Aims Chemokine-mediated monocyte infiltration into the damaged heart represents an initial step in inflammation during cardiac remodelling. Our recent study demonstrates a central role for chemokine receptor CXCR2 in monocyte recruitment and hypertension; however, the role of chemokine CXCL1 and its receptor CXCR2 in angiotensin II (Ang II)-induced cardiac remodelling remain unknown. Methods and results Angiotensin II (1000 ng kg-1 min-1) was administrated to wild-type (WT) mice treated with CXCL1 neutralizing antibody or CXCR2 inhibitor SB265610, knockout (CXCR2 KO) or bone marrow (BM) reconstituted chimeric mice for 14 days. Microarray revealed that CXCL1 was the most highly upregulated chemokine in the WT heart at Day 1 after Ang II infusion. The CXCR2 expression and the CXCR2+ immune cells were time-dependently increased in Ang II-infused hearts. Moreover, administration of CXCL1 neutralizing antibody markedly prevented Ang II-induced hypertension, cardiac dysfunction, hypertrophy, fibrosis, and macrophage accumulation compared with Immunoglobulin G (IgG) control. Furthermore, Ang II-induced cardiac remodelling and inflammatory response were also significantly attenuated in CXCR2 KO mice and in WT mice treated with SB265610 or transplanted with CXCR2-deficienct BM cells. Co-culture experiments in vitro further confirmed that CXCR2 deficiency inhibited macrophage migration and activation, and attenuated Ang II-induced cardiomyocyte hypertrophy and fibroblast differentiation through multiple signalling pathways. Notably, circulating CXCL1 level and CXCR2+ monocytes were higher in patients with heart failure compared with normotensive individuals. Conclusions Angiotensin II-induced infiltration of monocytes in the heart is largely mediated by CXCL1-CXCR2 signalling which initiates and aggravates cardiac remodelling. Inhibition of CXCL1 and/or CXCR2 may represent new therapeutic targets for treating hypertensive heart diseases.

中文翻译：

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CXCL1-CXCR2轴通过调节单核细胞浸润介导血管紧张素II诱导的心脏肥大和重塑

目的趋化因子介导的单核细胞浸润到受损心脏代表了心脏重塑过程中炎症的初始步骤。我们最近的研究证明了趋化因子受体 CXCR2 在单核细胞募集和高血压中的核心作用；然而，趋化因子 CXCL1 及其受体 CXCR2 在血管紧张素 II (Ang II) 诱导的心脏重塑中的作用仍然未知。方法和结果 血管紧张素 II (1000 ng kg-1 min-1) 被施用给用 CXCL1 中和抗体或 CXCR2 抑制剂 SB265610、敲除 (CXCR2 KO) 或骨髓 (BM) 重建的嵌合小鼠治疗的野生型 (WT) 小鼠14 天。微阵列显示CXCL1 是血管紧张素II 输注后第1 天WT 心脏中最高度上调的趋化因子。CXCR2 表达和 CXCR2+ 免疫细胞在 Ang II 输注的心脏中随时间增加。此外，与免疫球蛋白 G (IgG) 对照相比，CXCL1 中和抗体的施用显着防止了血管紧张素 II 诱导的高血压、心脏功能障碍、肥大、纤维化和巨噬细胞积聚。此外，在 CXCR2 KO 小鼠和用 SB265610 治疗或移植了 CXCR2 缺陷型 BM 细胞的 WT 小鼠中，Ang II 诱导的心脏重塑和炎症反应也显着减弱。体外共培养实验进一步证实，CXCR2 缺乏抑制巨噬细胞迁移和活化，并通过多种信号通路减弱 Ang II 诱导的心肌细胞肥大和成纤维细胞分化。尤其，与血压正常的个体相比，心力衰竭患者的循环 CXCL1 水平和 CXCR2+ 单核细胞更高。结论 血管紧张素 II 诱导的心脏单核细胞浸润主要由 CXCL1-CXCR2 信号传导介导，该信号启动和加重心脏重构。抑制 CXCL1 和/或 CXCR2 可能代表治疗高血压心脏病的新治疗靶点。