adeno\u2010associated viral vector serotype 9 (AAV9)\u2010<jats:italic>cytomegalovirus (CMV)\u2010Bmi\u20101\u2010RING1B<\/jats:italic> treatment significantly attenuated GATA4\u2010dependent SA\u2010PCH through promoting GATA4 autophagic degradation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Bmi\u20101\u2010RING1B maintained cardiac function and prevented SA\u2010PCH by promoting selective autophagy for degrading GATA4.<\/jats:p><\/jats:sec><jats:sec><jats:title>Translational perspective<\/jats:title><jats:p>AAV9\u2010<jats:italic>CMV<\/jats:italic>\u2010<jats:italic>Bmi\u20101<\/jats:italic>\u2010<jats:italic>RING1B<\/jats:italic> could be used for translational gene therapy to ubiquitinate GATA4 and prevent GATA4\u2010dependent SA\u2010PCH. Also, the combined domains between Bmi\u20101\u2010RING1B and GATA4 in aging cardiomyocytes could be therapeutic targets for identifying stapled peptides in clinical applications to promote the combination of Bmi\u20101\u2010RING1B with GATA4 and the ubiquitination of GATA4 to prevent SA\u2010PCH and heart failure. We found that degradation of cardiac GATA4 by Bmi\u20101 was mainly dependent on autophagy rather than proteasome, and autophagy agonists metformin and rapamycin could ameliorate the SA\u2010PCH, suggesting that activation of autophagy with metformin or rapamycin could also be a promising method to prevent SA\u2010PCH.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.574","type":"journal-article","created":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T17:05:23Z","timestamp":1649351123000},"source":"Crossref","is-referenced-by-count":32,"title":["Bmi\u20101\u2010RING1B prevents GATA4\u2010dependent senescence\u2010associated pathological cardiac hypertrophy by promoting autophagic degradation of GATA4"],"prefix":"10.1002","volume":"12","author":[{"given":"Haiyun","family":"Chen","sequence":"first","affiliation":[{"name":"The Research Center for Aging Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University  Nanjing Jiangsu 210029 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