IRX2 regulates angiotensin II-induced cardiac fibrosis by transcriptionally activating EGR1 in male mice.
Zhen-Guo MaYu-Pei YuanDi FanXin ZhangTeng TengPeng SongChun-Yan KongCan HuWen-Ying WeiQi-Zhu TangPublished in: Nature communications (2023)
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.
Keyphrases
- angiotensin ii
- angiotensin converting enzyme
- left ventricular
- vascular smooth muscle cells
- transcription factor
- systemic sclerosis
- idiopathic pulmonary fibrosis
- cystic fibrosis
- poor prognosis
- heart failure
- high glucose
- mouse model
- magnetic resonance imaging
- machine learning
- deep learning
- binding protein
- oxidative stress
- computed tomography
- long non coding rna
- drug induced
- endothelial cells
- ejection fraction
- atrial fibrillation
- neural network
- dna binding