Ginsenoside Rb1 mitigates atherosclerosis in part through modulating FTO-mediated m⁶A RNA modification in...

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Epigenetics

Background:

• Ginsenoside Rb1 (Rb1) shows potential in attenuating atherosclerosis.
• The role of neutrophil extracellular traps (NETs) in endothelial activation and atherosclerosis is increasingly recognized.
• The involvement of N6-methyladenosine (m6A) RNA modification in Rb1's anti-atherosclerotic effects remains unclear.

Purpose of the Study:

• To investigate whether Rb1 suppresses NETs-induced endothelial activation.
• To determine if m6A RNA modification is mechanistically involved in Rb1's anti-atherosclerotic effects.

Main Methods:

• High-fat diet-fed Apoe-/- mice and human aortic endothelial cells (HAECs) were used for in vivo and in vitro studies.
• Histological, immunohistological, and molecular analyses were performed.
• NETs-induced endothelial activation, m6A RNA methylation, and FTO expression were assessed.

Main Results:

• Rb1 mitigated atherosclerotic lesions and endothelial activation in vivo.
• Rb1 reduced neutrophil and monocyte adhesion to NETs-stimulated HAECs, counteracted NETs-induced upregulation of adhesion molecules (ICAM1, VCAM1, SELE, SELEP), and protected endothelial barrier function in vitro.
• NETs exposure decreased m6A RNA methylation and increased FTO expression in HAECs; Rb1 treatment reversed these effects.
• FTO overexpression abrogated Rb1's protective effects in vitro and partially abolished Rb1's benefits in vivo.

Conclusions:

• Rb1 mitigates atherosclerosis by suppressing NETs-induced endothelial activation.
• Rb1's anti-atherosclerotic effects are partly mediated by modulating FTO-dependent m6A RNA demethylation in endothelial cells.