Macrophage RAGE deficiency prevents myocardial fibrosis by repressing autophagy-mediated macrophage alternative activation
Macrophage RAGE deficiency prevents myocardial fibrosis by repressing autophagy-mediated macrophage alternative activation
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DOI：
10.1096/fj.202300173rr
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发表时间：
2023-11-01
期刊：
影响因子：
4.8
通讯作者：
Wang，Lingjun
中科院分区：
文献类型：
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作者：
He，Jiaqi;Wei，Lan;Wang，Lingjun
心肌纤维化(MF)是导致心力衰竭(HF)甚至致死的各种心血管疾病的特有病理特征。另外，活化的巨噬细胞参与了纤维化和组织重塑的发展。尽管晚期糖基化终产物受体(RAGE)参与了MF的发病，但其在心肌纤维化中调节巨噬细胞功能的潜在作用尚未得到充分研究。我们的目的是确定巨噬细胞RAGE在横断性主动脉缩窄(TAC)诱导的MF中的作用。在这项研究中，我们发现TAC后小鼠心脏内浸润性或活化的巨噬细胞中RAGE的表达显著增加。与野生型小鼠相比，RAGE基因敲除小鼠表现出较少的交替激活的巨噬细胞的渗透，并减轻了心肌肥大和纤维化。我们的数据表明，巨噬细胞特异性RAGE基因缺失的小鼠在压力超负荷时可以防止间质纤维化和心功能障碍，这导致心脏组织中可选激活的巨噬细胞比例下降。我们的体外实验表明，RAGE缺乏通过抑制自噬激活而抑制分化为交替激活的巨噬细胞。在共培养体系中，RAW264.7巨噬细胞在体外极化为交替激活的表型，刺激心脏成纤维细胞α-平滑肌肌动蛋白和胶原的表达。然而，抑制RAGE和抑制巨噬细胞的自噬显示成纤维细胞到肌成纤维细胞的转变(FMT)减少。总而言之，我们的结果表明，RAGE通过调节自噬在交替激活的巨噬细胞的募集和激活中发挥重要作用，这有助于MF的发生。因此，阻断RAGE信号通路可能成为治疗高血压性心脏病的一个有吸引力的靶点。
Myocardial fibrosis (MF) is the characteristic pathological feature of various cardiovascular diseases that lead to heart failure (HF) or even fatal outcomes. Alternatively, activated macrophages are involved in the development of fibrosis and tissue remodeling. Although the receptor for advanced glycation end products (RAGE) is involved in MF, its potential role in regulating macrophage function in cardiac fibrosis has not been fully investigated. We aimed to determine the role of macrophage RAGE in transverse aortic constriction (TAC)‐induced MF. In this study, we found that RAGE expression was markedly increased in the infiltrated alternatively activated macrophages within mice hearts after TAC. RAGE knockout mice showed less infiltration of alternatively activated macrophages and attenuated cardiac hypertrophy and fibrosis compared to the wild‐type mice. Our data suggest that mice with macrophage‐specific genetic deletion of RAGE were protected from interstitial fibrosis and cardiac dysfunction when subjected to pressure overload, which led to a decreased proportion of alternatively activated macrophages in heart tissues. Our in vitro experiments demonstrated that RAGE deficiency inhibited the differentiation into alternatively activated macrophages by suppressing autophagy activation. In the co‐culture system, in vitro polarization of RAW264.7 macrophages toward an alternatively activated phenotype stimulated the expression of α‐smooth muscle actin and collagen in cardiac fibroblasts. However, the knockdown of RAGE and inhibition of autophagy in macrophages showed reduced fibroblast‐to‐myofibroblast transition (FMT). Collectively, our results suggest that RAGE plays an important role in the recruitment and activation of alternatively activated macrophages by regulating autophagy, which contributes to MF. Thus, blockage of RAGE signaling may be an attractive therapeutic target for the treatment of hypertensive heart disease.