Ang II Enhances Atrial Fibroblast Autophagy and Promotes Atrial Remodeling Through the AT1-ERK-mTOR Signaling Pathway

Abstract Background: Atrial remodeling is a common pathological change in atrial fibrillation (AF), while the mechanism of atrial remodeling remains unclear. In the present study, we investigated the autophagy and collagen secretion in atrial fibroblasts in response to renin-angiotensin system (RAS) activation and elucidated the relationship between atrial fibroblast autophagy and atrial remodeling. Methods: Right atrial tissues was obtained from patients that underwent cardiac valve replacement after signed the informed consent form. In vivo, subcutaneous perfusion of angiotensin II (Ang II) was used to mimic activation of the RAS and induce atrial remodeling. Electrical remodeling and AF induction were assessed by electrophysiology and programmed stimulation. In vitro, atrial fibroblasts were isolated and cultured. Autophagic flux changes were assessed by mCherry‑GFP‑LC3 adenovirus transfection. All samples were collected, collagen expression, autophagy changes and atrial remodeling were evaluated by western blot, masson’s trichrome staining, immunohistochemistry and immunofluorescence mainly.Results: Atrial tissue samples from patients with atrial fibrillation showed more collagen deposition and enhanced autophagy than those with sinus rhythm. Chronic subcutaneous Ang II perfusion in mice promoted atrial remodeling and susceptible to AF induction. In cultured atrial fibroblasts, the expression of collagen I (COL-I) and collagen III (COL-III) and autophagy both increased when cells were treated with Ang II, and the autophagic flux was enhanced by Ang II. However, blocking autophagy reduced the expression of COL-I and COL-III. Besides, Ang II induced the phosphorylation of ERK and suppressed the phosphorylation of mTOR. In contrast, inhibition of the angiotensin II type 1 receptor (AT1) or ERK signaling pathway not only suppressed the autophagy induced by Ang II but also reduced COL-I and COL-III expression. Conclusions: In summary, these results suggest that Ang II promotes autophagy in atrial fibroblasts, which aggravates atrial remodeling and increases the susceptibility to AF induction. Autophagy may be a potential target for relieving atrial remodeling and AF after RAS activation.