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Abnormal levels of the transcription factor PU.1, a key regulator of fibrosis, are associated with cardiac injury and dysfunction following acute viral myocarditis. However, the role of PU.1 in atrial fibrosis and vulnerability to AF remain unclear. Here, an in vivo atrial fibrosis model was developed by the continuous infusion of C57 mice with subcutaneous Ang\u2010II, while the in vitro model comprised atrial fibroblasts that were isolated and cultured. The expression of PU.1 was significantly up\u2010regulated in the Ang\u2010II\u2010induced group compared with the sham\/control group in vivo and in vitro. Moreover, protein expression along the TGF\u2010\u03b21\/Smads pathway and the proliferation and differentiation of atrial fibroblasts induced by Ang\u2010II were significantly higher in the Ang\u2010II\u2010induced group than in the sham\/control group. These effects were attenuated by exposure to DB1976, a PU.1 inhibitor, both in vivo and in vitro. Importantly, in vitro treatment with small interfering RNA against Smad3 (key protein of TGF\u2010\u03b21\/Smads signalling pathway) diminished these Ang\u2010II\u2010mediated effects, and the si\u2010Smad3\u2010mediated effects were, in turn, antagonized by the addition of a PU.1\u2010overexpression adenoviral vector. Finally, PU.1 inhibition reduced the atrial fibrosis induced by Ang\u2010II and attenuated vulnerability to AF, at least in part through the TGF\u2010\u03b21\/Smads pathway. Overall, the study implicates PU.1 as a potential therapeutic target to inhibit Ang\u2010II\u2010induced atrial fibrosis and vulnerability to AF.<\/jats:p>","DOI":"10.1111\/jcmm.16678","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T01:08:09Z","timestamp":1623805689000},"page":"6746-6759","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["PU.1 inhibition attenuates atrial fibrosis and atrial fibrillation vulnerability induced by angiotensin\u2010II by reducing TGF\u2010\u03b21\/Smads pathway activation"],"prefix":"10.1111","volume":"25","author":[{"given":"Juan","family":"Hu","sequence":"first","affiliation":[{"name":"Heart Center of Henan Provincial People\u2019s Hospital Central China Fuwai Hospital Central China Fuwai Hospital of Zhengzhou University Zhengzhou 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