Krüppel-Like Factor 15 Modulates CXCL1/CXCR2 Signaling-Mediated Inflammatory Response Contributing to Angiotensin II-Induced Cardiac Remodeling.
Krüppel-Like Factor 15 Modulates CXCL1/CXCR2 Signaling-Mediated Inflammatory Response Contributing to Angiotensin II-Induced Cardiac Remodeling.
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Krüppel 样因子 15 调节 CXCL1/CXCR2 信号介导的炎症反应，有助于血管紧张素 II 诱导的心脏重塑
DOI：
10.3389/fcell.2021.644954
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发表时间：
2021
影响因子：
5.5
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
He S;Lu Y;Guo Y;Li S;Lu X;Shao S;Zhou H;Wang R;Wang J;Gao P;Li X
炎症参与心脏重塑。在响应病理刺激时，活化的心脏成纤维细胞（CF）分泌炎性细胞因子和趋化因子在单核细胞/巨噬细胞募集中起重要作用。然而，CF介导的炎症反应在高血压诱导的心脏重构中的确切机制仍不清楚。在本研究中，我们研究了转录因子Krüppel样因子15（KLF 15）在这一过程中的作用。我们发现，KLF 15的表达下降，而趋化因子CXCL 1及其受体CXCR 2的表达增加血管紧张素II（Ang II）注入小鼠的心脏。与野生型小鼠相比，KLF 15敲除（KO）小鼠加重了Ang II诱导的心脏肥大和纤维化。KLF 15缺乏可促进心肌巨噬细胞聚集、CXCL 1和CXCR 2表达增加以及mTOR、ERK 1/2、NF-κB-p65信号通路激活。从机制上讲，Ang II剂量依赖性地降低心脏成纤维细胞的KLF 15表达，增加CXCL 1分泌，但不影响心脏成肌细胞。功能丧失或获得的研究表明，KLF 15通过其反式激活结构域（transactivation domain，CXCL 1）负调控CXCL 1的表达。有趣的是，腺病毒介导的全长KLF 15-但不是KLF 15与cDNA 3缺失过表达-显着防止血管紧张素II输注小鼠的病理变化。值得注意的是，CXCR 2抑制剂SB 265610的施用逆转了KLF 15敲除介导的由Ang II诱导的心功能不全、重构和炎症的恶化。总之，我们的研究表明，心脏成纤维细胞中的KLF 15负性调节CXCL 1/CXCR 2轴介导的炎症反应和随后的高血压心脏重塑。
Inflammation is involved in cardiac remodeling. In response to pathological stimuli, activated cardiac fibroblasts (CFs) secreting inflammatory cytokines and chemokines play an important role in monocyte/macrophage recruitment. However, the precise mechanism of CF-mediated inflammatory response in hypertension-induced cardiac remodeling remains unclear. In the present study, we investigated the role of transcription factor Krüppel-like factor 15 (KLF15) in this process. We found that KLF15 expression decreased while chemokine CXCL1 and its receptor CXCR2 expression increased in the hearts of angiotensin II (Ang II)-infused mice. Compared to the wild-type mice, KLF15 knockout (KO) mice aggravated Ang II-induced cardiac hypertrophy and fibrosis. Deficiency of KLF15 promoted macrophage accumulation, increase of CXCL1 and CXCR2 expression, and mTOR, ERK1/2, NF-κB-p65 signaling activation in the hearts. Mechanistically, Ang II dose- dependently decreased KLF15 expression and increased CXCL1 secretion from cardiac fibroblasts but not cardiac myoblasts. Loss- or gain-of-function studies have shown that KLF15 negatively regulated CXCL1 expression through its transactivation domain (TAD). Intriguingly, the adenovirus-mediated full length of KLF15—but not KLF15 with TAD deletion overexpression—markedly prevented pathological change in Ang II-infused mice. Notably, the administration of CXCR2 inhibitor SB265610 reversed KLF15 knockout-mediated aggravation of cardiac dysfunction, remodeling, and inflammation induced by Ang II. In conclusion, our study identifies that KLF15 in cardiac fibroblasts negatively regulates CXCL1/CXCR2 axis-mediated inflammatory response and subsequent cardiac remodeling in hypertension.
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DOI：
10.1161/hypertensionaha.111.172700
发表时间：
2011-06
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Kurdi M;Booz GW
通讯作者：
Booz GW
影响因子：
37.8
作者：
Shirakawa, Kohsuke;Endo, Jin;Sano, Motoaki
通讯作者：
Sano, Motoaki
影响因子：
20.1
作者：
McMaster WG;Kirabo A;Madhur MS;Harrison DG
通讯作者：
Harrison DG
影响因子：
37.8
作者：
Burchfield JS;Xie M;Hill JA
通讯作者：
Hill JA
DOI：
10.1073/pnas.1017029108
发表时间：
2011-06-28
影响因子：
11.1
作者：
Mas, Caroline;Lussier-Price, Mathieu;Omichinski, James G.
通讯作者：
Omichinski, James G.