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Krüppel-Like Factor 15 Modulates CXCL1/CXCR2 Signaling-Mediated Inflammatory Response Contributing to Angiotensin II-Induced Cardiac Remodeling

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 h...

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Autores principales: He, Shun, Lu, Yuanyuan, Guo, Yuetong, Li, Shijin, Lu, Xiao, Shao, Shuai, Zhou, Handan, Wang, Ruiqi, Wang, Jiguang, Gao, Pingjin, Li, Xiaodong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047332/
https://www.ncbi.nlm.nih.gov/pubmed/33869197
http://dx.doi.org/10.3389/fcell.2021.644954
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author He, Shun
Lu, Yuanyuan
Guo, Yuetong
Li, Shijin
Lu, Xiao
Shao, Shuai
Zhou, Handan
Wang, Ruiqi
Wang, Jiguang
Gao, Pingjin
Li, Xiaodong
author_facet He, Shun
Lu, Yuanyuan
Guo, Yuetong
Li, Shijin
Lu, Xiao
Shao, Shuai
Zhou, Handan
Wang, Ruiqi
Wang, Jiguang
Gao, Pingjin
Li, Xiaodong
author_sort He, Shun
collection PubMed
description 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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spelling pubmed-80473322021-04-16 Krüppel-Like Factor 15 Modulates CXCL1/CXCR2 Signaling-Mediated Inflammatory Response Contributing to Angiotensin II-Induced Cardiac Remodeling He, Shun Lu, Yuanyuan Guo, Yuetong Li, Shijin Lu, Xiao Shao, Shuai Zhou, Handan Wang, Ruiqi Wang, Jiguang Gao, Pingjin Li, Xiaodong Front Cell Dev Biol Cell and Developmental Biology 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. Frontiers Media S.A. 2021-04-01 /pmc/articles/PMC8047332/ /pubmed/33869197 http://dx.doi.org/10.3389/fcell.2021.644954 Text en Copyright © 2021 He, Lu, Guo, Li, Lu, Shao, Zhou, Wang, Wang, Gao and Li. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
He, Shun
Lu, Yuanyuan
Guo, Yuetong
Li, Shijin
Lu, Xiao
Shao, Shuai
Zhou, Handan
Wang, Ruiqi
Wang, Jiguang
Gao, Pingjin
Li, Xiaodong
Krüppel-Like Factor 15 Modulates CXCL1/CXCR2 Signaling-Mediated Inflammatory Response Contributing to Angiotensin II-Induced Cardiac Remodeling
title Krüppel-Like Factor 15 Modulates CXCL1/CXCR2 Signaling-Mediated Inflammatory Response Contributing to Angiotensin II-Induced Cardiac Remodeling
title_full Krüppel-Like Factor 15 Modulates CXCL1/CXCR2 Signaling-Mediated Inflammatory Response Contributing to Angiotensin II-Induced Cardiac Remodeling
title_fullStr Krüppel-Like Factor 15 Modulates CXCL1/CXCR2 Signaling-Mediated Inflammatory Response Contributing to Angiotensin II-Induced Cardiac Remodeling
title_full_unstemmed Krüppel-Like Factor 15 Modulates CXCL1/CXCR2 Signaling-Mediated Inflammatory Response Contributing to Angiotensin II-Induced Cardiac Remodeling
title_short Krüppel-Like Factor 15 Modulates CXCL1/CXCR2 Signaling-Mediated Inflammatory Response Contributing to Angiotensin II-Induced Cardiac Remodeling
title_sort krüppel-like factor 15 modulates cxcl1/cxcr2 signaling-mediated inflammatory response contributing to angiotensin ii-induced cardiac remodeling
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047332/
https://www.ncbi.nlm.nih.gov/pubmed/33869197
http://dx.doi.org/10.3389/fcell.2021.644954
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