Institute of Cardiovascular Sciences, College of Medical and Dental Science, The Medical School, University of Birmingham, Birmingham, UK.
J Cell Mol Med. 2018 Sep;22(9):4317-4327. doi: 10.1111/jcmm.13721. Epub 2018 Jul 4.
The Src family kinases (SFK) are a group of signalling molecules with important regulatory functions in inflammation and haemostasis. Leucocytes and platelets express multiple isoforms of the SFKs. Previous studies used broad-spectrum pharmacological inhibitors, or murine models deficient in multiple SFK isoforms, to demonstrate the functional consequences of deficiencies in SFK signalling. Here, we hypothesized that individual SFK operate in a non-redundant fashion in the thrombo-inflammatory recruitment of monocyte during atherosclerosis. Using in vitro adhesion assays and single SFK knockout mice crossed with the ApoE model of atherosclerosis, we find that SFK signalling regulates platelet-dependent recruitment of monocytes. However, loss of a single SFK, Fgr or Lyn, reduced platelet-mediated monocyte recruitment in vitro. This translated into a significant reduction in the burden of atherosclerotic disease in Fgr /ApoE or Lyn /ApoE animals. SFK signalling is not redundant in thrombo-inflammatory vascular disease and individual SFK may represent targets for therapeutic intervention.
Src 家族激酶（SFK）是一组信号分子，在炎症和止血中具有重要的调节功能。白细胞和血小板表达多种 SFK 同工型。先前的研究使用广谱药理学抑制剂或缺乏多种 SFK 同工型的小鼠模型，证明了 SFK 信号转导缺陷的功能后果。在这里，我们假设在动脉粥样硬化过程中单核细胞的血栓炎症募集过程中，单个 SFK 以非冗余的方式发挥作用。使用体外黏附测定和与动脉粥样硬化 ApoE 模型杂交的单个 SFK 敲除小鼠，我们发现 SFK 信号转导调节血小板依赖性单核细胞募集。然而，单一 SFK（Fgr 或 Lyn）的缺失会减少体外血小板介导的单核细胞募集。这转化为 Fgr/ApoE 或 Lyn/ApoE 动物动脉粥样硬化疾病负担的显著减少。SFK 信号转导在血栓炎症性血管疾病中不是冗余的，并且单个 SFK 可能代表治疗干预的靶点。
