IRX2 regulates angiotensin II-induced cardiac fibrosis by transcriptionally activating EGR1 in male mice

Cardiac fibrosis is a common feature of chronic heart failure. Iroquois homeobox (IRX) family of transcription factors plays important roles in heart development; however, the role of IRX2 in cardiac fibrosis has not been clarified. Here we report that IRX2 expression is significantly upregulated in...

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Published in:Nature communications 2023-08, Vol.14 (1), p.4967-4967, Article 4967
Main Authors: Ma, Zhen-Guo, Yuan, Yu-Pei, Fan, Di, Zhang, Xin, Teng, Teng, Song, Peng, Kong, Chun-Yan, Hu, Can, Wei, Wen-Ying, Tang, Qi-Zhu
Format: Article
Language:English
Subjects:
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Angiotensin
Angiotensin II
Animal models
Congestive heart failure
EGR-1 protein
Fibrosis
Heart failure
Homeobox
Humanities and Social Sciences
Iroquois protein
Males
multidisciplinary
Native North Americans
Science
Science (multidisciplinary)
Stimulation
Transcription factors
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Summary:Cardiac fibrosis is a common feature of chronic heart failure. Iroquois homeobox (IRX) family of transcription factors plays important roles in heart development; however, the role of IRX2 in cardiac fibrosis has not been clarified. Here we report that IRX2 expression is significantly upregulated in the fibrotic hearts. Increased IRX2 expression is mainly derived from cardiac fibroblast (CF) during the angiotensin II (Ang II)-induced fibrotic response. Using two CF-specific Irx2 -knockout mouse models, we show that deletion of Irx2 in CFs protect against pathological fibrotic remodelling and improve cardiac function in male mice. In contrast, Irx2 gain of function in CFs exaggerate fibrotic remodelling. Mechanistically, we find that IRX2 directly binds to the promoter of the early growth response factor 1 (EGR1) and subsequently initiates the transcription of several fibrosis-related genes. Our study provides evidence that IRX2 regulates the EGR1 pathway upon Ang II stimulation and drives cardiac fibrosis. Cardiac fibrosis is a common feature of chronic heart failure, and the mechanisms of cardiac fibrosis are unclear. Here, the authors show that iroquois homeobox 2 (IRX2) regulates the early growth response factor 1 (EGR1) pathway upon fibrotic stimulation and drives cardiac fibrosis.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-40639-6