Knockdown of PATZ1 alleviates chronic heart failure through the USP22/HIF-1α axis

The pathogenesis of chronic heart failure (CHF) is complex and not fully understood. HIF-1α plays a paradoxical role in CHF, and its stability is regulated by the deubiquitinating enzyme USP22. However, the role of USP22 in CHF and its upstream regulatory mechanisms remain unclear. This study aims to investigate the role and regulatory mechanism of the PATZ1/USP22/HIF-1α axis in CHF pathogenesis. An in vitro CHF model was established using angiotensin II (Ang II)-induced H9c2 cardiomyocytes and an in vivo model was created by abdominal aortic constriction (AAC) in rats. Genetic manipulations were performed using shRNAs or overexpression plasmids. Cell viability and cardiac function were assessed by CCK-8, TUNEL staining, Western blot, immunohistochemistry, and hemodynamic measurements. Protein interactions, stability, and transcriptional regulation were analyzed via co-immunoprecipitation (Co-IP), ubiquitination assays, cycloheximide (CHX) chase assays, chromatin immunoprecipitation-qPCR (ChIP-qPCR), and dual-luciferase reporter assays. USP22 was significantly upregulated in human CHF datasets (GSE116250/GSE57345) and experimental models. USP22 knockdown reduced cardiomyocyte injury in vitro (increased viability, decreased apoptosis) and improved cardiac function in vivo (increased LVSP, decreased LVEDP, and reduced fibrosis). Mechanistically, USP22 bound to and stabilized HIF-1α protein by deubiquitination. HIF-1α overexpression reversed USP22 knockdown-mediated cardioprotection. Furthermore, PATZ1, which was upregulated in CHF, transcriptionally activated USP22 by binding to its promoter. PATZ1 silencing attenuated cardiac injury, while USP22 co-overexpression abrogated this protective effect by restoring HIF-1α levels. PATZ1 promotes CHF progression by transcriptionally upregulating USP22, which stabilizes HIF-1α via deubiquitination. Targeting the PATZ1/USP22/HIF-1α axis may offer novel therapeutic strategies for CHF.