AGEs–RAGE axis mediates myocardial fibrosis via activation of cardiac fibroblasts induced by autophagy in heart failure

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.

TFRC in cardiomyocytes promotes macrophage infiltration and activation during the process of heart failure through regulating Ccl2 expression mediated by hypoxia inducible factor‐1α

“…Heart‐resident macrophages are activated into pro‐inflammatory M1 type to trigger inflammatory response, resulting in accelerated deterioration of cardiac function in HF 11,12,17 . Cardiac fibroblasts are activated to trigger myocardial fibrosis in HF 18,19 . Single‐cell RNA sequencing of pressure overload‐induced pathological cardiac hypertrophy in mice showed that macrophage activation and subtype switching, a key event at middle‐stage of cardiac hypertrophy 20 .…”

Exploring novel biomarkers in dilated cardiomyopathy‑induced heart failure by integrated analysis and in vitro experiments

“…Previous studies have shown that the AGE/RAGE signaling pathway in diabetic complications can trigger fibroblast activation in the heart, leading to fibroblast-mediated matrix remodeling in HF ( 41 , 42 ). The present study further emphasizes the crucial roles of the AGE/RAGE signaling pathway in diabetic complications in the pathogenesis of DCM-induced HF.…”

Nε-(carboxymethyl)lysine promotes lipid uptake of macrophage via cluster of differentiation 36 and receptor for advanced glycation end products

“…RAGE is composed of an extracellular domain, a transmembrane protein and a highly charged cytoplasmic domain consisting of 43 amino acids[ 27 ]. Elevated RAGE expression and activation of AGEs-RAGE signaling have been found in a variety of diseases[ 28 , 29 ]. Our previous studies have confirmed that RAGE accelerated the progression of diabetic calcification[ 30 ].…”