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

Zhen-Guo Ma, Yu-Pei Yuan, Di Fan, Xin Zhang, Teng Teng, Peng Song, Chun-Yan Kong, Can Hu, Wen-Ying Wei and Qi-Zhu Tang ()
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Zhen-Guo Ma: Renmin Hospital of Wuhan University
Yu-Pei Yuan: Renmin Hospital of Wuhan University
Di Fan: Renmin Hospital of Wuhan University
Xin Zhang: Renmin Hospital of Wuhan University
Teng Teng: Renmin Hospital of Wuhan University
Peng Song: Renmin Hospital of Wuhan University
Chun-Yan Kong: Renmin Hospital of Wuhan University
Can Hu: Renmin Hospital of Wuhan University
Wen-Ying Wei: Renmin Hospital of Wuhan University
Qi-Zhu Tang: Renmin Hospital of Wuhan University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40639-6

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