巨噬细胞RAGE缺陷通过抑制自噬介导的巨噬细胞替代激活来预防心肌纤维化,The FASEB Journal

当前位置： X-MOL 学术 › FASEB J. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

巨噬细胞RAGE缺陷通过抑制自噬介导的巨噬细胞替代激活来预防心肌纤维化
The FASEB Journal ( IF 4.4 ) Pub Date : 2023-10-19 , DOI: 10.1096/fj.202300173rr
Jiaqi He _{1,

2} , Lan Wei _{1,

2} , Shengan Tan _{1,

2} , Birong Liang _{1,

2} , Jing Liu ₂ , Lu Lu _{1,

2,

3,

4} , Ting Wang ₅ , Junyan Wang _{1,

2} , Yusheng Huang _{1,

2,

3,

4} , Zixin Chen _{3,

4} , Huan Li _{1,

2,

3,

4} , Lu Zhang _{1,

2} , Zheng Zhou ₁ , Yanhong Cao _{1,

2} , Xiaohan Ye ₅ , Zhongqi Yang _{1,

2,

3,

4} , Shaoxiang Xian _{1,

2,

3,

4} , Lingjun Wang _{1,

2,

3,

4}

Affiliation

心肌纤维化（MF）是各种心血管疾病的典型病理特征，可导致心力衰竭（HF）甚至致命的结果。或者，活化的巨噬细胞参与纤维化和组织重塑的发展。尽管晚期糖基化终末产物 (RAGE) 受体与 MF 相关，但其在调节心脏纤维化中巨噬细胞功能中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 后小鼠心脏内浸润的交替激活的巨噬细胞中 RAGE 表达显着增加。与野生型小鼠相比，RAGE 基因敲除小鼠显示出较少的替代激活巨噬细胞浸润，并减轻了心脏肥大和纤维化。我们的数据表明，巨噬细胞特异性 RAGE 基因缺失的小鼠在承受压力超负荷时可以免受间质纤维化和心脏功能障碍的影响，从而导致心脏组织中替代激活的巨噬细胞比例下降。我们的体外实验表明，RAGE 缺陷通过抑制自噬激活来抑制分化为替代激活的巨噬细胞。在共培养系统中，RAW264.7 巨噬细胞在体外极化为选择性激活表型，刺激了心脏成纤维细胞中 α-平滑肌肌动蛋白和胶原蛋白的表达。然而，RAGE 的敲低和巨噬细胞自噬的抑制显示成纤维细胞向肌成纤维细胞的转变（FMT）减少。总的来说，我们的结果表明，RAGE 通过调节自噬，在替代激活的巨噬细胞的招募和激活中发挥着重要作用，这有助于 MF。因此，阻断RAGE信号传导可能是治疗高血压性心脏病的一个有吸引力的治疗靶点。

"点击查看英文标题和摘要"

Macrophage RAGE deficiency prevents myocardial fibrosis by repressing autophagy-mediated macrophage alternative activation

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.

更新日期：2023-10-19

点击分享查看原文

点击收藏

阅读更多本刊新发论文