ABSTRACT:
Heart failure is the end stage of
cardiovascular disease and is a critical medical condition that poses an important therapeutic challenge for physicians owing to its high morbidity and mortality. Myocardial
fibrosis is part of the remodelling process that occurs in
heart failure. Many studies have shown that
advanced glycation end products (AGEs) and
receptor for advanced glycation end products (RAGE) are implicated in
fibrosis and autophagy, but the mechanism remains unclear. In this study, we elucidated the mechanism by which the AGEs-RAGE axis mediates activation of cardiac fibroblasts (CFs) in
heart failure. We used C57BL/6J wild-type (WT) mice to establish a model of
heart failure by transverse aortic constriction (TAC). After 6 weeks of treatment, relevant indicators were detected. In mice subjected to TAC, AGEs were upregulated compared with
sham-operated mice. Inhibition of RAGE resulted in functional cardiac protection, with reduced
hypertrophy and
fibrosis in mice after TAC. Of note, autophagy mediated the activation of CFs that transformed to myofibroblasts and contributed to
fibrosis. In vitro, CFs were obtained from neonatal Sprague-Dawley rats and treated with AGEs,
bovine serum albumin and
short hairpin RNA (
shRNA) for RAGE, in order to verify the results obtained in vivo. These results suggest that the AGEs-RAGE axis is involved in the pathogenesis of myocardial
fibrosis in
heart failure through CF activation induced by autophagy. Inhibition of the AGEs-RAGE axis attenuates cardiac dysfunction and myocardial
fibrosis in mice with TAC by suppressing CF activation.