Downregulation of B4GALT5 attenuates cardiac fibrosis through Lumican and Akt/GSK-3β/β-catenin pathway.

Virtually all forms of cardiac disease exhibit cardiac fibrosis as a common trait, which ultimately leads to adverse ventricular remodeling and heart failure. To improve the prognosis of heart disease, it is crucial to halt the progression of cardiac fibrosis. Protein function is intricately linked with protein glycosylation, a vital post-translational modification. As a fundamental member of the β1,4-galactosyltransferase gene family (B4GALT), β1,4-galactosyltransferase V (B4GALT5) is associated with various disorders. In this study, significant levels of B4GALT5 expression were observed in cardiac fibrosis induced by transverse aortic constriction (TAC) or TGFβ1 and the activation of cardiac fibroblasts (CFs). Subsequently, by administering AAV9-shB4GALT5 injections to TAC animals, we were able to demonstrate that in vivo B4GALT5 knockdown decreased the transformation of CFs into myofibroblasts (myoFBs) and reduced the deposition of cardiac collagen fibers. In vitro tests revealed the same results. Conversely, both in vivo and in vitro experiments indicated that overexpression of B4GALT5 stimulates CFs activation and exacerbates cardiac fibrosis. Initially, we elucidated the primary mechanism by which B4GALT5 regulates the Akt/GSK-3β/β-catenin pathway and directly interacts with laminin, thereby affecting cardiac fibrosis. Our findings demonstrate that B4GALT5 promotes cardiac fibrosis through the Akt/GSK-3β/β-catenin pathway and reveal laminin as the target protein of B4GALT5.