Mechanism of BRCC36 affecting cardiac rupture after acute infarction through the Wnt‑JNK signaling pathway.

Abstract

The present study investigated the role of Lys‑63‑specific deubiquitinase BRCC36 (BRCC36) in preventing cardiac rupture following acute myocardial infarction (AMI) through the Wnt/β‑catenin signaling pathway. Cardiomyocyte‑specific BRCC36‑overexpressing transgenic mice (α‑MHC‑BRCC36) and their wild‑type littermates were used. Experimental mice were allocated into five distinct groups: Sham, AMI, sham + BRCC36, AMI + BRCC36 and AMI + BRCC36 + Wnt groups. The experimental groups subsequently underwent comprehensive assessment of cardiac parameters including cardiac function, hemodynamics, myocardial infarct size, apoptosis and tissue pathology. The AMI + BRCC36 group showed predominantly resolved lesions, minimal inflammatory infiltration and limited collagen fiber degradation compared with the AMI model group, which resulted in improved cardiac function and a reduction in infarct size, apoptosis and fibrosis. The protective effects of BRCC36 were compromised by the addition of Wnt5a, a member of the Wnt family involved in the Wnt/β‑catenin signaling pathway, which is important for cardiac function. No significant differences were observed between the sham and sham + BRCC36 groups. Compared with the sham groups, AMI mice sustained severe impairments in cardiac systolic/diastolic function, alongside enlarged infarct size, increased cardiomyocyte apoptosis and exacerbated myocardial fibrosis. These deleterious effects were markedly attenuated by BRCC36 overexpression, as evidenced by improved cardiac function, reduced infarct size and apoptosis and attenuated fibrosis. Notably, the cardioprotective effects of BRCC36 were substantially abolished by co‑administration of a Wnt agonist. At the molecular level, BRCC36 overexpression suppressed the activation of the Wnt/JNK/c‑Jun signaling pathway (as indicated by decreased levels of Wnt5a, p‑c‑Jun and p‑JNK) induced by AMI, whereas Wnt agonist treatment reversed this suppression. BRCC36 overexpression was therefore shown to inhibit cardiomyocyte apoptosis, diminish myocardial infarct size, suppress myocardial fibrosis and improve cardiac function in a mouse model of AMI, possibly by suppressing Wnt/JNK signaling pathway activation.