炎症
促炎细胞因子
血管紧张素II
心脏纤维化
生物
纤维化
细胞生物学
受体
癌症研究
免疫学
医学
内科学
生物化学
作者
Shiju Ye,He Huang,Xue Han,Wei Luo,Lili Wu,Yang Ye,Yingchao Gong,Xia Zhao,Weijian Huang,Yi Wang,Xiaohong Long,Guosheng Fu,Guang Liang
出处
期刊:Circulation Research
[Ovid Technologies (Wolters Kluwer)]
日期:2023-03-17
卷期号:132 (6): 707-722
被引量:7
标识
DOI:10.1161/circresaha.122.322259
摘要
Cardiac remodeling in heart failure involves macrophage-mediated immune responses. Recent studies have shown that a PRR (pattern recognition receptor) called dectin-1, expressed on macrophages, mediates proinflammatory responses. Whether dectin-1 plays a role in pathological cardiac remodeling is unknown. Here, we identified a potential role of dectin-1 in this disease.To model aberrant cardiac remodeling, we utilized mouse models of chronic Ang II (angiotensin II) infusion. In this model, we assessed the potential role of dectin-1 through using D1KO (dectin-1 knockout) mice and bone marrow transplantation chimeric mice. We then used cellular and molecular assays to discover the underlying mechanisms of dectin-1 function.We found that macrophage dectin-1 is elevated in mouse heart tissues following chronic Ang II administration. D1KO mice were significantly protected against Ang II-induced cardiac dysfunction, hypertrophy, fibrosis, inflammatory responses, and macrophage infiltration. Further bone marrow transplantation studies showed that dectin-1 deficiency in bone marrow-derived cells prevented Ang II-induced cardiac inflammation and dysfunction. Through detailed molecular studies, we show that Ang II binds directly to dectin-1, causing dectin-1 homodimerization and activating the downstream Syk (spleen tyrosine kinase)/NF-κB (nuclear factor kappa B) signaling pathway to induce expression of inflammatory and chemoattractant factors. Mutagenesis studies identified R184 in the C-type lectin domain to interact with Ang II. Blocking dectin-1 in macrophages suppresses Ang II-induced inflammatory mediators and subsequent intercellular cross talk with cardiomyocytes and fibroblasts.Our study has discovered dectin-1 as a new nonclassical receptor of Ang II and a key player in cardiac remolding and dysfunction. These studies suggest that dectin-1 may be a new target for treating hypertension-related heart failure.
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