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

愤怒(情绪) 自噬 糖基化 心肌纤维化 纤维化 心力衰竭 心脏纤维化 医学 内科学 心脏病学 心室重构 肌成纤维细胞 下调和上调 糖基化终产物 内分泌学 化学 受体 生物 细胞凋亡 神经科学 生物化学 基因
作者
Birong Liang,Zheng Zhou,Zhong-Qi Yang,Jing Liu,Lu Zhang,Jiaming He,Huan Li,Yu‐Sheng Huang,Qiuye Yang,Shaoxiang Xian,Lingjun Wang
出处
期刊:Experimental Physiology [Wiley]
卷期号:107 (8): 879-891 被引量:7
标识
DOI:10.1113/ep090042
摘要

New Findings What is the central question of this study? Does the advanced glycation end products (AGEs)–receptor for advanced glycation end products (RAGE) axis mediate myocardial fibrosis in heart failure? What is the main finding and its importance? The AGEs–RAGE axis is involved in the pathogenesis of myocardial fibrosis through activation of cardiac fibroblasts induced by autophagy in heart failure. By suppression of cardiac fibroblast activation, inhibition of the AGEs–RAGE axis attenuates cardiac dysfunction and myocardial fibrosis in mice with transverse aortic constriction. 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.
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