MFGE8 attenuates Ang-II-induced atrial fibrosis and vulnerability to atrial fibrillation through inhibition of TGF-β1/Smad2/3 pathway

• Published in: Journal of molecular and cellular cardiology 2020-02, Vol.139, p.164-175
• Main Authors: Ge, Zhuowang, Chen, Youming, Wang, Bo, Zhang, Xuan, Yan, Yexiang, Zhou, Lei, Zhang, Yachen, Xie, Yuquan
• Format: Article
• Language: English
• Subjects: Angiotensin II; Animals; Antigens, Surface - genetics; Antigens, Surface - metabolism; Atrial fibrillation; Atrial Fibrillation - genetics; Atrial Fibrillation - metabolism; Atrial Fibrillation - pathology; Atrial fibrosis; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Fibroblasts - metabolism; Fibroblasts - pathology; Fibrosis; Gene Expression Regulation - drug effects; Heart Atria - pathology; Humans; Integrin beta3 - metabolism; Male; MFGE8; Milk Proteins - genetics; Milk Proteins - metabolism; Models, Biological; Protein Binding - drug effects; Rats, Sprague-Dawley; Recombinant Proteins - pharmacology; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; Signal Transduction - drug effects; Smad Proteins - metabolism; Transforming Growth Factor beta1 - metabolism
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2020.01.001

Atrial fibrillation (AF) is characterized by potentiated growth of atrial fibroblasts and excessive deposition of the extracellular matrix. Atrial fibrosis has emerged as a hallmark of atrial structural remodeling linked to AF. Nonetheless, the specific mechanism underlying the progression of atrial fibrosis to AF is still largely unknown. MFGE8 (milk fat globule-EGF factor 8) is a soluble glycoprotein associated with many human diseases. Recently, a number of studies revealed that MFGE8 plays a crucial role in heart disease. Yet, MFGE8 regulation and function in the process of atrial fibrosis and vulnerability to AF remain unexplored. In this study, we found that the expression of MFGE8 was downregulated in the atriums of patients with AF compared with individuals without AF. In addition, the expression of MFGE8 was lower in atriums of angiotensin II (Ang-II)-stimulated rats as compared with the sham group. In vitro, silencing of MFGE8 by small interfering RNA significantly increased Ang-II-induced atrial fibrosis, whereas administration of recombinant human MFGE8 (rhMFGE8) attenuated the atrial fibrosis. Moreover, we found that the activated TGF-β1/Smad2/3 pathway after Ang-II treatment was significantly potentiated by the MFGE8 knockdown but inhibited by rhMFGE8 in vitro. Inhibition of integrin β3 which is the receptor for MFGE8, suppressed the TGF-β1/Smad2/3 activating effects of the MFGE8 knockdown in Ang-II-treated rat atrial fibroblasts. Finally, we administered rhMFGE8 to rats; it attenuated atrial fibrosis and remodeling and further reduced AF vulnerability induced by Ang-II, indicating that MFGE8 might have the potential both as a novel biomarker and as a therapeutic target in atrial fibrosis and AF. •For the first time, we demonstrated that Milk fat globule-EGF factor8 (MFGE8) is protective against Ang-II-induced atrial fibrosis and atrial fibrillation.•MFGE8 exerts its protective function by inhibiting the TGF-β1/Smad2/3 pathway by binding to integrin β3.•Rh-MFGE8 Protects against Ang-II induced atrial fibrosis and atrial fibrillation in rats.