Lentinan alleviates angiotensin II-induced myocardial remodeling through LMP7-SOCS3 signaling

Myocardial remodeling is a major pathological mechanism causing heart failure. As a critical negative modulator of cardiac remodeling, suppressor of cytokine signaling 3 (SOCS3) is regulated by immunoproteasome subunit large multifunctional peptidase 7 (LMP7). Lentinan (LNT), a β-polysaccharide extracted from Lentinus edodes, has anti-inflammatory and antioxidant properties. However, the role and molecular mechanisms of LNT in angiotensin II (Ang II)-triggered myocardial remodeling are unclear. Myocardial remodeling was established using Ang II infusion (1000 or 200 ng/kg/min) for 2 weeks. Cardiomyocytes and cardiac fibroblasts were triggered by Ang II. LNT was administered daily by oral gavage to mice starting 1 day before Ang II or saline treatment. Here, we found that LNT supplementation dose-dependently ameliorated Ang II-triggered myocardial dysfunction and remodeling (hypertrophy, fibrosis, inflammation, and superoxide production). Mechanistically, LNT suppressed SOCS3 protein degradation by downregulating immunoproteasome LMP7 activity and expression, thereby inactivating downstream signaling, such as STAT3, ERK, AKT, NF-κB, and TGF-β. Conversely, SOCS3 knockdown significantly blocked the protective effect of LNT on myocardial remodeling in Ang II-infused mice. Together, our findings suggest that LNT may be a new therapeutic approach for myocardial remodeling and heart failure.