Abstract：
BACKGROUND: Atherosclerosis is a leading cause of cardiovascular morbidity and mortality. Atherosclerotic lesions show increased levels of proteins associated with the fibroblast growth factor receptor (FGFR) pathway. However, the functional significance and mechanisms governed by FGFR signaling in atherosclerosis are not known. In the present study, we investigated FGFR1 signaling in atherosclerosis development and progression.
RESULTS: Examination of human atherosclerotic lesions and aortas of Apoe-/- mice fed a high-fat diet (HFD) showed increased levels of FGFR1 in macrophages. We deleted myeloid-expressed Fgfr1 in Apoe-/- mice and showed that Fgfr1 deficiency reduces atherosclerotic lesions and lipid accumulations in both male and female mice upon HFD feeding. These protective effects of myeloid Fgfr1 deficiency were also observed when mice with intact FGFR1 were treated with FGFR inhibitor AZD4547. To understand the mechanistic basis of this protection, we harvested macrophages from mice and show that FGFR1 is required for macrophage inflammatory responses and uptake of oxidized LDL. RNA sequencing showed that FGFR1 activity is mediated through phospholipase-C-gamma (PLCγ) and the activation of nuclear factor-κB (NF-κB) but is independent of FGFR substrate 2.
CONCLUSIONS: Our study provides evidence of a new FGFR1-PLCγ- NF-κB axis in macrophages in inflammatory atherosclerosis, supporting FGFR1 as a potentially therapeutic target for atherosclerosis-related diseases.
RESULTS: Examination of human atherosclerotic lesions and aortas of Apoe-/- mice fed a high-fat diet (HFD) showed increased levels of FGFR1 in macrophages. We deleted myeloid-expressed Fgfr1 in Apoe-/- mice and showed that Fgfr1 deficiency reduces atherosclerotic lesions and lipid accumulations in both male and female mice upon HFD feeding. These protective effects of myeloid Fgfr1 deficiency were also observed when mice with intact FGFR1 were treated with FGFR inhibitor AZD4547. To understand the mechanistic basis of this protection, we harvested macrophages from mice and show that FGFR1 is required for macrophage inflammatory responses and uptake of oxidized LDL. RNA sequencing showed that FGFR1 activity is mediated through phospholipase-C-gamma (PLCγ) and the activation of nuclear factor-κB (NF-κB) but is independent of FGFR substrate 2.
CONCLUSIONS: Our study provides evidence of a new FGFR1-PLCγ- NF-κB axis in macrophages in inflammatory atherosclerosis, supporting FGFR1 as a potentially therapeutic target for atherosclerosis-related diseases.
摘要：
背景：动脉粥样硬化是心血管发病率和死亡率的主要原因。动脉粥样硬化病变显示与成纤维细胞生长因子受体（FGFR）途径相关的蛋白质水平升高。然而,FGFR信号在动脉粥样硬化中的功能意义和作用机制尚不清楚.在本研究中,我们研究了FGFR1信号在动脉粥样硬化发生和进展中的作用.
结果：高脂饮食（HFD）喂养的Apoe-/-小鼠的人动脉粥样硬化病变和主动脉检查显示巨噬细胞中FGFR1水平升高。我们删除了Apoe-/-小鼠中髓样表达的Fgfr1，并显示Fgfr1缺乏可减少HFD喂养后雄性和雌性小鼠的动脉粥样硬化病变和脂质积累。当用FGFR抑制剂AZD4547处理具有完整FGFR1的小鼠时,也观察到髓样Fgfr1缺陷的这些保护作用。为了理解这种保护的机制基础，我们从小鼠中收集巨噬细胞，并显示FGFR1是巨噬细胞炎症反应和氧化LDL摄取所必需的。RNA测序表明，FGFR1活性是通过磷脂酶-C-γ（PLCγ）和核因子-κB（NF-κB）的激活介导的，但与FGFR底物2无关。
结论：我们的研究提供了一个新的FGFR1-PLCγ-NF-κB轴在炎性动脉粥样硬化的巨噬细胞，支持FGFR1作为动脉粥样硬化相关疾病的潜在治疗靶点。
结果：高脂饮食（HFD）喂养的Apoe-/-小鼠的人动脉粥样硬化病变和主动脉检查显示巨噬细胞中FGFR1水平升高。我们删除了Apoe-/-小鼠中髓样表达的Fgfr1，并显示Fgfr1缺乏可减少HFD喂养后雄性和雌性小鼠的动脉粥样硬化病变和脂质积累。当用FGFR抑制剂AZD4547处理具有完整FGFR1的小鼠时,也观察到髓样Fgfr1缺陷的这些保护作用。为了理解这种保护的机制基础，我们从小鼠中收集巨噬细胞，并显示FGFR1是巨噬细胞炎症反应和氧化LDL摄取所必需的。RNA测序表明，FGFR1活性是通过磷脂酶-C-γ（PLCγ）和核因子-κB（NF-κB）的激活介导的，但与FGFR底物2无关。
结论：我们的研究提供了一个新的FGFR1-PLCγ-NF-κB轴在炎性动脉粥样硬化的巨噬细胞，支持FGFR1作为动脉粥样硬化相关疾病的潜在治疗靶点。
