Naringin activates semaphorin 3A to ameliorate TGF‐β‐induced endothelial‐to‐mesenchymal transition related to atrial fibrillation

• Published in: Journal of cellular physiology 2024-05, Vol.239 (5), p.e31248-n/a
• Main Authors: Lai, Ying‐Ju, Chang, Shang‐Hung, Tung, Ying‐Chang, Chang, Gwo‐Jyh, Almeida, Celina De, Chen, Wei‐Jan, Yeh, Yung‐Hsin, Tsai, Feng‐Chun
• Format: Article
• Language: English
• Subjects: Animals; Atria; atrial endocardial endothelial cells; Atrial Fibrillation - drug therapy; Atrial Fibrillation - genetics; Atrial Fibrillation - metabolism; Atrial Fibrillation - pathology; atrial fibrosis; Cardiac arrhythmia; Cell Proliferation - drug effects; Cells, Cultured; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; endothelial‐to‐mesenchymal transition; Epithelial-Mesenchymal Transition - drug effects; Fibrillation; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Fibrosis; Flavanones - pharmacology; Growth factors; Heart Atria - drug effects; Heart Atria - metabolism; Heart Atria - pathology; Humans; Immunohistochemistry; Male; Mice; Mice, Transgenic; naringin; Pathogenesis; Proliferating cell nuclear antigen; semaphorin 3A; Semaphorin-3A - genetics; Semaphorin-3A - metabolism; Semaphorins; siRNA; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Transgenic animals; Transgenic mice
• ISSN: 0021-9541; 1097-4652; 1097-4652
• DOI: 10.1002/jcp.31248

The loss of semaphorin 3A (Sema3A), which is related to endothelial‐to‐mesenchymal transition (EndMT) in atrial fibrosis, is implicated in the pathogenesis of atrial fibrillation (AF). To explore the mechanisms by which EndMT affects atrial fibrosis and assess the potential of a Sema3A activator (naringin) to prevent atrial fibrosis by targeting transforming growth factor‐beta (TGF‐β)‐induced EndMT, we used human atria, isolated human atrial endocardial endothelial cells (AEECs), and used transgenic mice expressing TGF‐β specifically in cardiac tissues (TGF‐β transgenic mice). We evaluated an EndMT marker (Twist), a proliferation marker (proliferating cell nuclear antigen; PCNA), and an endothelial cell (EC) marker (CD31) through triple immunohistochemistry and confirmed that both EndMT and EC proliferation contribute to atrial endocardial fibrosis during AF in TGF‐β transgenic mice and AF patient tissue sections. Additionally, we investigated the impact of naringin on EndMT and EC proliferation in AEECs and atrial fibroblasts. Naringin exhibited an antiproliferative effect, to which AEECs were more responsive. Subsequently, we downregulated Sema3A in AEECs using small interfering RNA to clarify a correlation between the reduction in Sema3A and the elevation of EndMT markers. Naringin treatment induced the expression of Sema3A and a concurrent decrease in EndMT markers. Furthermore, naringin administration ameliorated AF and endocardial fibrosis in TGF‐β transgenic mice by stimulating Sema3A expression, inhibiting EndMT markers, reducing atrial fibrosis, and lowering AF vulnerability. This suggests therapeutic potential for naringin in AF treatment.