PRC1 mediates downstream PI3K-AKT activation through regulating PTEN ubiquitination degradation in TAC-induced cardiac remodeling.

Heart failure (HF) is characterized by pathological remodeling, the mechanisms of which remain unclear. The role of Polycomb repressive complex 1 (PRC1), an epigenetic regulator, in cardiac stress has not yet been extensively investigated. This study evaluated PRC1 expression in transverse aortic constriction (TAC)-induced HF in murine models and human cardiac tissues. The PRC1 inhibitor RB-3 (administered at 1 mg/kg) was tested in TAC mice. Assessments included cardiac function, histological changes, and signaling pathways (phosphatase and tensin homolog deleted on chromosome ten (PTEN)/pro-survival phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and transforming growth factor-beta 1/mothers against decapentaplegic homolog 2). PRC1 subunits, B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and really interesting new gene 1B (RING1B), were significantly upregulated in murine and human HF samples. Treatment with RB-3 improved left ventricular ejection fraction (LVEF), reduced cardiac fibrosis, and increased PTEN levels by inhibiting ubiquitination. However, co-administration of the PTEN inhibitor VO-Ohpic negated the beneficial effects of RB-3, as evidenced by a decrease in LVEF and an increase in fibrosis versus the TAC + RB-3 group. This study indicates that the suppression of PRC1 levels may mitigate TAC-induced ubiquitination and degradation of PTEN, consequently enhancing the activation of downstream signaling pathways associated with hypertrophy and fibrosis, and alleviating cardiac remodeling. Consequently, PRC1 is promising as a potential therapeutic agent for ameliorating HF.