IRX2 regulates angiotensin II-induced cardiac fibrosis by transcriptionally activating Egr1 in mice [ChIP-Seq]

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 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 the evidence that IRX2 regulates the EGR1 pathway upon Ang II stimulation and drives cardiac fibrosis. Overall design: Human CFs were infected with an adenovirus carrying IRX2 for 4 h and then subjected to Ang II stimulation for 24 h. ChIP-Seq was performed with an anti-IRX2 antibody (#PCRP-IRX2-1B7, Developmental Studies Hybridoma Bank, Houston, USA; or #PCRP-IRX2-1C1, Developmental Studies Hybridoma Bank).